The impact of phthalate on reproductive function in women with endometriosis

Chou YC, Ya-Ching Chou, Ya‐Ching Chou, Chii‐Ruey Tzeng
Reproductive medicine and biology · 2021 · vol. 20(2) , pp. 159–168 · doi:10.1002/rmb2.12364 · PMID:33850448 · PMC8022091 · W3118820041
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This review of literature indicates phthalate exposure negatively impacts granulosa cells, leading to inflammation, oxidative stress, and altered cell function, which may contribute to endometriosis pathogenesis and ovarian dysfunction.

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This retrospective review evaluates whether phthalate exposure is associated with endometriosis risk and whether it affects granulosa cell function, by searching PubMed for keywords including phthalate/endometriosis and phthalate effects on endometrial or granulosa cells. Across epidemiological studies and meta-analyses, the paper reports generally higher phthalate metabolite levels in women with endometriosis (e.g., DEHP and several urinary/plasma metabolites), with one meta-analysis finding significant risk for DEHP (OR 1.42, 95% CI 1.19–1.7) while other metabolites show mixed associations, which the authors attribute to issues such as lack of covariate adjustment or small sample sizes. Mechanistic findings summarized include phthalate effects on endometrial cells via MAPK/ERK and NF-κB pathways and evidence that granulosa cells in endometriosis exhibit steroidogenesis disruption, oxidative/ER stress, cytokine changes, altered cell cycle and apoptosis/senescence/autophagy markers, though the review’s main limitation is that it is a literature synthesis rather than new experimental or prospective exposure data. This paper is centrally about endometriosis—specifically phthalate exposure and its reported effects on granulosa and endometrial cells relevant to disease risk and ovarian dysfunction.

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Abstract

BACKGROUND: Endometriosis is a common gynecological condition in which stromal or glandular epithelium is implanted in extrauterine locations. Endometriosis causes detrimental effects on the granulosa cells, and phthalate interferes with the biological and reproductive function of endometrial cells at a molecular level. METHODS: This article retrospectively reviewed the studies on phthalate exposure and its relationship with endometriosis. A literature search was performed for scientific articles using the keywords "phthalate and endometriosis," "endometriosis and granulosa cells," "phthalate and granulosa cells," and "phthalates and endometrial cells." RESULTS: Endometriosis can affect cytokine production, steroidogenesis, cell cycle progression, expression of estrogen receptor-α (ER-α)/progesterone receptor (PR), and cause endoplasmic reticulum stress, senescence, apoptosis, autophagy, and oxidative stress in the granulosa cells. Mono-n-butyl phthalate (MnBP) alters the expression of cytokines, cell cycle-associated genes, ovarian stimulation, steroidogenesis, and progesterone production. Several in vitro studies have demonstrated that phthalate caused inflammation, invasion, change in cytokines, increased oxidative stress, viability, resistance to hydrogen peroxide, and proliferation of endometrial cells. CONCLUSION: This might provide new insights about the impact of phthalate on the pathogenesis of endometriosis and its consequences on the ovarian function.
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Effects

The first report of the effects of phthalate on endometrial cells showed that DEHP and MEHP stimulated the secretion of prostaglandin F2‐α (PGF2‐α) and inhibited the secretion of prostaglandin E2 (PGE2). 103 Kim et al. 104 also found that DEHP results in increased viability of the endometrial stromal cells in the serum‐free condition with exposure to hydrogen peroxide. Another study demonstrated that DEHP induced the expression of IL‐1β, IL‐8, matrix metalloproteinase‐2 (MMP2), intercellular cell adhesion molecule‐1 (ICAM‐1), cyclooxygenase‐2 (COX2), and PPARγ to stimulate the inflammatory response, and it might be mediated by PPARγ. 105 The effects of DEHP on human endometrial cells include increased ROS generation and decreased expression of superoxide dismutase (SOD), glutathione peroxidase (GPX), heme oxygenase (HO), and catalase (CAT), phosphorylated‐Erk/ phosphorylated‐p38 and NF‐κB‐mediated transcription, and estrogen receptor‐α (ER‐α) expression. 106 In DEHP‐treated mice, the volume of peritoneal endometriotic lesion increased, with higher expression of MMP‐2, MMP‐9, and p21‐activated kinase‐4 (Pak‐4). Increased cell invasion and phosphorylation of Erk were observed in DEHP‐treated endometrial cells. 41 Human endometrial cells from the eutopic endometrium of endometriosis showed upregulation of aldo‐keto reductase (AKR) 1C1, AKR1C2, AKR1C3, and AKR1B10 after DEHP exposure, while AKR1C3 continuously increased in the endometrial cells of the ectopic endometrium in patients of endometriosis both before and after DEHP exposure. 107 Under conditions of hypoxia, DEHP decreased the ER‐α protein and VEGF secretion in Ishikawa endometrial adenocarcinoma cells. 108 In chronic, low‐dose DEHP feeding mice, the endometrial stromal cells were significantly increased and changed the localization of steroid hormone receptors. 109 These studies are illustrated in Figure  3 . The effect of phthalates on endometrial cells. After phthalate stimulation, the endometrial cells showed inflammation, invasion, change of cytokines, increased oxidative stress, cell viability, resistance to hydrogen peroxide, and proliferation. The inflammatory effects stimulated the secretion of PGF2‐α, Pak‐4, PPARγ, ICAM‐1, COX2, cytokine (IL‐1β and IL‐8), and inhibited the secretion of PGE2. Phthalate also increased ROS generation and decreased the expression of SOD, GPX, HO, and CAT. In DEHP‐treated mice, the endometrial cell might show increased migration through MMP‐2 and MMP‐9. Increased ER‐α/PR activated p‐ERK/p‐p38 and NF‐κB. Exposure to phthalate induced endometrial cell viability, resistance to hydrogen peroxide and proliferation. PGF2‐α, prostaglandin F2‐α; IL‐1β, interleukin‐1β; IL‐8, interleukin‐8; Pak‐4, p21‐acticvated kinase‐4; PPARγ, peroxisome proliferator‐activated receptor‐γ; ICAM‐1, intercellular cell adhesion molecule‐1; COX2, cyclooxygenase‐2; prostaglandin E2, PGE2. ROS, reactive oxygen species; SOD, superoxide dismutase, GPX, glutathione peroxidase; HO, heme oxygenase; CAT, catalase; MMP2, matrix metalloproteinase‐2; MMP9, matrix metalloproteinase‐9; ER‐α, estrogen receptor‐α; PR, progesterone receptor; NF‐κB, nuclear factor‐κB. This figure was created with BioRender.com From these studies, it is evident that phthalate exposure might affect gene regulation, invasion, cell viability, and proliferation of endometrial cells to influence the development of endometriosis.

Granulosa

Endometriosis might affect the granulosa cell steroidogenesis, change the cell cycle progression, cytokine expression (interleukin‐6 [IL6], interleukin‐8 [IL‐8], interleukin‐12 [IL‐12], and tumor necrosis factor‐α [TNF‐α]), alter the mitochondrial gene expression, decrease the aromatase activity, and vascular endothelial growth factor (VEGF) and growth differentiation factor‐9 (GDF‐9) in human granulosa cells. 42 , 43 , 44 , 45 , 46 , 63 These reports suggest that endometriosis might be harmful to granulosa cells making them less sensitive to luteinizing hormone stimulation. 47 , 64 Moreover, the expression of progesterone receptor (PR) and estrogen‐α in granulosa cells was higher in women with endometriosis than in those with tubal infertility. 65 Sreerangaraja Urs et al. 66 demonstrated that decrease in steroidogenic acute regulatory protein (StAR) and 3β‐hydroxysteroid dehydrogenase (3β‐HSD), mitochondrial dysfunction, and apoptosis were found in the granulosa cells of women with endometriosis. Sanchex et al. 67 reported that dysregulation of the wingless‐related integration site (WNT) pathway and down‐regulation of survivin were found in the granulosa cells of women with endometriosis. Recently, Sirtuin 2 (silent information regulator proteins; SIRT2) and kisspeptin receptor (KISS1R) were found to be increased in the granulosa cells of women with endometriosis. 68 , 69 The granulosa cells from women with endometriosis had higher NF‐κB binding activity, increased expression of inhibitor of NF‐κB kinase subunit β (IKKβ) and NF‐κB inhibitor α (IκBα), which decreased the telomerase activity and human telomerase reverse transcriptase (hTERT). 70 Moreover, intrafollicular TNF‐α might decrease the telomerase activity and hTERT through NF‐κB activation. 70 Li et al. 71 found that down‐regulation of the long non‐coding RNA MALAT1 decreased the granulosa cell proliferation in women with endometriosis through an increase in the p21 expression via the MAPK/Erk activation pathway. In women with peritoneal endometriosis, the expression of bone morphogenetic protein 6 (BMP6) and mothers against decapentaplegic homolog 6 (SMAD6) were decreased in the granulosa cells. 72 Moreover, Ding et al. 73 demonstrated the increased Beclin‐1 (BECN1) and provoked autophagy in the late follicular progesterone elevation in the granulosa cells of women with ovarian endometriosis. There are many evidences about increased oxidative stress in the granulosa cells of women with endometriosis, who when compared to women with normal ovaries showed higher 8‐hydroxydeoxyguanosine and lipid peroxidation (4‐hydroxy‐2‐nonenal). 74 , 75 , 76 Lin et al. reported that the granulosa cells from women with endometriosis had excessive reactive oxygen species, which provoked senescence through endoplasmic reticulum (ER) stress, decrease in mitochondrial membrane potential, and reduction in ATP production. 77 ER stress is significantly associated with oxidative stress. Treating the oxidative stress inducer caused upregulation of the unfold protein response (UPR)‐associated genes and apoptosis in human granulosa cells. 78 Moreover, the granulosa cells from women with endometriosis expressed several transcripts associated with UPR and increased the phosphorylation of ER stress sensor proteins, including inositol‐requiring enzyme 1 and double‐stranded RNA‐activated protein kinase‐like ER kinase (PERK). These results suggested that high oxidative stress in the granulosa cells in women with endometriosis provoked ER stress and apoptosis. 78 These studies illustrated that endometriosis is harmful to the granulosa cells and might lead to ovarian dysfunction (Figure  1 ). The potential effects of endometriosis on granulosa cells. Endometriosis might affect steroidogenesis (aromatase, StAR, 3β‐HSD), cytokine production (IL6, IL‐8, IL‐12, TNF‐ α), cell cycle progression, ER‐α/ PR, oxidative stress, ER stress, apoptosis, senescence, and autophagy in granulosa cells. The granulosa cells in women with endometriosis showed increased oxidative stress, which induced DNA damage, and decreased the mitochondrial membrane potential and ATP production and induced apoptosis. The increased TNF‐α activated NF‐κβ to decrease the telomerase activity and hTERT. TNF‐α also induced extrinsic and intrinsic apoptosis pathway and decreased survivin expression. The increased oxidative stress in the granulosa cells in women with endometriosis stimulated senescence and apoptosis through ER stress. StAR, steroidogenic acute regulatory protein; 3β‐HSD, 3β‐hydroxysteroid dehydrogenase; IL‐6, interleukin‐6; IL‐8, interleukin‐8; IL‐12, interleukin‐12; TNF‐α, tumor necrosis factor α; ER‐α, estrogen receptor‐ α ; PR, progesterone receptor; NF‐κB, nuclear factor‐κB.; hTERT, human telomerase reverse transcriptase, ER stress, endoplasmic reticulum stress; BECN1, beclin‐1. This figure was created with BioRender.com

Phthalate

Several studies and meta‐analyses have suggested an association between phthalate exposure and the risk of endometriosis (Table  1 ). In 2003, Cobellis et al. 48 found a positive correlation between plasma DEHP and endometriosis. DEHP and MEHP were detected in the peritoneal fluid. Reddy et al. published two papers about higher levels of butyl benzyl phthalate (BBP), DEHP, di‐n‐butyl phthalate (DnBP), and di‐n‐octyl phthalate (DnOP) in women with endometriosis compared to those in the control group, which were also significantly associated with stage I‐IV of endometriosis. 49 , 50 Nazri et al. also reported that DEHP was increased in the serum of women with endometriosis. 51 In Taiwan, two studies demonstrated an increased level of urinary mono‐n‐butyl phthalate (MnBP) in women with endometriosis. 38 , 52 In Korea, Kim et al. reported that women with endometriosis had higher levels of DEHP and MEHP in the plasma, and the presence of mono‐2‐ethyl‐5‐hydroxyhexyl phthalate (MEHHP), mono‐2‐ethyl‐5‐oxohexyl phthalate (MEOHP), Log mono‐2‐ethyl‐5‐carboxyphentyl phthalate (MECPP), Log MEHHP, Log MEOHP in the urine. 41 , 53 In the United States, 14 phthalate metabolites were analyzed in both, population cohort comprised women matched on age and residence (n = 131) and operative cohort comprised women undergoing laparoscopy (n = 495). The study found that MnBP, mono‐2‐carboxymethyl hexyl phthalate (MCMHP), MECPP, MEHP, MEHHP, MEOHP were higher in the population cohort in women with endometriosis. Moreover, MEHP and monooctyl phthalate (MOP) were increased in the operative cohort in women with endometriosis. 8 Upson et al. 54 showed an inverse association between MEHP and the risk of endometriosis. However, some studies have reported a reverse correlation or no association between endometriosis and some phthalate metabolites, which might be due to non‐adjustment for other covariates or small sample size. 54 , 55 , 56 , 57 Epidemiological studies and meta‐analysis of the association between Phthalate or and endometriosis Abbreviations: BBP, butyl benzyl phthalate; DEHP, di‐2‐ethylhexyl phthalate; DnBP, di‐n‐butyl phthalate; DnOP, di‐n‐octyl phthalate; MBzP, monobenzyl phthalate; MCHP, monocyclohexyl phthalate; MCMHP, mono‐2‐carboxymethyl hexyl phthalate; MCPP, mono‐3‐carboxypropyl phthalate; MECPP, mono‐2‐ethyl‐5‐carboxyphentyl phthalate; MEHHP, mono‐2‐ethyl‐5‐hydroxyhexyl phthalate; MEHP, mono‐2‐ethylhexyl phthalate; MEOHP, mono‐2‐ethyl‐5‐oxohexyl phthalate; MEP, monoethyl phthalate; MIBP, mono‐2‐isobutyl phthalate; MMP, monomethyl phthalate;MNP, monoisonoyl phthalate; MnBP, mono‐n‐butyl phthalate; MOP, monooctyl phthalate; PAEs, phthalate esters. Recently, two meta‐analyses reported about the association between endometriosis and phthalate metabolites. The most commonly used phthalate, DEHP, showed a significant risk of endometriosis (OR = 1.42; 95% CI: 1.19‐1.7). 39 Another meta‐analysis analyzed five phthalate metabolites from eight studies and reported that only MEHHP was associated with endometriosis in Asia but not in the USA. 58 These studies and meta‐analyses strengthen the evidence that phthalate metabolites might play an important role in the occurrence of endometriosis. More studies on urine samples of women with endometriosis should be conducted to prove the association between phthalate exposure and endometriosis.

Conclusions

In this review, the interaction between phthalate exposure and granulosa cells in women with endometriosis has been discussed based on the evidence from several studies. A thorough understanding of the effects of phthalate on granulosa cells and endometrial cells might provide new insights into the pathogenesis of endometriosis and its biological effects on ovarian function. More studies are necessary to understand the detailed mechanisms of the interplay between phthalate, granulosa cells, and endometriosis.

Introduction

Endometriosis represents a common gynecological condition in which the stromal or glandular epithelium gets implanted in extrauterine locations. 1 , 2 , 3 The prevalence of endometriosis is estimated to be 10% among women of reproductive age, which is approximately 190 million women worldwide. 4 Some women with endometriosis are asymptomatic; however, most of them suffer from chronic pelvic pain, dysmenorrhea, deep dyspareunia, and infertility. 5 Although the hypotheses about the etiopathology of endometriosis have been reported for almost one century, the etiology remains unknown. 6 Several evidences suggested that environmental pollutants might be involved in the pathogenesis of endometriosis. 7 , 8 , 9 , 10 , 11 These endocrine‐disrupting chemicals interrupt hormonal homeostasis and result in estrogen signaling changes. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 Phthalate is diesters of phthalate, which are commonly used in several plastic products, and solubilize other agents. 24 , 25 , 26 Ingestion and inhalation are the common routes of phthalate exposure. 27 , 28 , 29 After entering the body, phthalates are hydrolyzed by the digestive tract into monoesters, then absorbed, oxidized, and excreted in the urine. 28 , 30 , 31 , 32 Several reports have suggested a link between phthalates and human reproductive health through their influence on spermatogenesis in males. 33 Previous studies have demonstrated that sexually mature female rats exposed to di (2‐ethylhexyl) phthalate (DEHP) and its metabolite, mono (2‐ethylhexyl) phthalate (MEHP) showed a decrease in serum progesterone, delayed ovulation, and smaller preovulatory follicles with high levels of serum follicle‐stimulating hormone (FSH). 17 , 19 , 34 , 35 Many studies demonstrated that phthalate exposure is significantly associated with endometriosis. 10 , 36 , 37 , 38 , 39 , 40 Kim et al. demonstrated the effects of DEHP on endometrial cells, including cell invasion, viability, proliferation, and oxidative stress through mitogen‐activated protein kinase (MAPK)/ extracellular regulated protein kinase (Erk), and nuclear factor‐κB (NF‐κB) pathways. 10 , 41 Endometriosis is harmful to granulosa cells, because it affects steroidogenesis and cell cycle progression, lowers aromatase activity, and alters the mitochondrial gene expression in human granulosa cells. 38 , 42 , 43 , 44 , 45 , 46 , 47 This article retrospectively searched the keywords “phthalate and endometriosis,” “endometriosis and granulosa cells,” “phthalate and granulosa cells,” and “phthalates and endometrial cells” on PubMed. This review aims to evaluate the exposure of phthalate and the risk of endometriosis, and its impact on the granulosa cells based on current data.

Coi Statement

Conflict of interest : The authors declare no conflict of interest. Human and Animal Rights : This article does not contain any study with human or animal participants that have been performed by any of the authors.

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