{"paper_id":"cfc4d375-c437-458a-ab55-3d1b83ab11ba","body_text":"9:6\nR134–R142R Cabry et al. Endocrine disruptors and \noocyte/embryo quality\nREVIEW\nThe impact of endocrine disruptor chemicals on \noocyte/embryo and clinical outcomes in IVF\nRosalie Cabry1, Philippe Merviel2, Aicha Madkour 3, Elodie Lefranc1, Florence Scheffler1, Rachel Desailloud1, \nVéronique Bach1 and Moncef Benkhalifa1\n1Amiens University, Amiens, Haut-de-France, France\n2Brest University, Brest, Bretagne, France\n3Mohammed V University of Rabat, Reproductive Medicine, Rabat, Morocco\nCorrespondence should be addressed to M Benkhalifa: benkhalifamoncef78@gmail.com\nAbstract\nThe negative impact of endocrine-disrupting pesticides on human fertility is now a key \nissue in reproductive health. There are much fewer literature data about the impact of \npesticide exposure on women than on men and very few studies of women participating \nin an in vitro fertilization (IVF) programme. In the present review, we found that (1) \nvarious pesticides with an endocrine-disrupting action are associated with poor oocyte \nmaturation and competency, embryonic defects and poor IVF outcomes, and (2) some \npesticide compounds are linked to specific causes of female infertility, such as premature \novarian insufficiency, polycystic ovarian syndrome, and endometriosis. IVF participants \nliving in agricultural regions should be informed about the fertility decline, low ongoing \npregnancy rates, and elevated risk of miscarriage associated with exposure to high doses \nof pesticides.\nIntroduction\nInfertility is defined as failure to obtain a clinical \npregnancy after 12 months of regular, unprotected sexual \nintercourse. On average, it affects 8–12% of couples of \nchild-bearing age ( 1). A decline in human fertility has \nprompted an increasing proportion of couples to enrol in \nin vitro  fertilization (IVF) programmes. Over the last 50 \nyears, the sperm count has fallen by 32–50% in Europe \nand United States ( 2, 3); this fall is too rapid to be due \nto a genetic factor but might be related to one or more \nenvironmental factors, such as exposure to pesticides.\nPesticide are substances or combinations of substances \nused in many areas of agriculture and industry. They \ninclude ( 1) phytosanitary products (also referred to as \nphytopharmaceuticals) used in agricultural or non-\nagricultural plant sectors to control insects (insecticides), \nweeds (herbicides), fungi and moulds (fungicides), or pests \n(rodenticides); (2) biocides used in industry (treatment of \nwood and textiles), hospital environments (hydroalcoholic \ngels), and domestic settings (disinfection); and ( 3) \nantiparasitics used in human and veterinary medicine \n(treatment of lice, scabies, mites, fleas, ticks, etc.) (4, 5).\nThe main families of pesticides by chemical \ncomposition are as follows:\n– Organophosphorus (OP) compounds, such as \nchlorpyrifos, cypermethrin, malathion, and parathion\n– Organochlorine (OC) compounds, such as \nmethoxychlor (MXC), 2,3,7,8-tetrachlorodibenzo-\npdioxin (TCDD), dichlorodiphenyldichloroethane \n(DDD), dichlorodiphenyldichloroethylene \n(DDE), dichlorodiphenyltrichloroethane (DDT), \npolychlorinated biphenyls (PCBs), dieldrin, endosulfan, \nhexachlorobenzene (HCB), hexachlorocyclohexane \n(HCH), and lindane\n– Carbamates, such as carbofuran, benomyl, and \nmancozeb\n– Pyrethroids, such as permethrin\n– Triazines, such as atrazine\n-20-0135\nKey Words\n f endocrine disruptor\n f oocyte-embryo\n f clinical outcome\n f IVF\nEndocrine Connections\n(2020) 9, R134–R142\nID: 20-0135\n9 6\nThis work is licensed under a Creative Commons \nAttribution-NonCommercial 4.0 International License.https://doi.org/10.1530/EC-20-0135\nhttps://ec.bioscientifica.com © 2020 The authors\nPublished by Bioscientifica Ltd Downloaded from Bioscientifica.com at 06/08/2026 11:53:00AM\nvia Open Access. This work is licensed under a Creative Commons\nAttribution-NonCommercial 4.0 International License.\nhttp://creativecommons.org/licenses/by-nc/4.0/\n\n\nR Cabry et al. Endocrine disruptors and \noocyte/embryo quality\nR135\nPB–XX\n9:6\nMany pesticides are known to be endocrine-disrupting \nchemicals (EDCs), defined as ‘exogenous agents, that \nare potentially capable of synthesis, secretion, transport, \nbinding, action, or elimination of the natural hormones \nresponsible for the maintenance of homeostasis, \nreproduction, and developmental processes in the body’ \n(5). Even though the involvement of EDCs in certain \nreproductive diseases is well documented, only few studies \nhave examined the direct impact of pesticides on fertility \n(and especially in female infertility) in IVF programmes. \nHence, the objective of the present review was to assess the \nimpact of the most frequently used pesticides on female \nfertility, oocyte-embryo quality, and clinical outcomes in \nIVF programmes.\nPesticides as EDCs\nA large body of evidence from animal studies and \nepidemiological surveys shows that pesticides \nlike bisphenol A (BPA) and phthalates have an \nendocrine-disrupting action and a reprotoxic impact \n(5, 6, 7, 8, 9, 10, 11). Furthermore, Manikkam ( 12) \nhighlighted the existence of a transgenerational risk \nin the rat:  in utero  exposure of pups to a mixture of \npesticides (administered by gavaging the pregnant \ndams) was associated with changes in puberty onset, \nspermatogenesis, and the development of ovarian \nfollicles up to the F3 generation.\nThe direct, toxic endocrine-disrupting effect (i.e. a \ndose-response relationship) has rarely been characterized \nfor a single target compound. In general, the major \ntoxic exposure is associated with a large number of low-\ndose compounds and the interactions between these \ncompounds. This ‘cocktail effect’ is why the presence \nof even very small amounts of some specific pesticides \ncan perturb an organism’s hormonal balance ( 13, 14). \nIndeed, some pesticides bind as agonists to hormone \nreceptors, which results in direct cell damage and/or the \ndysregulation of one or more biochemical or genetic \npathways. In turn, this dysregulation produces toxic \nmetabolites and increases the level of oxidative stress (14), \nwhich affects both male and female fertility. There are \nmore research data on the influence of various pesticides \non male fertility than on female fertility. However, even \nthe data on male fertility (with putative links between \nexposure and a range of disorders), especially those \ncorrelated with poor sperm quality and low testicular \nweight (15, 16, 17), make it hard to affirm the presence of \na direct, causal effect in humans.\nCompounds such as lindane, PCB, atrazine, and \nmancozeb might dysregulate hormonal status in \nwomen by decreasing LH concentrations and thus  \npromoting oligo-ovulation/anovulation and follicle \ndestruction (13, 14).\nPesticide exposure and female fertility\nIn 1994, De Cock et  al. ( 18) investigated the impact of \npesticide exposure in market gardeners in the Netherlands \nand found that the fecundability ratio fell as the \nintensity of pesticide exposure increased. In this study, \n28% of couples in the ‘high exposure’ group and 8% of \nthe couples in ‘low exposure’ group requested assisted \nreproductive technology (ART) support. Other studies \nhave emphasized this effect of pesticide exposure in \nwomen, with lengthening of the time required to conceive \n(19, 20, 21, 22). A risk of spontaneous miscarriage has also \nbeen observed, particularly in Bretveld et al.’s (23) study \nof female farmers (odds ratio (95% CI) = 4.0 (1.14–14.01).\nData from the Agricultural Health Study cohort \nshowed that menstrual cycles of women exposed to \npesticides increased in length, although no distinction \nwas made between occupational exposure and domestic \nexposure (24).\nThese results clearly converge on an impact of \npesticide use (especially in an occupational setting) on \nfemale reproductive capacity and certain female infertility \ndiseases, such as premature ovarian failure (POF), \npolycystic ovarian syndrome (PCOS), and endometriosis. \nFurthermore, pesticide exposure might have direct or \nindirect effects on oocyte/embryo quality and the clinical \noutcomes of IVF.\nThe association between pesticide exposure and \ncertain female infertility diseases\nThe negative impact of pesticides has been investigated \nin animal experiments. Many deficiencies have been \ndescribed, such as low ovarian weight ( 25, 26), impaired \nfolliculogenesis ( 27), a high aneuploidy rate, and the \nacceleration of follicular atresia (25, 26, 27).\nIndeed, women exposed to some endocrine-disrupting \npesticides (such as atrazine, lindane, and maneb) have \nan elevated risk of long menstrual cycles or anovulation \n(13). Conversely, high blood levels of DDE ( 28) and DDT \n(29) are associated with luteal phase deficiency and short \nmenstrual cycles. The most serious consequence is POF \n(Premature Ovarian failure), defined as the cessation \nThis work is licensed under a Creative Commons \nAttribution-NonCommercial 4.0 International License.https://doi.org/10.1530/EC-20-0135\nhttps://ec.bioscientifica.com © 2020 The authors\nPublished by Bioscientifica Ltd Downloaded from Bioscientifica.com at 06/08/2026 11:53:00AM\nvia Open Access. This work is licensed under a Creative Commons\nAttribution-NonCommercial 4.0 International License.\nhttp://creativecommons.org/licenses/by-nc/4.0/\n\n\nR Cabry et al. Endocrine disruptors and \noocyte/embryo quality\nR1369:6\nof menstrual cycles before the age of 40 years and \ncharacterized by very low blood levels of anti-Müllerian \nhormone (AMH). The prevalence of POF is around 1%, \nas a result of genetic or autoimmune/metabolic factors or \ncancer therapy ( 1). Nonetheless, POF might sometimes \nbe caused by environmental factors, including pesticide \nexposure. Indeed, a few studies have linked exposure to \nHCH, mirex (30), pyrethroids (31), and their metabolites \n(especially 3-phenoxybenzoic acid ( 32)), PCB, and DDT \n(33) to ovarian ageing and menopause at an earlier average \nage. Interestingly, low AMH levels were associated with \nthe presence of DDT in the serum (detected in more than \n40% of samples from patients with POF ( 33)) and with \nhigh concentrations of pyrethroids and their metabolites \nwith 25–26% reduction (31, 32). \nThe presence of DDE, MXC, or simazine (a triazine \nherbicide) was associated with follicular atresia (34). Given \nthat MXC, simazine, and other pesticides (as atrazine, \nendosulfan, and chlordecone) are oestrogen receptor \nagonists (in contrast to DDE, DDT, and vinclozolin), \nthey may have oestrogenic and/or antiandrogenic \neffects ( 5, 10, 35, 36). This implicitly explains why \nsome specific pesticides could be responsible for various \nfemale reproductive diseases to differing extents and \nwhy the effects of some pesticide compounds (such as \nDDE, PCB, and MXC) depend on the patient’s genetic \npredisposition. Indeed, these pesticides were associated \nwith abnormally high AMH levels and a high number of \nsmall antral follicles – reflecting the presence of PCOS (37, \n38, 39). Polycystic ovarian syndrome is a heterogeneous \ncondition that affects 5–10% of women. According to \nthe Rotterdam diagnostic criteria for PCOS, two of the \nfollowing three criteria must be met: infrequent or absent \novulation (oligospaniomenorrhea), an abnormal ovarian \nmorphology on ultrasound, and hyperandrogenism (1).\nMoreover, some pesticides (such as TCDD ( 40, 41, \n42), PCB ( 43), and permethrin ( 44)) have a documented \nimpact on the endometrium by increasing vascularization, \ncell proliferation, VEGF levels, and thus endometriosis \n(with prevalence of 0.8–6%) (1). However, other pesticides \n(cypermethrin ( 45), chlorpyrifos, malathion, diazinon, \nlindane, DDT, and pyrethroids ( 46)) have the opposite \neffect by indirectly inhibiting endometrial proliferation \nor causing oxidative damage to the uterus.\nMany studies have found an association between \npesticide concentrations in the follicular fluid on one \nhand and the number and quality of oocytes collected \nfor IVF ( 47, 48), endometrial thickness, and embryo \nimplantation rates ( 46) on the other. Studies of animal \nmodels have shown that pesticide exposure is associated \nwith elevated oxidative stress, which may be responsible \nfor the observed alterations (49).\nImpact on oocyte quality\nExposure to pesticides might cause generalized oxidative \nstress (49), with the elevated production of free radicals \nand impacts on superoxide dismutase, catalase, \nglutathione peroxidase, glutathione reductase, and \nglutathione transferase. This might explain why oocyte \nquality is impacted; oocyte dysmorphisms may reflect \npoor competence for development into a good embryo \nfor implantation.\nIndeed, we have highlighted ( 50) a conclusive \nlink between a high prevalence (>75%) of oocytes \nwith centrally located cytoplasm granulation (CLCG) \nand the patients’ exposure to pesticides in the highly \nagricultural Picardy area of northern France (annual \npesticide consumption: ~3900 tons). As a result, ongoing \npregnancy and live birth rates were lower in couples with \na high prevalence of oocytes with CLCG than in couples \nwith low (<25%) prevalence (14% vs 32% for the ongoing \npregnancy rate and 13% vs 30% for the live birth rate, \nrespectively). Conversely, the early miscarriage rate was \nhigher (47%) in the high-prevalence group than in the \nlow-prevalence group (11%; odds ratio: 3.1). This poor \nIVF outcome might be indirectly due to high levels of \npesticide exposure (over 3000 g/ha), which engenders a \nhigher risk of oocytes with CLCG.\nIn line with these results, some pesticides (e.g. \natrazine, cypermethrine, DDT, dieldrine, MCX, and \nvinclozoline) affect folliculogenesis (via the granulosa \nand theca cells) and thus induce meiotic aberrations \n(aneuploidy) and follicular atresia ( 51). For example, \nDDT stimulates aromatase and acts in synergy with FSH \nto induce a premature rise in oestradiol levels, affecting \noocyte maturation ( 51). Furthermore, PCB might \ndamage the ovarian reserve, the follicular response to \nadministered gonadotropins, and oocyte maturation (51). \nIndeed, exposure of immature porcine cumulus-oocyte \ncomplexes to an organochlorine mixture ( 48) or atrazine \n(52) during in vitro  maturation was associated with an \nelevated incidence of incompletely matured oocytes. The \nresearchers mentioned the following pathophysiological \nmechanisms: abnormal cellular shape (disrupted spindle \nmorphology), abnormal mitochondrial activity, and \nalterations in oocyte DNA (48, 51, 52).\nThe pesticides most frequently linked to defective \noocyte maturation and oocyte competence are malathion \n(53), parathion ( 54), MXC ( 55), DDD/DDE/DDT/PCB  \nThis work is licensed under a Creative Commons \nAttribution-NonCommercial 4.0 International License.https://doi.org/10.1530/EC-20-0135\nhttps://ec.bioscientifica.com © 2020 The authors\nPublished by Bioscientifica Ltd Downloaded from Bioscientifica.com at 06/08/2026 11:53:00AM\nvia Open Access. This work is licensed under a Creative Commons\nAttribution-NonCommercial 4.0 International License.\nhttp://creativecommons.org/licenses/by-nc/4.0/\n\n\nR Cabry et al. Endocrine disruptors and \noocyte/embryo quality\nR137\nPB–XX\n9:6\nTable 1 Summary of the negative impact of various pesticides on oocytes, embryos, the endometrium, and clinical outcomes in IVF.\nPesticide EReg\n \nOocyte quality\nOocyte \nmaturation\nOocyte \ngenetic\nEmbryo \ndevelopment Endometrium IR CPR References\nOrganophosphorus Chlorpyrifos + + + + (71)\n(46)\nCypermethrin + +  (45)\nMalathion + + + +  (53)\n (46)\nParathion + + + +  (80)\n(10)\n (54)\n(27)\nOrganochlorine MXC + + + +  (55)\n(81)\n (49)\nTCDD ++ + +  (40)\n (41)\n(42)\nDDD ++  (56)\nDDE ++ + + ++ +  (28)\n (56)\n (39)\n (26)\nDDT ++ + + ++ + + + +  (29)\n (56)\n (31) \n (20)\n (47)\n (51)\nPCB ++ + ++ ++ +++ ++  (43)\n (56)\n (77)\n (78)\n (39)\nDieldrin + ++  (72)\n (58)\n (51)\nEndosulfan ++ +++  (71)\n (79)\nHCB ++ ++ +  (57)\n (47)\nHCH ++ + + +  (30)\n (47)\nLindane + ++ ++ + + +  (13)\n (59)\n (46)\nThis work is licensed under a Creative Commons \nAttribution-NonCommercial 4.0 International License.https://doi.org/10.1530/EC-20-0135\nhttps://ec.bioscientifica.com © 2020 The authors\nPublished by Bioscientifica Ltd Downloaded from Bioscientifica.com at 06/08/2026 11:53:00AM\nvia Open Access. This work is licensed under a Creative Commons\nAttribution-NonCommercial 4.0 International License.\nhttp://creativecommons.org/licenses/by-nc/4.0/\n\n\nR Cabry et al. Endocrine disruptors and \noocyte/embryo quality\nR1389:6\n(56, 57), dieldrin ( 58), HCB/HCH ( 47), lindane ( 59), \nbenomyl (60), and mancozeb (61, 62) (Table 1).\nInterestingly, DDT was associated with a low \nproportion of diploid oocytes ( 56), while benomyl \ninterfered with microtubules ( 60) and lindane was \nassociated with cell damage (especially vacuolation \nand cytoplasmic fragmentation) ( 59). It was reported \nthat mancozeb can strongly affect the meiotic spindle \norganization of oocytes ( 61), but the degree of damage \ncould be decreased by treatment with resveratrol (62).\nMoreover, exposure to deltamethrin (another \ncommon insecticide) in a mouse model was linked to \ncellular oxidative stress and meiotic abnormalities via \nDNA damage ( 63). Liu et  al. ( 49) suggested that MXC \nexposure induces oxidative stress and affects mouse oocyte \nmeiotic maturation via the accumulation of superoxide \nradicals and other reactive oxygen species (ROS), \naberrant mitochondrial distribution, a low mitochondrial \nmembrane potential, and elevated lipid peroxidation. \nThus, exposure to MXC can negatively affect oocyte \nmeiotic maturation – primarily through impairments in \ncellular metabolism. In general, all these pesticide-linked \ndefects in oocyte quality are likely to degrade competence \nfor the development of a genetically undamaged embryo.\nImpact on embryo development\nPesticides can affect indirectly the embryo by dysregulating \nembryonic genome activation and embryonic metabolism, \nwhich is dependent on oxygen uptake. This latter is low \nat the 8-cell stage ( 64, 65, 66) and tends to increase after \nthe morula stage required for blastocyst expansion ( 67). \nBlastocyst formation and the number of cells per blastocyst \ndeclined with the concentration of organochlorines \n(48) and atrazine ( 52). Furthermore, the association of \npesticides like deltamethrin (63) and MXC (49) with poor \nmetabolic and genetic status during embryo development \nmight be due to the impairment of various biochemical \npathways (13) and high ROS production. Moreover, high \nROS concentrations and generalized oxidative stress are \nlikely to affect the integrity of cellular constituents, such \nas DNA and proteins (68, 69, 70).\nVarious pesticides (especially chlorpyrifos with \nendosulfan (71), malathion (53), DDE/DDT/PCB (56, 47), \ndieldrin (72), mancozeb ( 73) (Table 1), and pretilachlor/\ndiazinon ( 46)) may impact negatively embryonic \ndevelopment. Consequently, the use of low-quality \nembryos associated with pesticide exposure would give \npoor clinical outcomes (e.g. an elevated risk of miscarriage) \nin IVF programmes.\nCarbamate Carbofuran + +++ +  (82)\nBenomyl + ++ + ++  (61)\n (73)\n (62)\nMancozeb + +++ + ++ +  (60)\nPyrethroid Permethrin + + ++  (44)\n (51)\nTriazine Atrazine ++ + + +  (13)\n (36)\n (52)\nVinclozoline +++ +  (83)\n (51)\nThe ‘+’ symbols indicate a negative impact: ‘+’ rarely reported, with a low level of interest; ‘++’: widely reported; ‘+++’: widely reported, with a high level of interest.\nCPR: clinical pregnancy rate; DDD: dichlorodiphenyldichloroethane; DDE: dichlorodiphenyldichloroethylene; DDT: dichlorodiphenyltrichloroethane; EReg: endocrine regulation; HCB: \nhexachlorobenzene; HCH: hexachlorocyclohexane; IR: implantation rate; MXC: methoxychlor; PCB: polychlorated biphenyl; TCDD: 2,3,7 ,8-te trach lorod ibenz o-p-d ioxin .\nThis work is licensed under a Creative Commons \nAttribution-NonCommercial 4.0 International License.https://doi.org/10.1530/EC-20-0135\nhttps://ec.bioscientifica.com © 2020 The authors\nPublished by Bioscientifica Ltd Downloaded from Bioscientifica.com at 06/08/2026 11:53:00AM\nvia Open Access. This work is licensed under a Creative Commons\nAttribution-NonCommercial 4.0 International License.\nhttp://creativecommons.org/licenses/by-nc/4.0/\n\n\nR Cabry et al. Endocrine disruptors and \noocyte/embryo quality\nR139\nPB–XX\n9:6\nImpact on clinical outcomes in IVF programmes\nWomen who consume high levels of pesticide residues \nin fruits and vegetables ( 74) or who live in an area with \nhigh pesticide exposure ( 50, 75) have an above-average \nrisk of miscarriage. In one study, the probability of clinical \npregnancy was 18% below average and the live birth rate \nwas 26% below average in the women most exposed to \npesticides (74). However, in a study in California, there \nwere no differences in terms of spontaneous miscarriage, \npreeclampsia, and preterm birth rates between women \nexposed to pesticides (occupationally or through \nresidence in an agricultural area) and unexposed women \n(76). Pesticides associated with poor clinical outcomes \nin IVF are chlorpyrifos ( 46), TCDD ( 42), DDT/PCB ( 46, \n56, 77, 78), HCB/HCH ( 47, 56, 57), and endosulfan ( 79) \n(Table 1). Lindane, DDT, diazinon, and chlorpyrifos were \nassociated with a low implantation rate but did not have a \nclear impact on the clinical pregnancy and live birth rates \n(46). Nevertheless, PCB and endosulfan have been linked \nto repeated implantation failures (77, 79).\nConclusion\nA growing number of studies have assessed the putative \ncausal link between exposure to pesticides and female \nfertility disorders. Although awareness of these issues has \nincreased, the literature data are too scarce for conclusive, \ndecisive recommendations. The impact of exposure to \nvarious endocrine-disrupting pesticides on fertility is now a \npublic health issue that urgently requires the performance \nof more epidemiological studies – especially those focused \non female fertility and women in IVF programmes. \nFurthermore, it is important to design studies that assess \nthe severity of exposure and the nature of pesticides. There \nis also a need to develop more specific, rapid diagnosis \ntechniques and treatments that might decrease pesticide-\ninduced damage. Indeed, IVF participants living in \nagricultural regions should be informed about the fertility \ndecline, low ongoing pregnancy rates, and elevated risk \nof miscarriage associated with exposure to high doses  \nof pesticides.\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be \nperceived as prejudicing the impartiality of this review.\nFunding\nThis work was funded by Amiens-Picardie University Hospital  \n(Amiens, France) and Jules Verne University of Picardie (Peritox Laboratory, \nAmiens, France).\nAcknowledgements\nThe authors thank the staff at Amiens-Picardie University Hospital’s ART \nunit and the staff at the Peritox Laboratory for their support.\nReferences\n 1 Vander Borght M & Wyns C. Fertility and infertility: definition \nand epidemiology. Clinical Biochemistry 2018 62 2–10. (https://doi.\norg/10.1016/j.clinbiochem.2018.03.012)\n 2 Manikkam M, Tracey R, Guerrero-Bosagna C & Skinner MK. 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