Exposure to Per- and Polyfluoroalkyl Substances and Risk of Reproductive System Cancers: A Systematic Review and Meta-Analysis

Exposure to Per- and Polyfluoroalkyl Substances and Risk of Reproductive System Cancers: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exposure to Per- and Polyfluoroalkyl Substances and Risk of Reproductive System Cancers: A Systematic Review and Meta-Analysis Xin Liu, Zhihong Lv, Zixiang Huang, Rui Sun, Dingyu Zhu, Pengcheng Xu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7521500/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Per- and polyfluoroalkyl substances (PFAS), a class of highly stable synthetic organic compounds, have been detected ubiquitously in human biological samples, raising significant concerns about their safety. The aim of this study was to investigate whether PFAS exposure is associated with higher risk of reproductive cancers. Methods Three databases were searched from inception to August 2025. Case-control or cohort studies that examined the association between serum/plasma exposure to five PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA] and perfluorinated sulfonic acids [PFSA]) and reproductive system cancers, including female reproductive system (breast and ovarian cancers) and male reproductive system (prostate and testicular cancers), were included. Results 21 case-control studies were included. Pooled adjusted odds ratios (aORs) showed no significant association between PFAS exposure and female reproductive cancers. When comparing highest to lowest exposure, pooled aORs were 1.09 (95% CI: 0.83–1.43) for PFOA, 1.11 (0.82–1.48) for PFOS, 0.96 (0.68–1.36) for PFHxS, 1.11 (0.79–1.56) for PFNA, and 1.14 (0.46–2.80) for PFSA. PFOS showed a marginal positive association with male reproductive cancers (1.25, 1.02–1.52), whereas PFOA showed no association (0.87, 0.65–1.17). Notably, PFNA per ln-unit increase was significantly associated with female reproductive cancers (1.39, 1.07–1.79) in sensitivity analyses. Conclusions Overall, serum PFAS exposure was not significantly associated with female reproductive cancers, though PFNA showed a positive association in sensitivity analysis. PFOS may be associated with increased risk for male reproductive cancers. Per- and polyfluoroalkyl substances PFAS PFOS Reproductive system cancers Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Per- and polyfluoroalkyl substances (PFAS) are a family of synthetic organic compounds that include more than 7 million types, and are characterized by highly stable chemical structures [ 1 , 2 ]. Since the 1950s, PFAS have been widely utilized as surfactants in numerous commercial and industrial applications owing to their exceptional water- and oil-repellent properties [ 3 ]. It has been demonstrated that these chemicals are bio-accumulative, possess long half-life, and degrade at a slow rate [ 4 – 6 ]. Previous studies showed that PFAS has been detected in human biological samples both from various geographical regions, including industrialized and urbanized areas, as well as non-urbanized regions [ 7 , 8 ]. The general population can be exposed to PFAS through multiple pathways, including contaminated drinking water or food (particularly fish) [ 9 , 10 ], indoor air, dust, and various consumer products (e.g., food packaging, and non-stick coatings) [ 11 ]. Among PFAS, traditional long-chain perfluoroalkyl acids, such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorinated sulfonic acids [PFSA] (also refers to a mixture of PFOS and PFHxS), are the most prevalent in both the environment and the human body [ 12 ]. Data from the National Health and Nutrition Examination Survey (NHANES) indicate that PFAS are detectable in nearly all studied population groups, categorized by age (12–19 years, 20–39 years, 40–59 years, and ≥ 60 years), sex (male and female), and race (Mexican American, non-Hispanic Black, and non-Hispanic White) [ 11 ]. Recent epidemiological studies have demonstrated that PFAS exposure is associated with a range of adverse health outcomes, including disruptions in the immune, endocrine, cardiovascular-metabolic, and reproductive systems, as well as an increased risk of cancer [ 10 , 13 , 14 ]. The potential association between PFAS exposure and cancer has garnered significant attention [ 15 ]. Several meta-analyses have evaluated the relationship between PFAS exposure and overall or specific type cancer (e.g., thyroid cancer, breast cancer), though their conclusions remain inconsistent [ 16 – 19 ]. For example, a previous meta-analysis found that PFOS exposure significantly increased total cancer risk (odds ratios [ORs] = 1.12, 95% CI 1.00-1.25) [ 19 ]. Similarly, Jiang et al. included eight studies involving 13,603 participants and observed a positive association between PFOA and PFHxS exposure and breast cancer risk, with pooled ORs of 1.32 (95% CI 1.19–1.46) and 1.79 (95% CI 1.51–2.11), respectively [ 17 ]. In contrast, another meta-analysis including 11 studies with 3,233 participants found no significant association, with RRs ( Relative Risks) of 0.95 (95% CI: 0.77–1.18) for PFOA and 0.98 (95% CI: 0.87–1.11) for PFOS [ 16 ]. To date, evidence on the relationship between PFAS exposure and reproductive system cancers remains limited and inconsistent, exemplified by the ongoing debate regarding PFAS and breast cancer risk. To address these discrepancies, we expanded the scope of investigation beyond breast cancer to include ovarian cancer, aiming to provide a more comprehensive evaluation of female reproductive system cancers. While prior studies have examined breast and ovarian cancers separately, no meta-analysis has synthesized evidence for both cancers collectively, despite their shared hormonal and reproductive mechanisms. Therefore, we conducted this systematic review and meta-analysis to investigate whether PFAS exposure is associated with an increased risk of reproductive system cancers, including cancers of the female reproductive system (breast and ovarian cancers) and male reproductive system (prostate and testicular cancers). Building on previous reviews, this analysis enhances the current evidence by incorporating additional recent studies and focusing on PFAS measured directly in plasma or serum, thereby improving exposure assessment accuracy and reinforcing the reliability of the findings. 2. Materials and methods This study was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [ 20 ], with review protocol registered in PROSPERO (CRD42024628466). 2.1. Inclusion and exclusion criteria Studies meeting the following criteria were included in this meta-analysis: (1) case-control or cohort study that analyzed the association between PFAS concentrations in human serum or plasma and reproductive system cancers; (2) the study reported the association between PFAS exposure and reproductive system cancers, such as OR, RR, or hazard ratio (HR), or provided raw data that enabled the calculation of these measures. Exclusion criteria for the literature were as follows: (1) studies focusing on animal or cell experiments; (2) studies that lacked data to calculate the association between PFAS exposure and cancer; (3) letters, reviews, editorials, case reports, and abstracts. 2.2. Search strategy A search was performed in the PubMed, Embase, and Web of Science databases for studies published before November 16, 2024, with an update as of August 10, 2025. The following search terms were used to identify relevant articles: “perfluorinated”, “perfluorinated”, “perfluorooctane”, “perfluorooctane”, “PFOS”, “PFOA”, “PFHxS”, “neoplasms”, “tumor”, “neoplasm”, “tumors”, “neoplasia”, “neoplasias”, “cancer”, “cancers”, “malignancy”, “malignancies” and “malignant neoplasm”. The search strategy for each database is shown in the Supplementary Table 1. 2.3. Definition of exposure and outcome This study investigates PFAS exposure levels in serum or plasma, specifically focusing on PFOA, PFOS, PFHxS, PFNA and PFSA. PFAS concentrations were quantified using solid-phase extraction combined with liquid chromatography and isotope dilution tandem mass spectrometry [ 21 ]. The study examines outcomes related to reproductive system cancers, including breast cancer (ICD-10 code: C50), ovarian cancer (C56), prostate cancer (C61) and testicular cancer (C62) [ 22 ]. 2.4. Data extraction For each eligible study, the following information was extracted: first author, publication year, study location, study design, characteristics of the study population, sample size, study duration, biological samples, methods of exposure measurement, PFAS concentrations by group, estimate value of associations, timing of blood sample collection, adjusted ORs, and adjusted confounders. For studies utilizing multiple adjusted models, data from the fully adjusted model were extracted. Two researchers (Liu and Lv) independently extracted the data, and discrepancies were resolved through discussion. 2.5. Quality assessment The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) [ 23 ]. This scale evaluates three categories: selection of study groups, control of confounding factors, and determination of exposure. The study encompasses eight different items, with a total score of 9 points. A higher total score reflects better study quality. NOS scores of 1–3 points are classified as high-risk, 4–6 points as moderate-risk, and 7–9 points as low-risk. Each included study was independently assessed for quality by two authors (Liu and Lv) and discrepancies were resolved through discussion. 2. 6. Statistical analysis In this study, separate meta-analyses were conducted for female reproductive system (breast and ovarian cancer) and male reproductive system (prostate and testicular cancers). Given the low incidence of reproductive system cancers, RRs, ORs, and HRs were treated as equivalent. Adjusted ORs (aORs) were used as the effect estimates. In the pooled analysis, the Q test and I² statistic were used to assess heterogeneity [ 24 ]. A fixed-effects model (Mantel-Haenszel method) was applied when I² ≤ 50%, while a random-effects model (DerSimonian-Laird method) was used when I² >50% [ 25 ]. For each outcome, two pooled aORs were calculated: one based on the comparison between the highest and lowest PFAS concentration categories (e.g., percentiles), and the other one based on the change in each natural log (ln) unit of continuous PFAS concentrations (ng/mL). For studies reporting ORs of per- \(\:\:{\text{l}\text{o}\text{g}}_{x}\) -unit increase in PFAS concentrations, we transformed the ORs to per-ln-unit increase by applying the following formula: \(\:O{R}_{\text{per}\:\text{ln}\:\text{unit}\:\text{increase}}={e}^{{\text{log}}_{x}\left(O{R}_{\text{per}\:{\text{log}}_{x}\:\text{unit}\:\text{increase}}\right)}\:\:\) [16] . We performed several subgroup analyses. For female reproductive system cancers, subgroups were stratified by the timing of blood sample collection (prediagnostic vs. postdiagnostic) and menopausal status (premenopausal vs. postmenopausal). Age (using 50 years as the cutoff) was used as an indicator to distinguish between premenopausal and postmenopausal status in the context of female reproductive system cancers [ 16 , 26 , 27 ]. For prostate cancer, subgroup analyses were stratified by Gleason score (low-grade vs. high-grade) and tumor stage (non-advanced vs. advanced). Based on the Gleason scoring system, low-grade was defined as a score ≤ 7, and high-grade as a score ≥ 8. The American Joint Committee on Cancer (AJCC) staging system was employed to categorize tumors as non-advanced stage (AJCC stages 1–2) and advanced stage (AJCC stages 3–4) [ 28 ]. A meta-regression analysis was conducted for female reproductive system cancers using publication year (before 2020 vs. 2020 or later), geographic region (Western or Asian countries), sample size (< 500 or ≥ 500), study design (case–control, nested case–control, or case–cohort), timing of blood sample collection (prediagnostic or postdiagnostic), and NOS score (< 7 or ≥ 7), with a subsequent analysis performed for individual chemicals (PFOA, PFOS, PFHxS, and PFNA). To assess the robustness of the findings, three sensitivity analyses were conducted: (1) excluding studies with a NOS score below 7; (2) excluding studies that collected blood samples after diagnosis; and (3) excluding individual studies one at a time to determine whether any particular study had a significant impact on the combined results. Egger's regression test was employed to assess publication bias [ 29 ]. In this study, the meta-analysis of female reproductive system cancers included five types of PFAS: PFOA, PFOS, PFHxS, PFNA and PFSA. However, due to the limited number of included studies, only PFOA and PFOS were included in the analysis of male reproductive system cancers. Additionally, because of the small number of studies on male reproductive system cancers, sensitivity and publication bias analyses were not performed. All statistical analyses were performed using STATA 15.1 (Stata Corp LP, College Station, TX). 3. Results 3.1. Study characteristics and quality assessment A total of 1,945 articles were identified through the systematic literature search. After applying the inclusion and exclusion criteria, 21 studies were included (Fig. 1 ). Among these, 17 focused on female reproductive cancers, and 4 focused on male reproductive cancers. All included studies were case-control studies (Table 1 ), consisting of 10 nested case-control studies [ 30 – 39 ], 6 traditional case-control studies [ 40 – 45 ], and 5 case-cohort studies [ 28 , 46 – 49 ]. These studies were conducted in seven countries: four Western nations (Denmark, the United States, France, and Brazil) and three Asian countries (Japan, China, and the Philippines). There were 21 studies focusing on PFOA and PFOS, 15 studies focusing on PFHxS and PFNA, and 5 studies focusing on PFSA. The NOS assigned 15 studies (71.43%) to the low risk of bias category, with 10 studies scoring 7 points and 5 studies scoring 8 points. The other six studies (28.57%) were classified as moderate risk, all achieving a score of 6 points (Supplementary Table 2). Table 1 Characteristics of all included studies in the meta-analysis. First author (Year) Region Study design Study period Cancer type No. of subjects Exposure assessment Exposure time Confounding Variables Adjusted Quality score Eriksen (2009) Denmark Case-cohort 1993–2006 Prostate Cases:713; Subcohort:772 Plasma (PFOA, PFOS) Before diagnosis school years, BMI, dietary fat intake, fruit and vegetable intake 6 Bonefeld-Jørgensen (2014) and Ghisari a (2017) Denmark Nested-case control 1996–2010 Breast Cases:250; Controls:233 Serum (PFOA, PFOS, PFHxS, PFNA, PFSA) Before diagnosis age at blood sampling, BMI before pregnancy, gravidity, OC use, menarche age, smoking during pregnancy, alcohol intake, maternal education, physical activity 8 Wielsøe (2017) Denmark Case-control 2000–2003; 2011–2014 Breast Cases:77; Controls:84 Serum (PFOA, PFOS, PFHxS, PFNA, PFSA) After diagnosis age, BMI, cotinine levels, parity, breastfeeding 6 Hurley (2018) The US Nested-case control 2006–2015 Breast Cases:902; Controls:858 Serum (PFOA, PFOS, PFHxS, PFNA) After diagnosis baseline age, race/ethnicity, residential region, blood draw date, blood draw date 2, season of blood draw, cumulative smoking pack-years, BMI, family history of breast cancer, age at first full-term birth, menopausal status at blood draw, pork consumption 7 Tsai (2020) China Case-control 2014–2016 Breast Cases:120; Controls:119 Plasma (PFOA, PFOS, PFHxS, PFNA) After diagnosis age, gravidity, OC use, miscarriage, BMI, menopause, education 7 Table 1 (continued) First author (Year) Region Study design Study period Cancer type No. of subjects Exposure assessment Exposure time Confounding Variables Adjusted Quality score Mancini (2019) France Nested-case control 1994–2013 Breast Cases:194; Controls:194 Serum (PFOA, PFOS) Before diagnosis total blood lipids, BMI, smoking status, physical activity, education, personal history of benign breast disease, family history of breast cancer, parity, age at first full-term pregnancy, breastfeeding duration, menarche age, menopause age, OC use, current MHT use, western diet score, mediterranean diet score 7 Itoh (2021) Japan Case-control 2001–2005 Breast Cases:401; Controls:401 Serum (PFOA, PFOS, PFHxS, PFNA, PFSA) After diagnosis age, residential area, BMI, height, age at first childbirth, family history of breast cancer, smoking status, strenuous physical activity, moderate physical activity, menarche age, number of births, breastfeeding duration, alcohol intake, isoflavone intake, education 7 Feng (2022) China Case-cohort 2008–2018 Breast Cases:226; Subcohort:990 Plasma (PFOA, PFOS, PFHxS, PFNA, PFSA) Before diagnosis age, BMI, smoking, drinking, marital status, education, occupation type, batch to enter the cohort, parity, menopausal status, history of mastitis, HRT use, family history of cancer 7 Table 1 (continued) First author (Year) Region Study design Study period Cancer type No. of subjects Exposure assessment Exposure time Confounding Variables Adjusted Quality score Li (2022) China Case-control 2012–2016 Breast Cases:373; Controls:657 Plasma (PFOA, PFOS, PFHxS, PFNA) After diagnosis baseline age, BMI, smoking history, menarche age, menopause age, parity, breastfeeding duration, use of estrogen or estrogen replacement therapy, family history of breast cancer, education, household per capita monthly income, red meat intake, pickled food intake, fried food intake, smoked and barbecued food intake 6 Velarde (2022) Philippines Case-control 2018 Breast Cases:75; Controls:75 Serum (PFOA, PFOS, PFHxS, PFNA) After diagnosis age, residential area, employment status, monthly income 6 Chang (2023) The US Nested-case control 1993–2013 Breast Cases:621; Controls:621 Serum (PFOA, PFOS) Before diagnosis age at blood draw, study center, race/ethnicity, education, menarche age, age at first live birth, number of live births, menopause age, duration of MHT use, first-degree family history of female breast cancer, personal history of benign breast disease, BMI, smoking status, strenuous physical activity 7 Table 1 (continued) First author (Year) Region Study design Study period Cancer type No. of subjects Exposure assessment Exposure time Confounding Variables Adjusted Quality score Winquist (2023) and Shahi b (2025) The US Case-cohort 1998–2015 Breast Cases:780; Subcohort:497 Serum (PFOA, PFOS, PFHxS, PFNA) Before diagnosis year of serum collection, age at serum collection, race, education, smoking status, drinking 6 Rhee (2023) The US Nested-case control 1993–2013 Prostate Cases:750; Controls:750 Serum (PFOA, PFOS) Before diagnosis BMI, smoking status, family history of prostate cancer, history of diabetes 7 Purdue (2023) The US Nested-case control 1988–2017 Testicular Cases:530; Controls:530 Serum (PFOA, PFOS) Before diagnosis military rank, number of deployments 7 Dou (2024) China Nested-case control 2014–2016 Breast Cases:120; Controls:119 Serum (PFOA, PFOS, PFHxS, PFNA) After diagnosis smoking history, alcohol history, duration of long-term estrogen use, baseline menopausal status, history of benign breast disease, number of deliveries, history of miscarriage, menstrual regularity, dysmenorrhea, age at first live birth, TG, TC, year of blood draw 7 Troeschel (2024) The US Case-cohort 1998–2015 Prostate Cases:1599; Controls:491 Serum (PFOA, PFOS) Before diagnosis age, year of blood draw, education, drinking, smoking, race 8 Xing (2025) China Nested-case control 2015–2023 Ovarian Cases:159; Controls:159 Plasma (PFOA, PFOS, PFHxS, PFNA, PFSA) After diagnosis education, parity, passive smoking status, physical activities, residual lesions, waist circumference 8 Table 1 (continued) First author (Year) Region Study design Study period Cancer type No. of subjects Exposure assessment Exposure time Confounding Variables Adjusted Quality score Itoh (2025) Brazil Case-control 2001–2006 Breast Cases:471; Controls:471 Plasma (PFOA, PFOS, PFHxS, PFNA) After diagnosis BMI, height, menopausal status and age, menarche age, age at first childbirth, smoking status, strenuous and moderate physical activity (past 5 years), family history of breast cancer, breastfeeding duration, number of births, alcohol intake, education, calendar year of blood sampling, isoflavone intake, fish/shellfish intake 7 Jones (2025) The US Nested-case control 1993–2016 Ovarian Cases:318; Controls:472 Serum (PFOA, PFOS, PFHxS, PFNA) Before diagnosis smoking status, BMI, family history of breast and/or ovarian cancer, MHT use, parity, OC use, number of freeze-thaw cycles 7 PFOA, perfluorooctanoate; PFOS, perfluorooctane sulfonate; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoate; PFSA, perfluorinated sulfonic acids; BMI, body mass index; OC, oral contraceptive; MHT, menopausal hormone therapy; HRT, hormone replacement therapy; TG, triglycerides; TC, total cholesterol. a The sample size in Ghisari et al. changed to case = 178, control = 233. b The sample size in Shahi et al. changed to case = 781, control = 498. 3.2. The association between PFAS and female reproductive system cancers According to the pooled analysis of 21 studies, the results revealed no significant association between the five types of PFAS and female reproductive system cancers (Fig. 2 ). Specifically, compared to the lowest dose groups, the pooled aOR of highest dose groups of PFOA was 1.09 (95% CI 0.83–1.43; I² = 72.8%; 16 studies; Fig. 2 a), and that for PFOS was 1.11 (95% CI 0.82–1.48; I² = 75.6%; 16 studies; Fig. 2 b), for PFHxS was 0.96 (95% CI 0.68–1.36; I² = 80.4%, 14 studies; Fig. 2 c), for PFNA was 1.11 (95% CI 0.79–1.56; I² = 77.5%; 14 studies; Fig. 2 d), for PFSA was 1.14 (95% CI 0.46–2.80; I ² = 88.1%; 5 studies; Figure S1 ). Similarly, the pooled adjusted aORs of PFOA per ln-unit increase for female reproductive system cancers was 1.02 (95% CI 0.87–1.19; I² = 76.7%; 16 studies; Figure S2 a), and that for PFOS was 1.02 (95% CI 0.93–1.13; I² = 69.9%, 16 studies; Figure S2 b), for PFHxS was 1.00 (95% CI 0.87–1.14; I² = 81.6%, 14 studies; Figure S2 c), for PFNA was 0.99 (95% CI 0.86–1.15; I² = 80.4%, 14 studies; Figure S2 d), for PFSA was 1.01 (95% CI 0.99–1.03; I ² = 70.8% 5 studies; Figure S3). The subgroup analysis revealed that the combined results from studies using prediagnosis and postdiagnosis blood samples were not significant difference (all P value of subgroup interaction test > 0.05, Fig. 2 ), which were consistent with the overall pooled results. Similar findings were observed for each ln-unit increase (Figure S2 ). When using menopausal status for stratification, the combined results from studies involving premenopausal and postmenopausal women were also similar (Figure S4). According to meta-regression analyses for, none of the included study characteristics had significant influence on heterogeneity of association between individual chemicals (PFOA, PFOS, PFHxS and PFNA) and female reproductive system cancers (Supplementary Table 3). 3.3. The association between PFAS and male reproductive system cancers Compared to the lowest dose groups, the pooled aOR of highest dose groups of PFOS was 1.25 (95% CI 1.02–1.52; I² = 3.0%; 4 studies; Fig. 3 a), which indicated a marginally increased risk for male reproductive cancers. However, no significant association was observed for PFOA with pooled aOR of 0.87 (95% CI 0.65–1.17; I² = 52.9%; 4 studies; Fig. 3 b). Similarly, the pooled results of per ln-unit increase indicated a potential association for PFOS with aOR of 1.00 (95% CI 1.00-1.01; I² = 0.0%; 3 studies; Figure S5a), but not for PFOA (aOR = 0.98, 95% CI 0.91–1.06; I² = 52.0%, 3 studies; Figure S5b). In subgroup analyses, according to tumor stage and Gleason score, no significant association was observed between PFOS or PFOA and prostate cancer (Figure S6). 3.4. Sensitivity analysis For female reproductive system cancers, the results of two sensitivity analyses (i.e., excluding studies with a NOS score below 7, and excluding studies that collected blood samples after diagnosis) were consistent with primary pooled analyses for both per natural log-unit increase and highest versus lowest categories of serum/plasma PFAS concentration categories (Supplementary Table 4). Heterogeneity was generally reduced, and a significant association was observed for PFNA in the per ln-unit increase model (aOR = 1.39, 95% CI: 1.07–1.79). Additionally, excluding individual studies one at a time further supported the robustness of the primary analysis (Fig. 4 ). 3.5. Publication bias The Egger test revealed no publication bias in the combined analysis of the associations between PFOA ( P value = 0.897), PFOS ( P value = 0.871), PFHxS ( P value = 0.902), PFNA ( P value = 0.888), and female reproductive system cancers. A funnel plot (Fig. 5 ) was also generated to visualize the combined adjusted odds ratios for per natural log-unit increase in serum/plasma PFAS concentration categories for the four types of PFAS (PFOA, PFOS, PFHxS, and PFNA). 4. Discussion 4.1 Principal findings To the best of our knowledge, this is the first meta-analysis evaluating the association between PFAS exposure and the risk of reproductive system cancers. By including the most comprehensive study to date, our results indicated no significant association between five main types of PFAS and female reproductive system cancers, with aORs of 1.09 (95% CI 0.83–1.43) for PFOA, 1.11 (95% CI 0.82–1.48) for PFOS, 0.96 (95% CI 0.68–1.36) for PFHxS, 1.11 (95% CI 0.79–1.56) for PFNA and 1.14 (95% CI 0.46–2.80) for PFSA. Notably, PFNA per ln-unit increase was significantly associated with female reproductive cancers in sensitivity analyses excluding studies with a NOS score below 7 and post-diagnosis blood samples (aOR: 1.39, 95% CI: 1.07–1.79). However, for male reproductive system cancers, a marginally increased risk of PFOS was observed with aORs of 1.25 (95% CI 1.02–1.52), but not for PFOA with adjusted OR of 0.87 (95% CI 0.65–1.17). 4.2 Comparison with previous studies The finding that PFAS exposure was not significant associated with breast cancer aligns with a previous meta-analysis conducted by Chang et al. [ 16 ]. By including 11 studies, Chang et al. observed a pooled adjusted RR of 0.95 (95% CI 0.77–1.18) for PFOA, and 0.98 (95% CI 0.87–1.11) for PFOS [ 16 ]. However, these results were contrary to another previous meta-analysis conducted by Jiang et al. [ 17 ]. By including eight studies, Jiang et al. reported that PFOA and PFHxS were positively associated with an increased risk of breast cancer, with pooled ORs of 1.32 (95% CI 1.19–1.46) and 1.79 (95% CI 1.51–2.11), respectively. In contrast, PFNA showed a protective association with breast cancer risk, with a pooled OR of 0.76 (95% CI 0.60–0.96). The observed discrepancies in previous meta-analyses primarily stem from methodological differences in study selection and analytical approaches. In the study conducted by Jiang et al., the synthesis aggregated multiple association measures from the same study and combined distinct exposure levels, allowing individual studies to contribute multiple data points to pooled estimates [ 17 ]. This methodological flaw compromises the validity of the findings. For ovarian cancer, Seyyedsalehi et al. reported a relative risk (RR) of 1.07 (95% CI: 1.04–1.09; n = 12) for the association with PFAS [ 50 ]. Following a methodology similar to that of Jiang et al. the study combined the values of individual chemicals (e.g., PFOA, PFOS, PFHxS, and PFNA) and chemical mixtures (e.g., PFAS) in the analysis, without evaluating them separately. In this study, we analyzed breast and ovarian cancers collectively as female reproductive system cancers, including only studies that assessed PFAS directly in plasma or serum, while systematically excluding cross-sectional studies susceptible to reverse causality. Several subgroup and sensitivity analyses demonstrated the robustness of the findings that PFAS exposure was not significantly associated with an increased risk of female reproductive system cancers. Compared to female reproductive system cancers, only a few studies have examined the impact of PFAS exposure on male reproductive system cancers [ 28 , 37 , 38 , 46 ]. For prostate cancer, the findings remain inconclusive. Previous studies by Rhee et al. [ 38 ] and Eriksen et al. [ 46 ] reported no significant association between PFAS exposure and prostate cancer risk, with OR of 0.90 (95% CI 0.79–1.03) for PFOA and incidence rate ratios (IRR) of 0.90 (95% CI 0.79–1.03) for PFOS. However, Troeschel et al. [ 28 ] found a positive correlation between PFAS exposure and prostate cancer risk in men aged ≥ 70 years. Specifically, higher serum concentrations of PFOS and PFHxS were associated with an increased risk of prostate cancer, with HR of 1.62 (95% CI 1.08–2.44) for PFOS and 1.54 (95% CI 1.02–2.31) for PFHxS, when comparing the highest and lowest exposure groups [ 28 ]. For testicular cancer, elevated PFOS concentrations were positively associated with increased risk, with an OR of 1.62 (95% CI 1.1–6.4) when comparing the highest to the lowest exposure groups [ 37 ]. Combining these studies revealed a potential association for PFOS, with an OR of 1.25 (95% CI 1.02–1.52), while the aOR for PFOA was 0.87 (95% CI 0.65–1.17). Although the association between PFAS and breast cancer remains controversial in epidemiological studies, several in vitro and animal studies have explored the potential mechanism [ 51 – 54 ]. For instance, previous studies demonstrated that PFOA facilitates the transformation of normal human mammary epithelial cells into tumors by inducing cell migration and invasion. This process involves upregulating cyclin D1 and CDK4/6 levels, as well as downregulating the CDK inhibitor p27 through a non-estrogenic mechanism, which promotes the proliferation of MCF-10A cells [ 52 ]. Similarly, PFOS promotes the proliferation of MCF-10A cells by modulating key regulatory cyclins and accelerating the cell cycle [ 53 ]. Furthermore, PFAS, as a class of endocrine-disrupting chemicals (EDCs), may elevate estrogen levels or mimic its biological effects, potentially promoting the development of breast and ovarian cancers [ 42 ]. While no studies to date have established a direct link between PFAS exposure and male reproductive system cancers, toxicological research has consistently demonstrated the adverse effects of PFAS on male germ cells [ 55 – 60 ]. For example, PFOS has demonstrated male reproductive toxicity in adult mice (characterized by reduced testicular weight and sperm count), adult rats (marked by degeneration of gonadal and spermatogenic cells, along with testicular edema), and zebrafish (with alterations in gonadal structure and a reduction in spermatogonia) [ 55 , 59 , 60 ]. In studies examining the association between PFAS and cancer, there are several common issues need to be noted. First, most studies were retrospective designs, which are susceptible to selection bias and make it difficult to establish the temporal relationship between exposure and cancer. Furthermore, many studies suffer from small sample sizes, limiting their statistical reliability and the generalizability of their findings. Even when meta-analyses are performed, the limited number of included articles and participants results in low statistical power [ 44 ]. Moreover, prior research may have failed to account for confounding factors, such as the hormonal receptor and menopausal status of study subjects, as cancer risk factors and biological mechanisms differ based on these variables [ 61 , 62 ]. Finally, significant concerns have been raised about the limitations of exposure assessment [ 16 ], particularly the variation in how exposure is defined across studies. Some studies use environmental substance concentrations as proxies for individual exposure, while others employ different measurement methods, including modeled serum PFAS levels, PFAS concentrations in residential water, and direct blood measurements. Variations in measurement methods and sample sources may affect the accuracy of exposure assessments, thereby influencing study outcomes. In conclusion, further well-designed, adequately powered prospective studies are needed to better explore the relationship between PFAS exposure and cancer risk. While substantial epidemiological evidence associates PFAS with increased cancer risk, their carcinogenic mechanisms remain mechanistically uncharacterized. As recognized endocrine disruptors, PFAS impair hormonal homeostasis by disrupting hypothalamic-pituitary-gonadal (HPG) axis signaling, as demonstrated in both in vitro and in vivo studies [ 63 ]. Recent experimental studies have identified specific molecular targets of PFAS: these compounds modulate the transcriptional activity of sex steroid receptors (e.g., estrogen receptor and androgen receptor), thereby perturbing feedback regulation in reproductive hormone synthesis [ 64 , 65 ]. Critically, mechanistic research on sex-specific toxicities of PFAS remains limited, and further fundamental biomedical research is required to elucidate how biological sex influences molecular responses to PFAS exposure. 4.3 Strengths and limitations Our study is distinguished by three key strengths. First, we conducted a systematic literature search and comprehensively examined the association between five major PFAS and reproductive system cancers. The included studies measured PFAS directly in plasma or serum, providing more accurate exposure assessment, minimizing measurement bias, and thereby enhancing the validity and reliability of the pooled results. Second, our study is the first to evaluate the relationship between PFAS and the male reproductive system. Third, we employed multiple subgroup and sensitivity analyses to further validate the robustness of the results. Our study has several limitations. First, although aORs were combined, the inclusion of confounding factors in the original studies was not exhaustive (e.g., the lack of socioeconomic factors), and therefore, our combined results should be interpreted with caution. For instance, the higher incidence of prostate cancer among Black men compared to White men is largely attributed to socioeconomic and environmental disparities [ 66 ]. Additionally, individuals with lower socioeconomic status are at greater risk of PFAS exposure, often due to living near pollution sources or working with PFAS-containing materials [ 67 ]. Therefore, future studies should prioritize identifying and controlling these confounding factors to more accurately assess the health effects of PFAS exposure. Second, the limited number of studies on male reproductive system cancers included in the analysis prevented further sensitivity and publication bias analyses. Consequently, there is an urgent need for large-scale, multicenter prospective cohort studies to systematically examine the mechanisms underlying the association between PFAS exposure and male reproductive cancers, thereby establishing a robust causal association. Lastly, some combined OR values exhibited significant heterogeneity. Although subgroup analyses were conducted, the sources of this heterogeneity remain unexplained. These limitations may affect the reliability and accuracy of the study findings. 5. Conclusions Existing epidemiological studies provide no evidence to support an association between PFAS exposure and an increased risk of female reproductive system (breast and ovarian cancer). Notably, sensitivity analyses identified a significant positive association for PFNA. However, PFOS (a specific PFAS compound) demonstrated a marginally increased risk for combined male reproductive cancers (testicular and prostate). Given the limited number of studies included, these findings should be interpreted cautiously. There is a pressing need for more studies, especially high-quality prospective cohort studies, to further clarify the association between PFAS exposure and reproductive system cancers. Declarations Author Contributions Conceptualization, Data Curation, Writing-Original Draft Preparation: Liu Xin; Formal Analysis, Validation: Zhihong Lv, Zixiang Huang; Software: Rui Sun; Investigation, Data Analysis and Interpretation: Dingyu Zhu, Pengcheng Xu; Project Administration, Supervision: Yiquan Xiong, Junhua Zhou; Funding Acquisition: Xiaowei Guo. All authors have read and agreed to the published version of the manuscript. Research ethics Not applicable. Informed Consent Not applicable. Use of Large Language Models, AI and Machine Learning Tools None declared. Conflicts of Interest All other authors state no conflict of interest. Funding statement This work was supported by the following funding including Hunan Provincial Degree and Postgraduate Education Reform Research Project (2024JGYB101), Hunan Provincial Social Science Foundation Project (XSP25YBZ146), Changsha Natural Science Foundation Project (KQ2502189), Natural Science Foundation Project of Hunan Province (2023JJ20029), Hunan Provincial Technological Innovation Foundation of China (2023RC3132). Data Availability Statement The authors confirm that the data supporting the findings of this study are available within the article. References Schymanski EL, Zhang J, Thiessen PA, Chirsir P, Kondic T, Bolton EE. Per- and Polyfluoroalkyl Substances (PFAS) in PubChem: 7 Million and Growing. Environmental science & technology. 2023;57(44):16918-28. Wang Z, Buser AM, Cousins IT, Demattio S, Drost W, Johansson O, et al. A New OECD Definition for Per- and Polyfluoroalkyl Substances. Environmental science & technology. 2021;55(23):15575-8. Lindstrom AB, Strynar MJ, Libelo EL. Polyfluorinated Compounds: Past, Present, and Future. Environmental science & technology. 2011;45(19):7954-61. Cousins IT, DeWitt JC, Glüge J, Goldenman G, Herzke D, Lohmann R, et al. The high persistence of PFAS is sufficient for their management as a chemical class. ENVIRONMENTAL SCIENCE-PROCESSES & IMPACTS. 2020;22(12):2307-12. Wang Z, DeWitt JC, Higgins CP, Cousins IT. A Never-Ending Story of Per- and Polyfluoroalkyl Substances (PFASs)? Environmental science & technology. 2017;51(5):2508-18. Xu Y, Fletcher T, Pineda D, Lindh CH, Nilsson C, Glynn A, et al. Serum Half-Lives for Short- and Long-Chain Perfluoroalkyl Acids after Ceasing Exposure from Drinking Water Contaminated by Firefighting Foam. Environmental health perspectives. 2020;128(7). Houde M, Martin JW, Letcher RJ, Solomon KR, Muir DCG. Biological Monitoring of Polyfluoroalkyl Substances: A Review. Environmental science & technology. 2006;40(11):3463-73. Jørgensen KT, Specht IO, Lenters V, Bach CC, Rylander L, Jönsson BAG, et al. Perfluoroalkyl substances and time to pregnancy in couples from Greenland, Poland and Ukraine. Environmental Health. 2014;13(1):116. Papadopoulou E, Haug Line S, Sakhi Amrit K, Andrusaityte S, Basagaña X, Brantsaeter Anne L, et al. Diet as a Source of Exposure to Environmental Contaminants for Pregnant Women and Children from Six European Countries. Environmental health perspectives. 2019;127(10):107005. Sunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG. A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. Journal of exposure science & environmental epidemiology. 2019;29(2):131-47. Calafat Antonia M, Wong L-Y, Kuklenyik Z, Reidy John A, Needham Larry L. Polyfluoroalkyl Chemicals in the U.S. Population: Data from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 and Comparisons with NHANES 1999–2000. Environmental health perspectives. 2007;115(11):1596-602. Jane LEL, Yamada M, Ford J, Owens G, Prow T, Juhasz A. Health-related toxicity of emerging per- and polyfluoroalkyl substances: Comparison to legacy PFOS and PFOA. Environmental research. 2022;212(Pt C):113431. Fenton SE, Ducatman A, Boobis A, DeWitt JC, Lau C, Ng C, et al. Per- and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research. Environmental toxicology and chemistry. 2021;40(3):606-30. Schrenk D, Bignami M, Bodin L, Chipman JK, del Mazo J, Grasl-Kraupp B, et al. Risk to human health related to the presence of perfluoroalkyl substances in food. EFSA JOURNAL. 2020;18(9). Steenland K, Winquist A. PFAS and cancer, a scoping review of the epidemiologic evidence. Environmental research. 2021;194:110690. Chang CJ, Ish JL, Chang VC, Daniel M, Jones RR, White AJ. Exposure to per- and polyfluoroalkyl substances and breast cancer risk: a systematic review and meta-analysis of epidemiologic studies. American journal of epidemiology. 2024;193(8):1182-96. Jiang HH, Liu H, Liu G, Yu J, Liu NN, Jin YQ, et al. Associations between Polyfluoroalkyl Substances Exposure and Breast Cancer: A Meta-Analysis. Toxics. 2022;10(6). van Gerwen M, Chung T, Monaghan M, Vermeulen R, Petrick L, Leung AM. Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer: Systematic review and meta-analysis. Toxicology letters. 2024;399:52-8. Yang J, Zhang K, Shi J, Li Z, Dai H, Yang W. Perfluoroalkyl and polyfluoroalkyl substances and Cancer risk: results from a dose-response Meta-analysis. Journal of environmental health science & engineering. 2024;22(2):455-69. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. REVISTA PANAMERICANA DE SALUD PUBLICA-PAN AMERICAN JOURNAL OF PUBLIC HEALTH. 2022;46. Kato K, Kalathil AA, Patel AM, Ye X, Calafat AM. Per- and polyfluoroalkyl substances and fluorinated alternatives in urine and serum by on-line solid phase extraction–liquid chromatography–tandem mass spectrometry. Chemosphere. 2018;209:338-45. Organization WH. International Statistical Classification of Diseases and Related Health Problems: 10th revision, version for 2007-ICD-10. 2009. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010;25(9):603-5. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed). 2003;327(7414):557-60. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in medicine. 2002;21(11):1539-58. Ali AT, Al-Ani O, Al-Ani F. Epidemiology and risk factors for ovarian cancer. Przeglad menopauzalny = Menopause review. 2023;22(2):93-104. Singletary SE. Rating the risk factors for breast cancer. Annals of surgery. 2003;237(4):474-82. Troeschel AN, Teras LR, Hodge JM, Rodriguez J, Wang Y, Daniel J, et al. A case-cohort study of per- and polyfluoroalkyl substance concentrations and incident prostate cancer in the cancer prevention Study-II LifeLink cohort study. Environmental research. 2024;259:119560. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed). 1997;315(7109):629. Bonefeld-Jørgensen EC, Long M, Fredslund SO, Bossi R, Olsen J. Breast cancer risk after exposure to perfluorinated compounds in Danish women: a case–control study nested in the Danish National Birth Cohort. Cancer Causes and Control. 2014;25(11):1439-48. Chang VC, Rhee J, Berndt SI, Moore SC, Freedman ND, Jones RR, et al. Serum perfluorooctane sulfonate and perfluorooctanoate and risk of postmenopausal breast cancer according to hormone receptor status: An analysis in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. International journal of cancer. 2023;153(4):775-82. Dou Q, Bai YA, Li YJ, Zheng S, Wang MZ, Wang ZG, et al. Perfluoroalkyl substances exposure and the risk of breast cancer: A nested case-control study in Jinchang Cohort. Environmental research. 2024;262. Ghisari M, Long M, Røge DM, Olsen J, Bonefeld-Jørgensen EC. Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort. Environmental research. 2017;154:325-33. Hurley S, Goldberg D, Wang MM, Park JS, Petreas M, Bernstein L, et al. Breast cancer risk and serum levels of per- and poly-fluoroalkyl substances: a case-control study nested in the California Teachers Study. Environmental Health. 2018;17. Jones RR, Madrigal JM, Medgyesi DN, Fisher JA, Calafat AM, Botelho JC, et al. Serum concentrations of per- and polyfluoroalkyl substances and risk of ovarian cancer. JNCI: Journal of the National Cancer Institute. 2025:djaf204. Mancini FR, Cano-Sancho G, Gambaretti J, Marchand P, Boutron-Ruault MC, Severi G, et al. Perfluorinated alkylated substances serum concentration and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort. International journal of cancer. 2020;146(4):917-28. Purdue MP, Rhee J, Denic-Roberts H, McGlynn KA, Byrne C, Sampson J, et al. A Nested Case-Control Study of Serum Per- and Polyfluoroalkyl Substances and Testicular Germ Cell Tumors among US Air Force Servicemen. Environmental health perspectives. 2023;131(7). Rhee J, Barry KH, Huang WY, Sampson JN, Hofmann JN, Silverman DT, et al. A prospective nested case-control study of serum concentrations of per- and polyfluoroalkyl substances and aggressive prostate cancer risk. Environmental research. 2023;228:115718. Xing WY, Liu FH, Wang DD, Liu JM, Zheng WR, Liu JX, et al. Association between plasma perfluoroalkyl substances and high-grade serous ovarian cancer overall survival: A nested case-control study. Ecotoxicology and environmental safety. 2025;291:117825. Itoh H, Harada KH, Hamada GS, Lyu Z, Fujitani T, Harada Sassa M, et al. Plasma perfluoroalkyl substances and breast cancer risk in Brazilian women: a case-control study. Environmental health : a global access science source. 2025;24(1):13. Itoh H, Harada KH, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, et al. Serum perfluoroalkyl substances and breast cancer risk in Japanese women: A case-control study. Science of the Total Environment. 2021;800. Li XJ, Song FJ, Liu XT, Shan AQ, Huang YB, Yang ZJ, et al. Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population. Environmental Health. 2022;21(1). Tsai MS, Chang SH, Kuo WH, Kuo CH, Li SY, Wang MY, et al. A case-control study of perfluoroalkyl substances and the risk of breast cancer in Taiwanese women. Environment international. 2020;142:105850. Velarde MC, Chan AFO, Sajo M, Zakharevich I, Melamed J, Uy GLB, et al. Elevated levels of perfluoroalkyl substances in breast cancer patients within the Greater Manila Area. Chemosphere. 2022;286. Wielsoe M, Kern P, Bonefeld-Jorgensen EC. Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study. Environmental Health. 2017;16. Eriksen KT, Sorensen M, McLaughlin JK, Lipworth L, Tjonneland A, Overvad K, et al. Perfluorooctanoate and Perfluorooctanesulfonate Plasma Levels and Risk of Cancer in the General Danish Population. Jnci-Journal of the National Cancer Institute. 2009;101(8):605-9. Feng Y, Bai YS, Lu YJ, Chen MS, Fu M, Guan X, et al. Plasma perfluoroalkyl substance exposure and incidence risk of breast cancer: A case-cohort study in the Dongfeng-Tongji cohort. Environmental Pollution. 2022;306. Shahi S, Winquist A, Troeschel AN, Diver WR, Hodge JM, Deubler E, et al. A case-cohort study of the association between per- and polyfluoroalkyl substances (PFAS) and breast cancer among participants in the American Cancer Society’s Cancer Prevention Study-II. Environmental research. 2025;285:122381. Winquist A, Hodge JM, Diver WR, Rodriguez JL, Troeschel AN, Daniel J, et al. Case-Cohort Study of the Association between PFAS and Selected Cancers among Participants in the American Cancer Society's Cancer Prevention Study II LifeLink Cohort. Environmental health perspectives. 2023;131(12):127007. Seyyedsalehi MS, Maria Kappil E, Zhang S, Zheng T, Boffetta P. Per- And Poly-Fluoroalkyl Substances (PFAS) Exposure and Risk of Breast, and Female Genital Cancers: A Systematic Review and Meta-Analysis: PFAS Exposure and Risk of Breast and Female Genital Cancers. La Medicina del lavoro. 2024;115(6):e2024043. Chandran K, Goswami S, Sharma-Walia N. Implications of a peroxisome proliferator-activated receptor alpha (PPARα) ligand clofibrate in breast cancer. Oncotarget. 2016;7(13):15577-99. Pierozan P, Jerneren F, Karlsson O. Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells. Archives of toxicology. 2018;92(5):1729-39. Pierozan P, Karlsson O. PFOS induces proliferation, cell-cycle progression, and malignant phenotype in human breast epithelial cells. Archives of toxicology. 2018;92(2):705-16. Roberts-Thomson SJ, Snyderwine EG. Characterization of peroxisome proliferator-activated receptor alpha in normal rat mammary gland and 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine-induced mammary gland tumors from rats fed high and low fat diets. Toxicology letters. 2000;118(1):79-86. Chen J, Wang X, Ge X, Wang D, Wang T, Zhang L, et al. Chronic perfluorooctanesulphonic acid (PFOS) exposure produces estrogenic effects in zebrafish. Environmental Pollution. 2016;218:702-8. Hu W-Y, Lu R, Hu DP, Imir OB, Zuo Q, Moline D, et al. Per- and polyfluoroalkyl substances target and alter human prostate stem-progenitor cells. Biochemical pharmacology. 2022;197:114902. Law HD, Armstrong BK, D’este C, Hosking R, Smurthwaite KS, Trevenar S, et al. Relative rates of cancers and deaths in Australian communities with PFAS environmental contamination associated with firefighting foams: A cohort study using linked data. Cancer Epidemiology. 2023;82:102296. Li H, Hammarstrand S, Midberg B, Xu Y, Li Y, Olsson DS, et al. Cancer incidence in a Swedish cohort with high exposure to perfluoroalkyl substances in drinking water. Environmental research. 2022;204:112217. López-Doval S, Salgado R, Pereiro N, Moyano R, Lafuente A. Perfluorooctane sulfonate effects on the reproductive axis in adult male rats. Environmental research. 2014;134:158-68. Qu J-H, Lu C-C, Xu C, Chen G, Qiu L-L, Jiang J-K, et al. Perfluorooctane sulfonate-induced testicular toxicity and differential testicular expression of estrogen receptor in male mice. Environmental toxicology and pharmacology. 2016;45:150-7. Kerlikowske K, Gard CC, Tice JA, Ziv E, Cummings SR, Miglioretti DL, et al. Risk Factors That Increase Risk of Estrogen Receptor–Positive and –Negative Breast Cancer. JNCI: Journal of the National Cancer Institute. 2017;109(5):djw276. St-Hilaire S, Mandal R, Commendador A, Mannel S, Derryberry D. Estrogen receptor positive breast cancers and their association with environmental factors. International Journal of Health Geographics. 2011;10(1):32. Ding N, Harlow SD, Randolph Jr JF, Loch-Caruso R, Park SK. Perfluoroalkyl and polyfluoroalkyl substances (PFAS) and their effects on the ovary. Human Reproduction Update. 2020;26(5):724-52. Tachachartvanich P, Singam ERA, Durkin KA, Furlow JD, Smith MT, La Merrill MA. In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor. Journal of hazardous materials. 2022;429:128243. Villeneuve DL, Blackwell BR, Cavallin JE, Collins J, Hoang JX, Hofer RN, et al. Verification of In Vivo Estrogenic Activity for Four Per- and Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists via New Approach Methodologies. Environmental science & technology. 2023;57(9):3794-803. Pernar CH, Ebot EM, Wilson KM, Mucci LA. The Epidemiology of Prostate Cancer. Cold Spring Harbor perspectives in medicine. 2018;8(12). Smalling Kelly L, Bradley Paul M. Invited Perspective: Per- and Polyfluoroalkyl Substances in Drinking Water—Disparities in Community Exposures Based on Race and Socioeconomic Status. Environmental health perspectives. 2024;132(4):041302. Supplementary Files PRISMA2020checklist.docx SupplementaryMaterial.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 18 Sep, 2025 Reviewers invited by journal 13 Sep, 2025 Editor assigned by journal 04 Sep, 2025 First submitted to journal 03 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7521500","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":514477454,"identity":"f1c2d15a-0e30-4ede-a3d6-a63ecc7c33dc","order_by":0,"name":"Xin Liu","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Liu","suffix":""},{"id":514477455,"identity":"c5bb190a-8187-41cd-a59c-78c6f76d7639","order_by":1,"name":"Zhihong Lv","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Zhihong","middleName":"","lastName":"Lv","suffix":""},{"id":514477456,"identity":"1cfc47a3-46c0-426c-928f-807825a05f3e","order_by":2,"name":"Zixiang Huang","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Zixiang","middleName":"","lastName":"Huang","suffix":""},{"id":514477457,"identity":"36272651-98b7-417e-8cab-54fb0c75204f","order_by":3,"name":"Rui Sun","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Sun","suffix":""},{"id":514477458,"identity":"965f9be8-3ac2-49f8-9ea9-df1cc17590a5","order_by":4,"name":"Dingyu Zhu","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Dingyu","middleName":"","lastName":"Zhu","suffix":""},{"id":514477459,"identity":"fcedf594-f158-4e5e-bf70-d62dfabe1148","order_by":5,"name":"Pengcheng Xu","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Pengcheng","middleName":"","lastName":"Xu","suffix":""},{"id":514477460,"identity":"de20cef5-d77d-47c2-88bd-14c8634c6d71","order_by":6,"name":"Yiquan Xiong","email":"","orcid":"","institution":"Sichuan Medical University: Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yiquan","middleName":"","lastName":"Xiong","suffix":""},{"id":514477461,"identity":"553050b3-7b79-4987-b5d3-6a1c08a70d0d","order_by":7,"name":"Xiaowei Guo","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Xiaowei","middleName":"","lastName":"Guo","suffix":""},{"id":514477462,"identity":"42af4e28-649d-4ba2-b5ea-b073b2d6c143","order_by":8,"name":"Yaxuan Ren","email":"","orcid":"","institution":"Hunan Normal University","correspondingAuthor":false,"prefix":"","firstName":"Yaxuan","middleName":"","lastName":"Ren","suffix":""},{"id":514477463,"identity":"6ffbf648-72e8-42dd-b9f1-6b728ff60549","order_by":9,"name":"junhua zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYDACCQhOYGBgPgYTMyBWC1saCVoYwFp4zIjTIj+7+ZiEZdudPIPjZ7495t1xJ7GBvXmbBEPNHZxaGOccS5OQbHtWbHAmd7sx75lniQ08x8okGI49w6mFWSLHDKjlcOKGA7nbpHmBjAaQCGPDYZxa2OBazr95BtEi/wa/Fh64lhs5bFBbePBrkZBIS7aQOHc4ceaNZ2aSc9sOG7fxpBVbJBzDrUV+RvLB2xJlhxP7zic/k3jbdli2n/3wxhsfanBrgQQBiu9ARAJeDcCA/kBAwSgYBaNgFIxwAADLFFT9soOz5QAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-5538-6671","institution":"Hunan Normal University","correspondingAuthor":true,"prefix":"","firstName":"junhua","middleName":"","lastName":"zhou","suffix":""}],"badges":[],"createdAt":"2025-09-03 00:10:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7521500/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7521500/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91937875,"identity":"a84042bd-adf8-4657-ad43-e1a244e6cff8","added_by":"auto","created_at":"2025-09-23 03:03:08","extension":"xml","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":13927,"visible":true,"origin":"","legend":"","description":"","filename":"jehsJEHSD2500439.xml","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/74cb771a9e7c824f1ac4eca9.xml"},{"id":91936340,"identity":"94469fcd-2ef3-43e1-a473-9a67e9ac6178","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1024,"visible":true,"origin":"","legend":"","description":"","filename":"JEHSD250043914701.go.xml","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/561982df463f1a5bb1f5ac36.xml"},{"id":91936354,"identity":"4070fea8-e5e1-421c-b1a3-89a16ffe7a22","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":944,"visible":true,"origin":"","legend":"","description":"","filename":"JEHSD2500439Import.xml","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/f8e251c6c2f9cc8d7a4c15a0.xml"},{"id":91936357,"identity":"562549da-bee8-4529-a853-a9e23a1ed6f6","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":170322,"visible":true,"origin":"","legend":"","description":"","filename":"JEHSD25004390enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/530e5e47142cfe0df13bc899.xml"},{"id":91937874,"identity":"e5ea632a-569a-463e-81aa-d3b7fffea0d1","added_by":"auto","created_at":"2025-09-23 03:03:08","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":336506,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/94dcf018b9dbfa5285602390.jpeg"},{"id":91936346,"identity":"68d51d1f-6c18-48c2-97b2-f45ea2369e44","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":593684,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/363da1dadd9491b2af1436da.jpeg"},{"id":91937397,"identity":"1cdd9670-8921-4814-8f59-db0d84ca6db6","added_by":"auto","created_at":"2025-09-23 02:55:08","extension":"jpeg","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":296588,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/8f078e3d70ce31c26f9b4c1d.jpeg"},{"id":91939416,"identity":"c48d3d22-9058-43f9-9bd0-98fb3399b417","added_by":"auto","created_at":"2025-09-23 03:11:08","extension":"jpeg","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":442928,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/1e77da7def9b8712e616e681.jpeg"},{"id":91936359,"identity":"10f0847b-0619-46b8-bc94-5be7447263a6","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":267532,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/afbf499c678ba83696855dfe.jpeg"},{"id":91937392,"identity":"1d009b6d-57bf-43a2-869e-2070229cf387","added_by":"auto","created_at":"2025-09-23 02:55:08","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":61822,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/887230fbc6aae65a44e57462.png"},{"id":91937394,"identity":"f2f65aed-2e09-45bf-98bc-cb7351b44342","added_by":"auto","created_at":"2025-09-23 02:55:08","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69498,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/830075cdc5434b5cec0b4d82.png"},{"id":91936353,"identity":"77974ea8-6f02-47ab-b711-858ab93f5469","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43151,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/8975f7a1c27ea345fc70f8d7.png"},{"id":91936349,"identity":"fda49cd0-a761-4299-af20-c078d4955419","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60270,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/2db34459fb2855edd896bdbd.png"},{"id":91936352,"identity":"eab2a50c-0d81-4c60-9b0f-abc2307b772e","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":31071,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/a5d7ed0df517942bc462d74e.png"},{"id":91937399,"identity":"fee817ad-9843-458b-8983-186dcb088088","added_by":"auto","created_at":"2025-09-23 02:55:08","extension":"xml","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":170313,"visible":true,"origin":"","legend":"","description":"","filename":"JEHSD25004390structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/58c959cda8621be78e41c3c3.xml"},{"id":91936360,"identity":"50248fa2-e80b-4947-b33e-6eeab0a9651a","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":181259,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/01847d3fceff6ee2e2a13b26.html"},{"id":91936342,"identity":"29dbe9f7-a275-46e1-8ce9-4a725c08d159","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":436206,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram of the retrieved eligible articles.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/f6add4b1eded27c8b2cfb69d.png"},{"id":91936341,"identity":"619c068c-f684-40ff-a2ee-51dae34dbcbf","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":401686,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the studies that evaluated the adjusted odds ratios (aORs) between PFAS and female reproductive system cancers. PFOA, perfluorooctanoate; PFOS, perfluorooctane sulfonate; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoate.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/632ac3d41faa3c91afcfe3fc.png"},{"id":91936345,"identity":"1afdf03c-421a-4c82-be87-4c10ba6554fe","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":261424,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the studies that evaluated the adjusted odds ratios (aORs) between PFAS and male reproductive system cancers. PFOA, perfluorooctanoate; PFOS, perfluorooctane sulfonate.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/d6a76859f3a6057ab50b587e.png"},{"id":91936343,"identity":"faed370b-b667-4a0a-93b4-7f5660aa457b","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":375880,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis of studies that evaluated the adjusted odds ratios (aORs) between PFAS and female reproductive system cancers. PFOA, perfluorooctanoate; PFOS, perfluorooctane sulfonate; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoate.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/6f4057aab95d1c682363768e.png"},{"id":91937876,"identity":"c51c1eeb-be25-41ad-aed8-069251a7b70e","added_by":"auto","created_at":"2025-09-23 03:03:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":215659,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot assessing publication bias in breast cancer studies. PFOA, perfluorooctanoate; PFOS, perfluorooctane sulfonate; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoate.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/cae3559ea62cca5cefc458af.png"},{"id":91939654,"identity":"df696cd6-a0dd-4e51-8765-20c581a0bd40","added_by":"auto","created_at":"2025-09-23 03:19:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2989357,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/04c56e5d-8e92-4a44-8fd8-806d659f63eb.pdf"},{"id":91937393,"identity":"74eb6e41-a113-4bb8-b0d3-4ebe394f4c40","added_by":"auto","created_at":"2025-09-23 02:55:08","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":22955,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/1097ff7981fdb44abef7ade4.docx"},{"id":91936362,"identity":"a7945e25-7c24-4559-976f-44fc8d848776","added_by":"auto","created_at":"2025-09-23 02:47:08","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":3536615,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7521500/v1/8e3e402d4d165aeebcfdd297.docx"}],"financialInterests":"","formattedTitle":"Exposure to Per- and Polyfluoroalkyl Substances and Risk of Reproductive System Cancers: A Systematic Review and Meta-Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePer- and polyfluoroalkyl substances (PFAS) are a family of synthetic organic compounds that include more than 7\u0026nbsp;million types, and are characterized by highly stable chemical structures [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Since the 1950s, PFAS have been widely utilized as surfactants in numerous commercial and industrial applications owing to their exceptional water- and oil-repellent properties [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It has been demonstrated that these chemicals are bio-accumulative, possess long half-life, and degrade at a slow rate [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Previous studies showed that PFAS has been detected in human biological samples both from various geographical regions, including industrialized and urbanized areas, as well as non-urbanized regions [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The general population can be exposed to PFAS through multiple pathways, including contaminated drinking water or food (particularly fish) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], indoor air, dust, and various consumer products (e.g., food packaging, and non-stick coatings) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Among PFAS, traditional long-chain perfluoroalkyl acids, such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorinated sulfonic acids [PFSA] (also refers to a mixture of PFOS and PFHxS), are the most prevalent in both the environment and the human body [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Data from the National Health and Nutrition Examination Survey (NHANES) indicate that PFAS are detectable in nearly all studied population groups, categorized by age (12\u0026ndash;19 years, 20\u0026ndash;39 years, 40\u0026ndash;59 years, and \u0026ge;\u0026thinsp;60 years), sex (male and female), and race (Mexican American, non-Hispanic Black, and non-Hispanic White) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Recent epidemiological studies have demonstrated that PFAS exposure is associated with a range of adverse health outcomes, including disruptions in the immune, endocrine, cardiovascular-metabolic, and reproductive systems, as well as an increased risk of cancer [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe potential association between PFAS exposure and cancer has garnered significant attention [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Several meta-analyses have evaluated the relationship between PFAS exposure and overall or specific type cancer (e.g., thyroid cancer, breast cancer), though their conclusions remain inconsistent [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. For example, a previous meta-analysis found that PFOS exposure significantly increased total cancer risk (odds ratios [ORs]\u0026thinsp;=\u0026thinsp;1.12, 95% CI 1.00-1.25) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Similarly, Jiang \u003cem\u003eet al.\u003c/em\u003e included eight studies involving 13,603 participants and observed a positive association between PFOA and PFHxS exposure and breast cancer risk, with pooled ORs of 1.32 (95% CI 1.19\u0026ndash;1.46) and 1.79 (95% CI 1.51\u0026ndash;2.11), respectively [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In contrast, another meta-analysis including 11 studies with 3,233 participants found no significant association, with RRs (\u003cb\u003eRelative Risks)\u003c/b\u003e of 0.95 (95% CI: 0.77\u0026ndash;1.18) for PFOA and 0.98 (95% CI: 0.87\u0026ndash;1.11) for PFOS [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. To date, evidence on the relationship between PFAS exposure and reproductive system cancers remains limited and inconsistent, exemplified by the ongoing debate regarding PFAS and breast cancer risk. To address these discrepancies, we expanded the scope of investigation beyond breast cancer to include ovarian cancer, aiming to provide a more comprehensive evaluation of female reproductive system cancers. While prior studies have examined breast and ovarian cancers separately, no meta-analysis has synthesized evidence for both cancers collectively, despite their shared hormonal and reproductive mechanisms.\u003c/p\u003e\u003cp\u003eTherefore, we conducted this systematic review and meta-analysis to investigate whether PFAS exposure is associated with an increased risk of reproductive system cancers, including cancers of the female reproductive system (breast and ovarian cancers) and male reproductive system (prostate and testicular cancers). Building on previous reviews, this analysis enhances the current evidence by incorporating additional recent studies and focusing on PFAS measured directly in plasma or serum, thereby improving exposure assessment accuracy and reinforcing the reliability of the findings.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cp\u003eThis study was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], with review protocol registered in PROSPERO (CRD42024628466).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Inclusion and exclusion criteria\u003c/h2\u003e\u003cp\u003eStudies meeting the following criteria were included in this meta-analysis: (1) case-control or cohort study that analyzed the association between PFAS concentrations in human serum or plasma and reproductive system cancers; (2) the study reported the association between PFAS exposure and reproductive system cancers, such as OR, RR, or hazard ratio (HR), or provided raw data that enabled the calculation of these measures.\u003c/p\u003e\u003cp\u003eExclusion criteria for the literature were as follows: (1) studies focusing on animal or cell experiments; (2) studies that lacked data to calculate the association between PFAS exposure and cancer; (3) letters, reviews, editorials, case reports, and abstracts.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Search strategy\u003c/h2\u003e\u003cp\u003eA search was performed in the PubMed, Embase, and Web of Science databases for studies published before November 16, 2024, with an update as of August 10, 2025. The following search terms were used to identify relevant articles: \u0026ldquo;perfluorinated\u0026rdquo;, \u0026ldquo;perfluorinated\u0026rdquo;, \u0026ldquo;perfluorooctane\u0026rdquo;, \u0026ldquo;perfluorooctane\u0026rdquo;, \u0026ldquo;PFOS\u0026rdquo;, \u0026ldquo;PFOA\u0026rdquo;, \u0026ldquo;PFHxS\u0026rdquo;, \u0026ldquo;neoplasms\u0026rdquo;, \u0026ldquo;tumor\u0026rdquo;, \u0026ldquo;neoplasm\u0026rdquo;, \u0026ldquo;tumors\u0026rdquo;, \u0026ldquo;neoplasia\u0026rdquo;, \u0026ldquo;neoplasias\u0026rdquo;, \u0026ldquo;cancer\u0026rdquo;, \u0026ldquo;cancers\u0026rdquo;, \u0026ldquo;malignancy\u0026rdquo;, \u0026ldquo;malignancies\u0026rdquo; and \u0026ldquo;malignant neoplasm\u0026rdquo;. The search strategy for each database is shown in the Supplementary Table\u0026nbsp;1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Definition of exposure and outcome\u003c/h2\u003e\u003cp\u003eThis study investigates PFAS exposure levels in serum or plasma, specifically focusing on PFOA, PFOS, PFHxS, PFNA and PFSA. PFAS concentrations were quantified using solid-phase extraction combined with liquid chromatography and isotope dilution tandem mass spectrometry [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The study examines outcomes related to reproductive system cancers, including breast cancer (ICD-10 code: C50), ovarian cancer (C56), prostate cancer (C61) and testicular cancer (C62) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Data extraction\u003c/h2\u003e\u003cp\u003eFor each eligible study, the following information was extracted: first author, publication year, study location, study design, characteristics of the study population, sample size, study duration, biological samples, methods of exposure measurement, PFAS concentrations by group, estimate value of associations, timing of blood sample collection, adjusted ORs, and adjusted confounders. For studies utilizing multiple adjusted models, data from the fully adjusted model were extracted. Two researchers (Liu and Lv) independently extracted the data, and discrepancies were resolved through discussion.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Quality assessment\u003c/h2\u003e\u003cp\u003eThe quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This scale evaluates three categories: selection of study groups, control of confounding factors, and determination of exposure. The study encompasses eight different items, with a total score of 9 points. A higher total score reflects better study quality. NOS scores of 1\u0026ndash;3 points are classified as high-risk, 4\u0026ndash;6 points as moderate-risk, and 7\u0026ndash;9 points as low-risk. Each included study was independently assessed for quality by two authors (Liu and Lv) and discrepancies were resolved through discussion.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e\u003cb\u003e2.\u003c/b\u003e6. \u003cb\u003eStatistical analysis\u003c/b\u003e\u003c/h2\u003e\u003cp\u003eIn this study, separate meta-analyses were conducted for female reproductive system (breast and ovarian cancer) and male reproductive system (prostate and testicular cancers). Given the low incidence of reproductive system cancers, RRs, ORs, and HRs were treated as equivalent. Adjusted ORs (aORs) were used as the effect estimates. In the pooled analysis, the Q test and \u003cem\u003eI\u0026sup2;\u003c/em\u003e statistic were used to assess heterogeneity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. A fixed-effects model (Mantel-Haenszel method) was applied when \u003cem\u003eI\u0026sup2;\u003c/em\u003e \u0026le; 50%, while a random-effects model (DerSimonian-Laird method) was used when \u003cem\u003eI\u0026sup2;\u003c/em\u003e \u0026gt;50% [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. For each outcome, two pooled aORs were calculated: one based on the comparison between the highest and lowest PFAS concentration categories (e.g., percentiles), and the other one based on the change in each natural log (ln) unit of continuous PFAS concentrations (ng/mL). For studies reporting ORs of per-\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\:{\\text{l}\\text{o}\\text{g}}_{x}\\)\u003c/span\u003e\u003c/span\u003e-unit increase in PFAS concentrations, we transformed the ORs to per-ln-unit increase by applying the following formula: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:O{R}_{\\text{per}\\:\\text{ln}\\:\\text{unit}\\:\\text{increase}}={e}^{{\\text{log}}_{x}\\left(O{R}_{\\text{per}\\:{\\text{log}}_{x}\\:\\text{unit}\\:\\text{increase}}\\right)}\\:\\:\\)\u003c/span\u003e\u003c/span\u003e\u003csup\u003e[16]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eWe performed several subgroup analyses. For female reproductive system cancers, subgroups were stratified by the timing of blood sample collection (prediagnostic vs. postdiagnostic) and menopausal status (premenopausal vs. postmenopausal). Age (using 50 years as the cutoff) was used as an indicator to distinguish between premenopausal and postmenopausal status in the context of female reproductive system cancers [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. For prostate cancer, subgroup analyses were stratified by Gleason score (low-grade vs. high-grade) and tumor stage (non-advanced vs. advanced). Based on the Gleason scoring system, low-grade was defined as a score\u0026thinsp;\u0026le;\u0026thinsp;7, and high-grade as a score\u0026thinsp;\u0026ge;\u0026thinsp;8. The American Joint Committee on Cancer (AJCC) staging system was employed to categorize tumors as non-advanced stage (AJCC stages 1\u0026ndash;2) and advanced stage (AJCC stages 3\u0026ndash;4) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. A meta-regression analysis was conducted for female reproductive system cancers using publication year (before 2020 vs. 2020 or later), geographic region (Western or Asian countries), sample size (\u0026lt;\u0026thinsp;500 or \u0026ge;\u0026thinsp;500), study design (case\u0026ndash;control, nested case\u0026ndash;control, or case\u0026ndash;cohort), timing of blood sample collection (prediagnostic or postdiagnostic), and NOS score (\u0026lt;\u0026thinsp;7 or \u0026ge;\u0026thinsp;7), with a subsequent analysis performed for individual chemicals (PFOA, PFOS, PFHxS, and PFNA).\u003c/p\u003e\u003cp\u003eTo assess the robustness of the findings, three sensitivity analyses were conducted: (1) excluding studies with a NOS score below 7; (2) excluding studies that collected blood samples after diagnosis; and (3) excluding individual studies one at a time to determine whether any particular study had a significant impact on the combined results. Egger's regression test was employed to assess publication bias [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In this study, the meta-analysis of female reproductive system cancers included five types of PFAS: PFOA, PFOS, PFHxS, PFNA and PFSA. However, due to the limited number of included studies, only PFOA and PFOS were included in the analysis of male reproductive system cancers. Additionally, because of the small number of studies on male reproductive system cancers, sensitivity and publication bias analyses were not performed. All statistical analyses were performed using STATA 15.1 (Stata Corp LP, College Station, TX).\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Study characteristics and quality assessment\u003c/h2\u003e\u003cp\u003eA total of 1,945 articles were identified through the systematic literature search. After applying the inclusion and exclusion criteria, 21 studies were included (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among these, 17 focused on female reproductive cancers, and 4 focused on male reproductive cancers. All included studies were case-control studies (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e), consisting of 10 nested case-control studies [\u003cspan additionalcitationids=\"CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], 6 traditional case-control studies [\u003cspan additionalcitationids=\"CR41 CR42 CR43 CR44\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], and 5 case-cohort studies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan additionalcitationids=\"CR47 CR48\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. These studies were conducted in seven countries: four Western nations (Denmark, the United States, France, and Brazil) and three Asian countries (Japan, China, and the Philippines). There were 21 studies focusing on PFOA and PFOS, 15 studies focusing on PFHxS and PFNA, and 5 studies focusing on PFSA. The NOS assigned 15 studies (71.43%) to the low risk of bias category, with 10 studies scoring 7 points and 5 studies scoring 8 points. The other six studies (28.57%) were classified as moderate risk, all achieving a score of 6 points (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of all included studies in the meta-analysis.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst author (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCancer type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo. of subjects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExposure assessment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExposure time\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eConfounding Variables Adjusted\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eQuality \u003c/p\u003e\u003cp\u003escore\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEriksen (2009)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDenmark\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1993\u0026ndash;2006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProstate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:713; Subcohort:772\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlasma\u003c/p\u003e\u003cp\u003e(PFOA, PFOS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eschool years, BMI, dietary fat intake, fruit and vegetable intake\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBonefeld-J\u0026oslash;rgensen (2014) and Ghisari\u003csup\u003ea\u003c/sup\u003e (2017)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDenmark\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1996\u0026ndash;2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:250; Controls:233\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA,\u003c/p\u003e\u003cp\u003ePFSA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage at blood sampling, BMI before pregnancy, gravidity, OC use, menarche age, smoking during pregnancy, alcohol intake, maternal education, physical activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWiels\u0026oslash;e (2017)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDenmark\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2000\u0026ndash;2003; 2011\u0026ndash;2014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:77; Controls:84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA,\u003c/p\u003e\u003cp\u003ePFSA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage, BMI, cotinine levels, parity, breastfeeding\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHurley (2018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2006\u0026ndash;2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:902; Controls:858\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ebaseline age, race/ethnicity, residential region, blood draw date, blood draw date 2, season of blood draw, cumulative smoking pack-years, BMI, family history of breast cancer, age at first full-term birth, menopausal status at blood draw, pork consumption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTsai (2020)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2014\u0026ndash;2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:120; Controls:119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlasma\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage, gravidity, OC use, miscarriage, BMI, menopause, education\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e(continued)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst author (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCancer type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo. of \u003c/p\u003e\u003cp\u003esubjects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExposure assessment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExposure time\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eConfounding Variables Adjusted\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eQuality\u003c/p\u003e\u003cp\u003escore\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMancini (2019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFrance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1994\u0026ndash;2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:194; Controls:194\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003etotal blood lipids, BMI, smoking status, physical activity, education, personal history of benign breast disease, family history of breast cancer, parity, age at first full-term pregnancy, breastfeeding duration, menarche age, menopause age, OC use, current MHT use, western diet score, mediterranean diet score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eItoh (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2001\u0026ndash;2005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:401; Controls:401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA,\u003c/p\u003e\u003cp\u003ePFSA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage, residential area, BMI, height, age at first childbirth, family history of breast cancer, smoking status, strenuous physical activity, moderate physical activity, menarche age, number of births, breastfeeding duration, alcohol intake, isoflavone intake, education\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFeng (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2008\u0026ndash;2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:226; Subcohort:990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlasma\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA,\u003c/p\u003e\u003cp\u003ePFSA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage, BMI, smoking, drinking, marital status, education, occupation type, batch to enter the cohort, parity, menopausal status, history of mastitis, HRT use, family history of cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e (continued)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst author (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCancer type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo. of \u003c/p\u003e\u003cp\u003esubjects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExposure assessment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExposure time\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eConfounding Variables Adjusted\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eQuality\u003c/p\u003e\u003cp\u003escore\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLi (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2012\u0026ndash;2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:373; Controls:657\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlasma\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ebaseline age, BMI, smoking history, menarche age, menopause age, parity, breastfeeding duration, use of estrogen or estrogen replacement therapy, family history of breast cancer, education, household per capita monthly income, red meat intake, pickled food intake, fried food intake, smoked and barbecued food intake\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVelarde (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhilippines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:75; Controls:75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage, residential area, employment status, monthly income\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChang (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1993\u0026ndash;2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:621; Controls:621\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage at blood draw, study center, race/ethnicity, education, menarche age, age at first live birth, number of live births, menopause age, duration of MHT use, first-degree family history of female breast cancer, personal history of benign breast disease, BMI, smoking status, strenuous physical activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e (continued)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst author (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCancer type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo. of \u003c/p\u003e\u003cp\u003esubjects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExposure assessment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExposure time\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eConfounding Variables Adjusted\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eQuality\u003c/p\u003e\u003cp\u003escore\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWinquist (2023)\u003c/p\u003e\u003cp\u003eand Shahi\u003csup\u003eb\u003c/sup\u003e (2025)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1998\u0026ndash;2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:780; Subcohort:497\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eyear of serum collection, age at serum collection, race, education, smoking status, drinking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRhee (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1993\u0026ndash;2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProstate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:750; Controls:750\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBMI, smoking status, family history of prostate cancer, history of diabetes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePurdue (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1988\u0026ndash;2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTesticular\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:530; Controls:530\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003emilitary rank, number of deployments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDou (2024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2014\u0026ndash;2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:120; Controls:119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003esmoking history, alcohol history, duration of long-term estrogen use, baseline menopausal status, history of benign breast disease, number of deliveries, history of miscarriage, menstrual regularity, dysmenorrhea, age at first live birth, TG, TC, year of blood draw\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTroeschel (2024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1998\u0026ndash;2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProstate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:1599; Controls:491\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eage, year of blood draw, education, drinking, smoking, race\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eXing (2025)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2015\u0026ndash;2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOvarian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:159; Controls:159\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlasma\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA,\u003c/p\u003e\u003cp\u003ePFSA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eeducation, parity, passive smoking status, physical activities, residual lesions, waist circumference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e (continued)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst author (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCancer type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo. of \u003c/p\u003e\u003cp\u003esubjects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExposure assessment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExposure time\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eConfounding Variables Adjusted\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003eQuality score\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eItoh (2025)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBrazil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase-control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2001\u0026ndash;2006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBreast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:471; Controls:471\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlasma\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAfter diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e\u003cp\u003eBMI, height, menopausal status and age, menarche age, age at first childbirth, smoking status, strenuous and moderate physical activity (past 5 years), family history of breast cancer, breastfeeding duration, number of births, alcohol intake, education, calendar year of blood sampling, isoflavone intake, fish/shellfish intake\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJones (2025)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNested-case control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1993\u0026ndash;2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOvarian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCases:318; Controls:472\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum\u003c/p\u003e\u003cp\u003e(PFOA, PFOS, PFHxS, PFNA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBefore diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e\u003cp\u003esmoking status, BMI, family history of breast and/or ovarian cancer, MHT use, parity, OC use, number of freeze-thaw cycles\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003ePFOA, perfluorooctanoate; PFOS, perfluorooctane sulfonate; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoate; PFSA, perfluorinated sulfonic acids; BMI, body mass index; OC, oral contraceptive; MHT, menopausal hormone therapy; HRT, hormone replacement therapy; TG, triglycerides; TC, total cholesterol.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eThe sample size in Ghisari et al. changed to case\u0026thinsp;=\u0026thinsp;178, control\u0026thinsp;=\u0026thinsp;233.\u003c/p\u003e\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eThe sample size in Shahi et al. changed to case\u0026thinsp;=\u0026thinsp;781, control\u0026thinsp;=\u0026thinsp;498.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.2. The association between PFAS and female reproductive system cancers\u003c/h2\u003e\u003cp\u003eAccording to the pooled analysis of 21 studies, the results revealed no significant association between the five types of PFAS and female reproductive system cancers (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Specifically, compared to the lowest dose groups, the pooled aOR of highest dose groups of PFOA was 1.09 (95% CI 0.83\u0026ndash;1.43; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 72.8%; 16 studies; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea), and that for PFOS was 1.11 (95% CI 0.82\u0026ndash;1.48; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 75.6%; 16 studies; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb), for PFHxS was 0.96 (95% CI 0.68\u0026ndash;1.36; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 80.4%, 14 studies; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ec), for PFNA was 1.11 (95% CI 0.79\u0026ndash;1.56; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 77.5%; 14 studies; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ed), for PFSA was 1.14 (95% CI 0.46\u0026ndash;2.80; \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 88.1%; 5 studies; Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Similarly, the pooled adjusted aORs of PFOA per ln-unit increase for female reproductive system cancers was 1.02 (95% CI 0.87\u0026ndash;1.19; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 76.7%; 16 studies; Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003ea), and that for PFOS was 1.02 (95% CI 0.93\u0026ndash;1.13; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 69.9%, 16 studies; Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003eb), for PFHxS was 1.00 (95% CI 0.87\u0026ndash;1.14; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 81.6%, 14 studies; Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003ec), for PFNA was 0.99 (95% CI 0.86\u0026ndash;1.15; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 80.4%, 14 studies; Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003ed), for PFSA was 1.01 (95% CI 0.99\u0026ndash;1.03; \u003cem\u003eI\u003c/em\u003e\u0026sup2; = 70.8% 5 studies; Figure S3).\u003c/p\u003e\u003cp\u003eThe subgroup analysis revealed that the combined results from studies using prediagnosis and postdiagnosis blood samples were not significant difference (all P value of subgroup interaction test\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e), which were consistent with the overall pooled results. Similar findings were observed for each ln-unit increase (Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e). When using menopausal status for stratification, the combined results from studies involving premenopausal and postmenopausal women were also similar (Figure S4).\u003c/p\u003e\u003cp\u003eAccording to meta-regression analyses for, none of the included study characteristics had significant influence on heterogeneity of association between individual chemicals (PFOA, PFOS, PFHxS and PFNA) and female reproductive system cancers (Supplementary Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3. The association between PFAS and male reproductive system cancers\u003c/h2\u003e\u003cp\u003eCompared to the lowest dose groups, the pooled aOR of highest dose groups of PFOS was 1.25 (95% CI 1.02\u0026ndash;1.52; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 3.0%; 4 studies; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003ea), which indicated a marginally increased risk for male reproductive cancers. However, no significant association was observed for PFOA with pooled aOR of 0.87 (95% CI 0.65\u0026ndash;1.17; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 52.9%; 4 studies; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). Similarly, the pooled results of per ln-unit increase indicated a potential association for PFOS with aOR of 1.00 (95% CI 1.00-1.01; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 0.0%; 3 studies; Figure S5a), but not for PFOA (aOR\u0026thinsp;=\u0026thinsp;0.98, 95% CI 0.91\u0026ndash;1.06; \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 52.0%, 3 studies; Figure S5b).\u003c/p\u003e\u003cp\u003eIn subgroup analyses, according to tumor stage and Gleason score, no significant association was observed between PFOS or PFOA and prostate cancer (Figure S6).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.4. Sensitivity analysis\u003c/h2\u003e\u003cp\u003eFor female reproductive system cancers, the results of two sensitivity analyses (i.e., excluding studies with a NOS score below 7, and excluding studies that collected blood samples after diagnosis) were consistent with primary pooled analyses for both per natural log-unit increase and highest versus lowest categories of serum/plasma PFAS concentration categories (Supplementary Table\u0026nbsp;4). Heterogeneity was generally reduced, and a significant association was observed for PFNA in the per ln-unit increase model (aOR\u0026thinsp;=\u0026thinsp;1.39, 95% CI: 1.07\u0026ndash;1.79). Additionally, excluding individual studies one at a time further supported the robustness of the primary analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.5. Publication bias\u003c/h2\u003e\u003cp\u003eThe Egger test revealed no publication bias in the combined analysis of the associations between PFOA (\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;=\u0026thinsp;0.897), PFOS (\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;=\u0026thinsp;0.871), PFHxS (\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;=\u0026thinsp;0.902), PFNA (\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;=\u0026thinsp;0.888), and female reproductive system cancers. A funnel plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e5\u003c/span\u003e) was also generated to visualize the combined adjusted odds ratios for per natural log-unit increase in serum/plasma PFAS concentration categories for the four types of PFAS (PFOA, PFOS, PFHxS, and PFNA).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Principal findings\u003c/h2\u003e\u003cp\u003eTo the best of our knowledge, this is the first meta-analysis evaluating the association between PFAS exposure and the risk of reproductive system cancers. By including the most comprehensive study to date, our results indicated no significant association between five main types of PFAS and female reproductive system cancers, with aORs of 1.09 (95% CI 0.83\u0026ndash;1.43) for PFOA, 1.11 (95% CI 0.82\u0026ndash;1.48) for PFOS, 0.96 (95% CI 0.68\u0026ndash;1.36) for PFHxS, 1.11 (95% CI 0.79\u0026ndash;1.56) for PFNA and 1.14 (95% CI 0.46\u0026ndash;2.80) for PFSA. Notably, PFNA per ln-unit increase was significantly associated with female reproductive cancers in sensitivity analyses excluding studies with a NOS score below 7 and post-diagnosis blood samples (aOR: 1.39, 95% CI: 1.07\u0026ndash;1.79). However, for male reproductive system cancers, a marginally increased risk of PFOS was observed with aORs of 1.25 (95% CI 1.02\u0026ndash;1.52), but not for PFOA with adjusted OR of 0.87 (95% CI 0.65\u0026ndash;1.17).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Comparison with previous studies\u003c/h2\u003e\u003cp\u003eThe finding that PFAS exposure was not significant associated with breast cancer aligns with a previous meta-analysis conducted by Chang et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. By including 11 studies, Chang et al. observed a pooled adjusted RR of 0.95 (95% CI 0.77\u0026ndash;1.18) for PFOA, and 0.98 (95% CI 0.87\u0026ndash;1.11) for PFOS [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, these results were contrary to another previous meta-analysis conducted by Jiang et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. By including eight studies, Jiang et al. reported that PFOA and PFHxS were positively associated with an increased risk of breast cancer, with pooled ORs of 1.32 (95% CI 1.19\u0026ndash;1.46) and 1.79 (95% CI 1.51\u0026ndash;2.11), respectively. In contrast, PFNA showed a protective association with breast cancer risk, with a pooled OR of 0.76 (95% CI 0.60\u0026ndash;0.96). The observed discrepancies in previous meta-analyses primarily stem from methodological differences in study selection and analytical approaches. In the study conducted by Jiang et al., the synthesis aggregated multiple association measures from the same study and combined distinct exposure levels, allowing individual studies to contribute multiple data points to pooled estimates [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This methodological flaw compromises the validity of the findings. For ovarian cancer, Seyyedsalehi et al. reported a relative risk (RR) of 1.07 (95% CI: 1.04\u0026ndash;1.09; n\u0026thinsp;=\u0026thinsp;12) for the association with PFAS [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Following a methodology similar to that of Jiang et al. the study combined the values of individual chemicals (e.g., PFOA, PFOS, PFHxS, and PFNA) and chemical mixtures (e.g., PFAS) in the analysis, without evaluating them separately. In this study, we analyzed breast and ovarian cancers collectively as female reproductive system cancers, including only studies that assessed PFAS directly in plasma or serum, while systematically excluding cross-sectional studies susceptible to reverse causality. Several subgroup and sensitivity analyses demonstrated the robustness of the findings that PFAS exposure was not significantly associated with an increased risk of female reproductive system cancers.\u003c/p\u003e\u003cp\u003eCompared to female reproductive system cancers, only a few studies have examined the impact of PFAS exposure on male reproductive system cancers [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. For prostate cancer, the findings remain inconclusive. Previous studies by Rhee et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and Eriksen et al. [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] reported no significant association between PFAS exposure and prostate cancer risk, with OR of 0.90 (95% CI 0.79\u0026ndash;1.03) for PFOA and incidence rate ratios (IRR) of 0.90 (95% CI 0.79\u0026ndash;1.03) for PFOS. However, Troeschel et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] found a positive correlation between PFAS exposure and prostate cancer risk in men aged\u0026thinsp;\u0026ge;\u0026thinsp;70 years. Specifically, higher serum concentrations of PFOS and PFHxS were associated with an increased risk of prostate cancer, with HR of 1.62 (95% CI 1.08\u0026ndash;2.44) for PFOS and 1.54 (95% CI 1.02\u0026ndash;2.31) for PFHxS, when comparing the highest and lowest exposure groups [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. For testicular cancer, elevated PFOS concentrations were positively associated with increased risk, with an OR of 1.62 (95% CI 1.1\u0026ndash;6.4) when comparing the highest to the lowest exposure groups [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Combining these studies revealed a potential association for PFOS, with an OR of 1.25 (95% CI 1.02\u0026ndash;1.52), while the aOR for PFOA was 0.87 (95% CI 0.65\u0026ndash;1.17).\u003c/p\u003e\u003cp\u003eAlthough the association between PFAS and breast cancer remains controversial in epidemiological studies, several in vitro and animal studies have explored the potential mechanism [\u003cspan additionalcitationids=\"CR52 CR53\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. For instance, previous studies demonstrated that PFOA facilitates the transformation of normal human mammary epithelial cells into tumors by inducing cell migration and invasion. This process involves upregulating cyclin D1 and CDK4/6 levels, as well as downregulating the CDK inhibitor p27 through a non-estrogenic mechanism, which promotes the proliferation of MCF-10A cells [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Similarly, PFOS promotes the proliferation of MCF-10A cells by modulating key regulatory cyclins and accelerating the cell cycle [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Furthermore, PFAS, as a class of endocrine-disrupting chemicals (EDCs), may elevate estrogen levels or mimic its biological effects, potentially promoting the development of breast and ovarian cancers [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. While no studies to date have established a direct link between PFAS exposure and male reproductive system cancers, toxicological research has consistently demonstrated the adverse effects of PFAS on male germ cells [\u003cspan additionalcitationids=\"CR56 CR57 CR58 CR59\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. For example, PFOS has demonstrated male reproductive toxicity in adult mice (characterized by reduced testicular weight and sperm count), adult rats (marked by degeneration of gonadal and spermatogenic cells, along with testicular edema), and zebrafish (with alterations in gonadal structure and a reduction in spermatogonia) [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn studies examining the association between PFAS and cancer, there are several common issues need to be noted. First, most studies were retrospective designs, which are susceptible to selection bias and make it difficult to establish the temporal relationship between exposure and cancer. Furthermore, many studies suffer from small sample sizes, limiting their statistical reliability and the generalizability of their findings. Even when meta-analyses are performed, the limited number of included articles and participants results in low statistical power [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Moreover, prior research may have failed to account for confounding factors, such as the hormonal receptor and menopausal status of study subjects, as cancer risk factors and biological mechanisms differ based on these variables [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Finally, significant concerns have been raised about the limitations of exposure assessment [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], particularly the variation in how exposure is defined across studies. Some studies use environmental substance concentrations as proxies for individual exposure, while others employ different measurement methods, including modeled serum PFAS levels, PFAS concentrations in residential water, and direct blood measurements. Variations in measurement methods and sample sources may affect the accuracy of exposure assessments, thereby influencing study outcomes. In conclusion, further well-designed, adequately powered prospective studies are needed to better explore the relationship between PFAS exposure and cancer risk.\u003c/p\u003e\u003cp\u003eWhile substantial epidemiological evidence associates PFAS with increased cancer risk, their carcinogenic mechanisms remain mechanistically uncharacterized. As recognized endocrine disruptors, PFAS impair hormonal homeostasis by disrupting hypothalamic-pituitary-gonadal (HPG) axis signaling, as demonstrated in both in vitro and in vivo studies [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Recent experimental studies have identified specific molecular targets of PFAS: these compounds modulate the transcriptional activity of sex steroid receptors (e.g., estrogen receptor and androgen receptor), thereby perturbing feedback regulation in reproductive hormone synthesis [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. Critically, mechanistic research on sex-specific toxicities of PFAS remains limited, and further fundamental biomedical research is required to elucidate how biological sex influences molecular responses to PFAS exposure.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Strengths and limitations\u003c/h2\u003e\u003cp\u003eOur study is distinguished by three key strengths. First, we conducted a systematic literature search and comprehensively examined the association between five major PFAS and reproductive system cancers. The included studies measured PFAS directly in plasma or serum, providing more accurate exposure assessment, minimizing measurement bias, and thereby enhancing the validity and reliability of the pooled results. Second, our study is the first to evaluate the relationship between PFAS and the male reproductive system. Third, we employed multiple subgroup and sensitivity analyses to further validate the robustness of the results.\u003c/p\u003e\u003cp\u003eOur study has several limitations. First, although aORs were combined, the inclusion of confounding factors in the original studies was not exhaustive (e.g., the lack of socioeconomic factors), and therefore, our combined results should be interpreted with caution. For instance, the higher incidence of prostate cancer among Black men compared to White men is largely attributed to socioeconomic and environmental disparities [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Additionally, individuals with lower socioeconomic status are at greater risk of PFAS exposure, often due to living near pollution sources or working with PFAS-containing materials [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Therefore, future studies should prioritize identifying and controlling these confounding factors to more accurately assess the health effects of PFAS exposure. Second, the limited number of studies on male reproductive system cancers included in the analysis prevented further sensitivity and publication bias analyses. Consequently, there is an urgent need for large-scale, multicenter prospective cohort studies to systematically examine the mechanisms underlying the association between PFAS exposure and male reproductive cancers, thereby establishing a robust causal association. Lastly, some combined OR values exhibited significant heterogeneity. Although subgroup analyses were conducted, the sources of this heterogeneity remain unexplained. These limitations may affect the reliability and accuracy of the study findings.\u003c/p\u003e\u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eExisting epidemiological studies provide no evidence to support an association between PFAS exposure and an increased risk of female reproductive system (breast and ovarian cancer). Notably, sensitivity analyses identified a significant positive association for PFNA. However, PFOS (a specific PFAS compound) demonstrated a marginally increased risk for combined male reproductive cancers (testicular and prostate). Given the limited number of studies included, these findings should be interpreted cautiously. There is a pressing need for more studies, especially high-quality prospective cohort studies, to further clarify the association between PFAS exposure and reproductive system cancers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, Data Curation, Writing-Original Draft Preparation: Liu Xin; Formal Analysis, Validation: Zhihong Lv, Zixiang Huang; Software: Rui Sun; Investigation, Data Analysis and Interpretation: Dingyu Zhu, Pengcheng Xu; Project Administration, Supervision: Yiquan Xiong, Junhua Zhou; Funding Acquisition: Xiaowei Guo. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUse of Large Language Models, AI and Machine Learning Tools\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll other authors state no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the following funding including Hunan Provincial Degree and Postgraduate Education Reform Research Project (2024JGYB101), Hunan Provincial Social Science Foundation Project (XSP25YBZ146), Changsha Natural Science Foundation Project (KQ2502189), Natural Science Foundation Project of Hunan Province (2023JJ20029), Hunan Provincial Technological Innovation Foundation of China (2023RC3132).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the data supporting the findings of this study are available within the article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSchymanski EL, Zhang J, Thiessen PA, Chirsir P, Kondic T, Bolton EE. Per- and Polyfluoroalkyl Substances (PFAS) in PubChem: 7 Million and Growing. Environmental science \u0026amp; technology. 2023;57(44):16918-28.\u003c/li\u003e\n\u003cli\u003eWang Z, Buser AM, Cousins IT, Demattio S, Drost W, Johansson O, et al. A New OECD Definition for Per- and Polyfluoroalkyl Substances. Environmental science \u0026amp; technology. 2021;55(23):15575-8.\u003c/li\u003e\n\u003cli\u003eLindstrom AB, Strynar MJ, Libelo EL. Polyfluorinated Compounds: Past, Present, and Future. Environmental science \u0026amp; technology. 2011;45(19):7954-61.\u003c/li\u003e\n\u003cli\u003eCousins IT, DeWitt JC, Gl\u0026uuml;ge J, Goldenman G, Herzke D, Lohmann R, et al. The high persistence of PFAS is sufficient for their management as a chemical class. ENVIRONMENTAL SCIENCE-PROCESSES \u0026amp; IMPACTS. 2020;22(12):2307-12.\u003c/li\u003e\n\u003cli\u003eWang Z, DeWitt JC, Higgins CP, Cousins IT. A Never-Ending Story of Per- and Polyfluoroalkyl Substances (PFASs)? Environmental science \u0026amp; technology. 2017;51(5):2508-18.\u003c/li\u003e\n\u003cli\u003eXu Y, Fletcher T, Pineda D, Lindh CH, Nilsson C, Glynn A, et al. Serum Half-Lives for Short- and Long-Chain Perfluoroalkyl Acids after Ceasing Exposure from Drinking Water Contaminated by Firefighting Foam. Environmental health perspectives. 2020;128(7).\u003c/li\u003e\n\u003cli\u003eHoude M, Martin JW, Letcher RJ, Solomon KR, Muir DCG. Biological Monitoring of Polyfluoroalkyl Substances:\u0026thinsp; A Review. Environmental science \u0026amp; technology. 2006;40(11):3463-73.\u003c/li\u003e\n\u003cli\u003eJ\u0026oslash;rgensen KT, Specht IO, Lenters V, Bach CC, Rylander L, J\u0026ouml;nsson BAG, et al. Perfluoroalkyl substances and time to pregnancy in couples from Greenland, Poland and Ukraine. Environmental Health. 2014;13(1):116.\u003c/li\u003e\n\u003cli\u003ePapadopoulou E, Haug Line S, Sakhi Amrit K, Andrusaityte S, Basaga\u0026ntilde;a X, Brantsaeter Anne L, et al. Diet as a Source of Exposure to Environmental Contaminants for Pregnant Women and Children from Six European Countries. Environmental health perspectives. 2019;127(10):107005.\u003c/li\u003e\n\u003cli\u003eSunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG. A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. Journal of exposure science \u0026amp; environmental epidemiology. 2019;29(2):131-47.\u003c/li\u003e\n\u003cli\u003eCalafat Antonia M, Wong L-Y, Kuklenyik Z, Reidy John A, Needham Larry L. Polyfluoroalkyl Chemicals in the U.S. Population: Data from the National Health and Nutrition Examination Survey (NHANES) 2003\u0026ndash;2004 and Comparisons with NHANES 1999\u0026ndash;2000. Environmental health perspectives. 2007;115(11):1596-602.\u003c/li\u003e\n\u003cli\u003eJane LEL, Yamada M, Ford J, Owens G, Prow T, Juhasz A. Health-related toxicity of emerging per- and polyfluoroalkyl substances: Comparison to legacy PFOS and PFOA. Environmental research. 2022;212(Pt C):113431.\u003c/li\u003e\n\u003cli\u003eFenton SE, Ducatman A, Boobis A, DeWitt JC, Lau C, Ng C, et al. Per- and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research. Environmental toxicology and chemistry. 2021;40(3):606-30.\u003c/li\u003e\n\u003cli\u003eSchrenk D, Bignami M, Bodin L, Chipman JK, del Mazo J, Grasl-Kraupp B, et al. Risk to human health related to the presence of perfluoroalkyl substances in food. EFSA JOURNAL. 2020;18(9).\u003c/li\u003e\n\u003cli\u003eSteenland K, Winquist A. PFAS and cancer, a scoping review of the epidemiologic evidence. Environmental research. 2021;194:110690.\u003c/li\u003e\n\u003cli\u003eChang CJ, Ish JL, Chang VC, Daniel M, Jones RR, White AJ. Exposure to per- and polyfluoroalkyl substances and breast cancer risk: a systematic review and meta-analysis of epidemiologic studies. American journal of epidemiology. 2024;193(8):1182-96.\u003c/li\u003e\n\u003cli\u003eJiang HH, Liu H, Liu G, Yu J, Liu NN, Jin YQ, et al. Associations between Polyfluoroalkyl Substances Exposure and Breast Cancer: A Meta-Analysis. Toxics. 2022;10(6).\u003c/li\u003e\n\u003cli\u003evan Gerwen M, Chung T, Monaghan M, Vermeulen R, Petrick L, Leung AM. Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer: Systematic review and meta-analysis. Toxicology letters. 2024;399:52-8.\u003c/li\u003e\n\u003cli\u003eYang J, Zhang K, Shi J, Li Z, Dai H, Yang W. Perfluoroalkyl and polyfluoroalkyl substances and Cancer risk: results from a dose-response Meta-analysis. Journal of environmental health science \u0026amp; engineering. 2024;22(2):455-69.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. REVISTA PANAMERICANA DE SALUD PUBLICA-PAN AMERICAN JOURNAL OF PUBLIC HEALTH. 2022;46.\u003c/li\u003e\n\u003cli\u003eKato K, Kalathil AA, Patel AM, Ye X, Calafat AM. Per- and polyfluoroalkyl substances and fluorinated alternatives in urine and serum by on-line solid phase extraction\u0026ndash;liquid chromatography\u0026ndash;tandem mass spectrometry. Chemosphere. 2018;209:338-45.\u003c/li\u003e\n\u003cli\u003eOrganization WH. International Statistical Classification of Diseases and Related Health Problems: 10th revision, version for 2007-ICD-10. 2009.\u003c/li\u003e\n\u003cli\u003eStang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010;25(9):603-5.\u003c/li\u003e\n\u003cli\u003eHiggins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed). 2003;327(7414):557-60.\u003c/li\u003e\n\u003cli\u003eHiggins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in medicine. 2002;21(11):1539-58.\u003c/li\u003e\n\u003cli\u003eAli AT, Al-Ani O, Al-Ani F. Epidemiology and risk factors for ovarian cancer. Przeglad menopauzalny = Menopause review. 2023;22(2):93-104.\u003c/li\u003e\n\u003cli\u003eSingletary SE. Rating the risk factors for breast cancer. Annals of surgery. 2003;237(4):474-82.\u003c/li\u003e\n\u003cli\u003eTroeschel AN, Teras LR, Hodge JM, Rodriguez J, Wang Y, Daniel J, et al. A case-cohort study of per- and polyfluoroalkyl substance concentrations and incident prostate cancer in the cancer prevention Study-II LifeLink cohort study. Environmental research. 2024;259:119560.\u003c/li\u003e\n\u003cli\u003eEgger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed). 1997;315(7109):629.\u003c/li\u003e\n\u003cli\u003eBonefeld-J\u0026oslash;rgensen EC, Long M, Fredslund SO, Bossi R, Olsen J. Breast cancer risk after exposure to perfluorinated compounds in Danish women: a case\u0026ndash;control study nested in the Danish National Birth Cohort. Cancer Causes and Control. 2014;25(11):1439-48.\u003c/li\u003e\n\u003cli\u003eChang VC, Rhee J, Berndt SI, Moore SC, Freedman ND, Jones RR, et al. Serum perfluorooctane sulfonate and perfluorooctanoate and risk of postmenopausal breast cancer according to hormone receptor status: An analysis in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. International journal of cancer. 2023;153(4):775-82.\u003c/li\u003e\n\u003cli\u003eDou Q, Bai YA, Li YJ, Zheng S, Wang MZ, Wang ZG, et al. Perfluoroalkyl substances exposure and the risk of breast cancer: A nested case-control study in Jinchang Cohort. Environmental research. 2024;262.\u003c/li\u003e\n\u003cli\u003eGhisari M, Long M, R\u0026oslash;ge DM, Olsen J, Bonefeld-J\u0026oslash;rgensen EC. Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort. Environmental research. 2017;154:325-33.\u003c/li\u003e\n\u003cli\u003eHurley S, Goldberg D, Wang MM, Park JS, Petreas M, Bernstein L, et al. Breast cancer risk and serum levels of per- and poly-fluoroalkyl substances: a case-control study nested in the California Teachers Study. Environmental Health. 2018;17.\u003c/li\u003e\n\u003cli\u003eJones RR, Madrigal JM, Medgyesi DN, Fisher JA, Calafat AM, Botelho JC, et al. Serum concentrations of per- and polyfluoroalkyl substances and risk of ovarian cancer. JNCI: Journal of the National Cancer Institute. 2025:djaf204.\u003c/li\u003e\n\u003cli\u003eMancini FR, Cano-Sancho G, Gambaretti J, Marchand P, Boutron-Ruault MC, Severi G, et al. Perfluorinated alkylated substances serum concentration and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort. International journal of cancer. 2020;146(4):917-28.\u003c/li\u003e\n\u003cli\u003ePurdue MP, Rhee J, Denic-Roberts H, McGlynn KA, Byrne C, Sampson J, et al. A Nested Case-Control Study of Serum Per- and Polyfluoroalkyl Substances and Testicular Germ Cell Tumors among US Air Force Servicemen. Environmental health perspectives. 2023;131(7).\u003c/li\u003e\n\u003cli\u003eRhee J, Barry KH, Huang WY, Sampson JN, Hofmann JN, Silverman DT, et al. A prospective nested case-control study of serum concentrations of per- and polyfluoroalkyl substances and aggressive prostate cancer risk. Environmental research. 2023;228:115718.\u003c/li\u003e\n\u003cli\u003eXing WY, Liu FH, Wang DD, Liu JM, Zheng WR, Liu JX, et al. Association between plasma perfluoroalkyl substances and high-grade serous ovarian cancer overall survival: A nested case-control study. Ecotoxicology and environmental safety. 2025;291:117825.\u003c/li\u003e\n\u003cli\u003eItoh H, Harada KH, Hamada GS, Lyu Z, Fujitani T, Harada Sassa M, et al. Plasma perfluoroalkyl substances and breast cancer risk in Brazilian women: a case-control study. Environmental health : a global access science source. 2025;24(1):13.\u003c/li\u003e\n\u003cli\u003eItoh H, Harada KH, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, et al. Serum perfluoroalkyl substances and breast cancer risk in Japanese women: A case-control study. Science of the Total Environment. 2021;800.\u003c/li\u003e\n\u003cli\u003eLi XJ, Song FJ, Liu XT, Shan AQ, Huang YB, Yang ZJ, et al. Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population. Environmental Health. 2022;21(1).\u003c/li\u003e\n\u003cli\u003eTsai MS, Chang SH, Kuo WH, Kuo CH, Li SY, Wang MY, et al. A case-control study of perfluoroalkyl substances and the risk of breast cancer in Taiwanese women. Environment international. 2020;142:105850.\u003c/li\u003e\n\u003cli\u003eVelarde MC, Chan AFO, Sajo M, Zakharevich I, Melamed J, Uy GLB, et al. Elevated levels of perfluoroalkyl substances in breast cancer patients within the Greater Manila Area. Chemosphere. 2022;286.\u003c/li\u003e\n\u003cli\u003eWielsoe M, Kern P, Bonefeld-Jorgensen EC. Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study. Environmental Health. 2017;16.\u003c/li\u003e\n\u003cli\u003eEriksen KT, Sorensen M, McLaughlin JK, Lipworth L, Tjonneland A, Overvad K, et al. Perfluorooctanoate and Perfluorooctanesulfonate Plasma Levels and Risk of Cancer in the General Danish Population. Jnci-Journal of the National Cancer Institute. 2009;101(8):605-9.\u003c/li\u003e\n\u003cli\u003eFeng Y, Bai YS, Lu YJ, Chen MS, Fu M, Guan X, et al. Plasma perfluoroalkyl substance exposure and incidence risk of breast cancer: A case-cohort study in the Dongfeng-Tongji cohort. Environmental Pollution. 2022;306.\u003c/li\u003e\n\u003cli\u003eShahi S, Winquist A, Troeschel AN, Diver WR, Hodge JM, Deubler E, et al. A case-cohort study of the association between per- and polyfluoroalkyl substances (PFAS) and breast cancer among participants in the American Cancer Society\u0026rsquo;s Cancer Prevention Study-II. Environmental research. 2025;285:122381.\u003c/li\u003e\n\u003cli\u003eWinquist A, Hodge JM, Diver WR, Rodriguez JL, Troeschel AN, Daniel J, et al. Case-Cohort Study of the Association between PFAS and Selected Cancers among Participants in the American Cancer Society\u0026apos;s Cancer Prevention Study II LifeLink Cohort. Environmental health perspectives. 2023;131(12):127007.\u003c/li\u003e\n\u003cli\u003eSeyyedsalehi MS, Maria Kappil E, Zhang S, Zheng T, Boffetta P. Per- And Poly-Fluoroalkyl Substances (PFAS) Exposure and Risk of Breast, and Female Genital Cancers: A Systematic Review and Meta-Analysis: PFAS Exposure and Risk of Breast and Female Genital Cancers. La Medicina del lavoro. 2024;115(6):e2024043.\u003c/li\u003e\n\u003cli\u003eChandran K, Goswami S, Sharma-Walia N. Implications of a peroxisome proliferator-activated receptor alpha (PPAR\u0026alpha;) ligand clofibrate in breast cancer. Oncotarget. 2016;7(13):15577-99.\u003c/li\u003e\n\u003cli\u003ePierozan P, Jerneren F, Karlsson O. Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells. Archives of toxicology. 2018;92(5):1729-39.\u003c/li\u003e\n\u003cli\u003ePierozan P, Karlsson O. PFOS induces proliferation, cell-cycle progression, and malignant phenotype in human breast epithelial cells. Archives of toxicology. 2018;92(2):705-16.\u003c/li\u003e\n\u003cli\u003eRoberts-Thomson SJ, Snyderwine EG. Characterization of peroxisome proliferator-activated receptor alpha in normal rat mammary gland and 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine-induced mammary gland tumors from rats fed high and low fat diets. Toxicology letters. 2000;118(1):79-86.\u003c/li\u003e\n\u003cli\u003eChen J, Wang X, Ge X, Wang D, Wang T, Zhang L, et al. Chronic perfluorooctanesulphonic acid (PFOS) exposure produces estrogenic effects in zebrafish. Environmental Pollution. 2016;218:702-8.\u003c/li\u003e\n\u003cli\u003eHu W-Y, Lu R, Hu DP, Imir OB, Zuo Q, Moline D, et al. Per- and polyfluoroalkyl substances target and alter human prostate stem-progenitor cells. Biochemical pharmacology. 2022;197:114902.\u003c/li\u003e\n\u003cli\u003eLaw HD, Armstrong BK, D\u0026rsquo;este C, Hosking R, Smurthwaite KS, Trevenar S, et al. Relative rates of cancers and deaths in Australian communities with PFAS environmental contamination associated with firefighting foams: A cohort study using linked data. Cancer Epidemiology. 2023;82:102296.\u003c/li\u003e\n\u003cli\u003eLi H, Hammarstrand S, Midberg B, Xu Y, Li Y, Olsson DS, et al. Cancer incidence in a Swedish cohort with high exposure to perfluoroalkyl substances in drinking water. Environmental research. 2022;204:112217.\u003c/li\u003e\n\u003cli\u003eL\u0026oacute;pez-Doval S, Salgado R, Pereiro N, Moyano R, Lafuente A. Perfluorooctane sulfonate effects on the reproductive axis in adult male rats. Environmental research. 2014;134:158-68.\u003c/li\u003e\n\u003cli\u003eQu J-H, Lu C-C, Xu C, Chen G, Qiu L-L, Jiang J-K, et al. Perfluorooctane sulfonate-induced testicular toxicity and differential testicular expression of estrogen receptor in male mice. Environmental toxicology and pharmacology. 2016;45:150-7.\u003c/li\u003e\n\u003cli\u003eKerlikowske K, Gard CC, Tice JA, Ziv E, Cummings SR, Miglioretti DL, et al. Risk Factors That Increase Risk of Estrogen Receptor\u0026ndash;Positive and \u0026ndash;Negative Breast Cancer. JNCI: Journal of the National Cancer Institute. 2017;109(5):djw276.\u003c/li\u003e\n\u003cli\u003eSt-Hilaire S, Mandal R, Commendador A, Mannel S, Derryberry D. Estrogen receptor positive breast cancers and their association with environmental factors. International Journal of Health Geographics. 2011;10(1):32.\u003c/li\u003e\n\u003cli\u003eDing N, Harlow SD, Randolph Jr JF, Loch-Caruso R, Park SK. Perfluoroalkyl and polyfluoroalkyl substances (PFAS) and their effects on the ovary. Human Reproduction Update. 2020;26(5):724-52.\u003c/li\u003e\n\u003cli\u003eTachachartvanich P, Singam ERA, Durkin KA, Furlow JD, Smith MT, La Merrill MA. In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor. Journal of hazardous materials. 2022;429:128243.\u003c/li\u003e\n\u003cli\u003eVilleneuve DL, Blackwell BR, Cavallin JE, Collins J, Hoang JX, Hofer RN, et al. Verification of In Vivo Estrogenic Activity for Four Per- and Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists via New Approach Methodologies. Environmental science \u0026amp; technology. 2023;57(9):3794-803.\u003c/li\u003e\n\u003cli\u003ePernar CH, Ebot EM, Wilson KM, Mucci LA. The Epidemiology of Prostate Cancer. Cold Spring Harbor perspectives in medicine. 2018;8(12).\u003c/li\u003e\n\u003cli\u003eSmalling Kelly L, Bradley Paul M. Invited Perspective: Per- and Polyfluoroalkyl Substances in Drinking Water\u0026mdash;Disparities in Community Exposures Based on Race and Socioeconomic Status. Environmental health perspectives. 2024;132(4):041302.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-environmental-health-science-and-engineering","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jehs","sideBox":"Learn more about [Journal of Environmental Health Science and Engineering](https://www.springer.com/journal/40201)","snPcode":"40201","submissionUrl":"https://www.editorialmanager.com/jehs/","title":"Journal of Environmental Health Science and Engineering","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Per- and polyfluoroalkyl substances, PFAS, PFOS, Reproductive system cancers, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-7521500/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7521500/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePer- and polyfluoroalkyl substances (PFAS), a class of highly stable synthetic organic compounds, have been detected ubiquitously in human biological samples, raising significant concerns about their safety. The aim of this study was to investigate whether PFAS exposure is associated with higher risk of reproductive cancers.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThree databases were searched from inception to August 2025. Case-control or cohort studies that examined the association between serum/plasma exposure to five PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA] and perfluorinated sulfonic acids [PFSA]) and reproductive system cancers, including female reproductive system (breast and ovarian cancers) and male reproductive system (prostate and testicular cancers), were included.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e21 case-control studies were included. Pooled adjusted odds ratios (aORs) showed no significant association between PFAS exposure and female reproductive cancers. When comparing highest to lowest exposure, pooled aORs were 1.09 (95% CI: 0.83\u0026ndash;1.43) for PFOA, 1.11 (0.82\u0026ndash;1.48) for PFOS, 0.96 (0.68\u0026ndash;1.36) for PFHxS, 1.11 (0.79\u0026ndash;1.56) for PFNA, and 1.14 (0.46\u0026ndash;2.80) for PFSA. PFOS showed a marginal positive association with male reproductive cancers (1.25, 1.02\u0026ndash;1.52), whereas PFOA showed no association (0.87, 0.65\u0026ndash;1.17). Notably, PFNA per ln-unit increase was significantly associated with female reproductive cancers (1.39, 1.07\u0026ndash;1.79) in sensitivity analyses.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eOverall, serum PFAS exposure was not significantly associated with female reproductive cancers, though PFNA showed a positive association in sensitivity analysis. PFOS may be associated with increased risk for male reproductive cancers.\u003c/p\u003e","manuscriptTitle":"Exposure to Per- and Polyfluoroalkyl Substances and Risk of Reproductive System Cancers: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:47:03","doi":"10.21203/rs.3.rs-7521500/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-09-18T05:09:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-13T05:53:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-05T01:46:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Environmental Health Science and Engineering","date":"2025-09-03T21:04:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-environmental-health-science-and-engineering","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jehs","sideBox":"Learn more about [Journal of Environmental Health Science and Engineering](https://www.springer.com/journal/40201)","snPcode":"40201","submissionUrl":"https://www.editorialmanager.com/jehs/","title":"Journal of Environmental Health Science and Engineering","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"51441e87-5bad-4b0e-b18d-58dd497e6f49","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-03T09:26:36+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 02:47:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7521500","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7521500","identity":"rs-7521500","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}