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• W4223996103 abstract "An ongoing interest in environmental exposures and female fertility has led to an increasing number of studies focusing on endocrine-disrupting chemicals (EDCs). Both natural and synthetic compounds have the ability to impact reproductive health by altering the structure and/or function of genes and proteins that facilitate normal ovarian and endometrial functions. This mini-review aims to summarize the effects of some of the most common EDCs on female fertility, including the effects of pesticides and plasticizer alternatives (phthalates, bisphenol A), based on available data in human studies. A literature search was performed using the key words “pesticides, fertility, reproduction, plasticizers, bisphenol A, phthalate, miscarriage, and in vitro fertilization.” The data supporting EDCs’ role in female infertility remain limited, but existing evidence suggests that exposure may have an adverse impact. Accumulating evidence in animal studies provides important insights into the mechanisms underlying EDC effects. As dose-response dynamics are better elucidated, understanding the effects of EDCs on female fertility will help in the development of guidelines for both industry and individuals. An ongoing interest in environmental exposures and female fertility has led to an increasing number of studies focusing on endocrine-disrupting chemicals (EDCs). Both natural and synthetic compounds have the ability to impact reproductive health by altering the structure and/or function of genes and proteins that facilitate normal ovarian and endometrial functions. This mini-review aims to summarize the effects of some of the most common EDCs on female fertility, including the effects of pesticides and plasticizer alternatives (phthalates, bisphenol A), based on available data in human studies. A literature search was performed using the key words “pesticides, fertility, reproduction, plasticizers, bisphenol A, phthalate, miscarriage, and in vitro fertilization.” The data supporting EDCs’ role in female infertility remain limited, but existing evidence suggests that exposure may have an adverse impact. Accumulating evidence in animal studies provides important insights into the mechanisms underlying EDC effects. As dose-response dynamics are better elucidated, understanding the effects of EDCs on female fertility will help in the development of guidelines for both industry and individuals. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/xfre-d-21-00206 Endocrine-disrupting chemicals (EDCs) comprise a diverse group of chemical compounds that have recently become a topic of interest because of their potentially harmful effects on human health. Some EDCs are naturally occurring compounds; however, most EDCs are synthetic and were released into the environment without any prior knowledge of their effects on human and animal health. These natural and synthetic compounds have the ability to alter the actions of endogenous hormones and as a result, EDCs may disrupt the functions of the endocrine system. Although the term “endocrine disruptor” was first proposed 30 years ago, the United States Environmental Protection Agency has now identified 1,482 man-made chemicals that are considered EDCs (1Green M.P. Harvey A.J. Finger B.J. Tarulli G.A. Endocrine disrupting chemicals: impacts on human fertility and fecundity during the peri-conception period.Environ Res. 2021; 194: 110694Crossref PubMed Scopus (33) Google Scholar). More recently, the American College of Obstetricians and Gynecologists has partnered with the American Society for Reproductive Medicine to publish committee opinion regarding EDCs and reproductive health (2Segal T.R. Giudice L.C. Before the beginning: environmental exposures and reproductive and obstetrical outcomes.Fertil Steril. 2019; 112: 613-621Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Despite their identification, understanding their mechanism of action and potential negative health implications remain incomplete. This review will focus on the effects of 2 common classes of EDCs on female fertility. An exhaustive review of EDCs and female reproduction and fertility is beyond the scope of this mini-review; our aim is to summarize the effects of 2 of the most common EDCs—pesticides and plasticizer alternatives (phthalates, bisphenol A [BPA])—on the basis of available data in human studies (Table 1) (3Chiu Y.H. Williams P.L. Gillman M.W. Gaskins A.J. Mínguez-Alarcón L. Souter I. et al.Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology.J Am Med Assoc Intern Med. 2018; 178: 17-26Google Scholar, 4Chevrier C. Warembourg C. Gaudreau E. Monfort C. Le Blanc A. Guldner L. et al.Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy.Epidemiology. 2013; 24: 251-260Crossref PubMed Scopus (60) Google Scholar, 5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar, 6Venners S.A. Korrick S. Xu X. Chen C. Guang W. Huang A. et al.Preconception serum DDT and pregnancy loss: a prospective study using a biomarker of pregnancy.Am J Epidemiol. 2005; 162: 709-716Crossref PubMed Scopus (76) Google Scholar, 7Jirsová S. Masata J. Jech L. Zvárová J. Effect of polychlorinated biphenyls (PCBs) and 1,1,1-trichloro-2,2,-bis (4-chlorophenyl)-ethane (DDT) in follicular fluid on the results of in vitro fertilization-embryo transfer (IVF-ET) programs.Fertil Steril. 2010; 93: 1831-1836Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 8Williams A.L. Watson R.E. DeSesso J.M. Developmental and reproductive outcomes in humans and animals after glyphosate exposure: a critical analysis.J Toxicol Environ Health B Crit Rev. 2012; 15: 39-96Crossref PubMed Scopus (99) Google Scholar, 9Mok-Lin E. Ehrlich S. Williams P.L. Petrozza J. Wright D.L. Calafat A.M. et al.Urinary bisphenol A concentrations and ovarian response among women undergoing IVF.Int J Androl. 2010; 33: 385-393Crossref PubMed Scopus (90) Google Scholar, 10Ehrlich S. Williams P.L. Missmer S.A. Flaws J.A. Ye X. Calafat A.M. et al.Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF.Hum Reprod. 2012; 27: 3583-3592Crossref PubMed Scopus (180) Google Scholar, 11Deng T. Du Y. Wang Y. Teng X. Hua X. Yuan X. et al.The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: a prospective single-center study.Ecotoxicol Environ Saf. 2020; 188: 109884Crossref PubMed Scopus (18) Google Scholar, 12Lathi R.B. Liebert C.A. Brookfield K.F. Taylor J.A. vom Saal F.S. Fujimoto V.Y. et al.Conjugated bisphenol A in maternal serum in relation to miscarriage risk.Fertil Steril. 2014; 102: 123-128Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 13Shen Y. Zheng Y. Jiang J. Liu Y. Luo X. Shen Z. et al.Higher urinary bisphenol A concentration is associated with unexplained recurrent miscarriage risk: evidence from a case-control study in eastern China.PLoS One. 2015; 10e0127886Google Scholar, 14Sugiura-Ogasawara M. Ozaki Y. Sonta S. Makino T. Suzumori K. Exposure to bisphenol A is associated with recurrent miscarriage.Hum Reprod. 2005; 20: 2325-2329Crossref PubMed Scopus (329) Google Scholar, 15Buck Louis G.M. Sundaram R. Sweeney A.M. Schisterman E.F. Maisog J. Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) study.Fertil Steril. 2014; 101: 1359-1366Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 16Vélez M.P. Arbuckle T.E. Fraser W.D. Female exposure to phenols and phthalates and time to pregnancy: the Maternal-Infant Research on Environmental Chemicals (MIREC) study.Fertil Steril. 2015; 103: 1011-1020.e2Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 17Mínguez-Alarcón L. Gaskins A.J. Chiu Y.H. Williams P.L. Erlich S. Chavarro J.E. et al.Urinary bisphenol A concentrations and association with in vitro fertilization outcomes among women from a fertility clinic.Hum Reprod. 2015; 30: 2120-2128Crossref PubMed Scopus (55) Google Scholar, 18Hauser R. Gaskins A.J. Souter I. Smith K.W. Dodge L.E. Ehrich S. et al.Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study.Environ Health Perspect. 2016; 124: 831-839Crossref PubMed Scopus (122) Google Scholar, 19Thomsen A.M. Riis A.H. Olsen J. Jönsson B.A. Lindh C.H. Hjollund N.H. et al.Female exposure to phthalates and time to pregnancy: a first pregnancy planner study.Hum Reprod. 2017; 32: 232-238PubMed Google Scholar, 20Malott K.F. Luderer U. Toxicant effects on mammalian oocyte mitochondria.Biol Reprod. 2021; 104: 784-793Crossref PubMed Scopus (10) Google Scholar).Table 1Effects of pesticides and plasticizers on female fertility.EDCExposure sourceNegative effect on female fertilityNo effect or positive effect on female fertilityPesticidesContaminated food, water, air, dust, and soilDecreased ART clinical pregnancy and live birth rates (3Chiu Y.H. Williams P.L. Gillman M.W. Gaskins A.J. Mínguez-Alarcón L. Souter I. et al.Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology.J Am Med Assoc Intern Med. 2018; 178: 17-26Google Scholar)DDEDecreased fecundability (3Chiu Y.H. Williams P.L. Gillman M.W. Gaskins A.J. Mínguez-Alarcón L. Souter I. et al.Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology.J Am Med Assoc Intern Med. 2018; 178: 17-26Google Scholar), fertilization rate, and number of high-quality embryos (4Chevrier C. Warembourg C. Gaudreau E. Monfort C. Le Blanc A. Guldner L. et al.Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy.Epidemiology. 2013; 24: 251-260Crossref PubMed Scopus (60) Google Scholar, 5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar). Increased risk of miscarriage (1Green M.P. Harvey A.J. Finger B.J. Tarulli G.A. Endocrine disrupting chemicals: impacts on human fertility and fecundity during the peri-conception period.Environ Res. 2021; 194: 110694Crossref PubMed Scopus (33) Google Scholar)No effect on ART pregnancy or live birth rate (5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar)β-ΗCΗDecreased fecundability (3Chiu Y.H. Williams P.L. Gillman M.W. Gaskins A.J. Mínguez-Alarcón L. Souter I. et al.Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology.J Am Med Assoc Intern Med. 2018; 178: 17-26Google Scholar), fertilization rate, and number of high-quality embryos (4Chevrier C. Warembourg C. Gaudreau E. Monfort C. Le Blanc A. Guldner L. et al.Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy.Epidemiology. 2013; 24: 251-260Crossref PubMed Scopus (60) Google Scholar, 5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar)No effect on ART pregnancy or live birth rate (5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar)HCBDecreased fecundability (3Chiu Y.H. Williams P.L. Gillman M.W. Gaskins A.J. Mínguez-Alarcón L. Souter I. et al.Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology.J Am Med Assoc Intern Med. 2018; 178: 17-26Google Scholar), fertilization rate, and number of high-quality embryos (4Chevrier C. Warembourg C. Gaudreau E. Monfort C. Le Blanc A. Guldner L. et al.Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy.Epidemiology. 2013; 24: 251-260Crossref PubMed Scopus (60) Google Scholar, 5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar)No effect on ART pregnancy or live birth rate (5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar)DDTIncreased risk of miscarriage (1Green M.P. Harvey A.J. Finger B.J. Tarulli G.A. Endocrine disrupting chemicals: impacts on human fertility and fecundity during the peri-conception period.Environ Res. 2021; 194: 110694Crossref PubMed Scopus (33) Google Scholar, 6Venners S.A. Korrick S. Xu X. Chen C. Guang W. Huang A. et al.Preconception serum DDT and pregnancy loss: a prospective study using a biomarker of pregnancy.Am J Epidemiol. 2005; 162: 709-716Crossref PubMed Scopus (76) Google Scholar)No association with number or quality of oocytes retrieved, fertilization rate, embryo quality, or pregnancy rate (7Jirsová S. Masata J. Jech L. Zvárová J. Effect of polychlorinated biphenyls (PCBs) and 1,1,1-trichloro-2,2,-bis (4-chlorophenyl)-ethane (DDT) in follicular fluid on the results of in vitro fertilization-embryo transfer (IVF-ET) programs.Fertil Steril. 2010; 93: 1831-1836Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar)GlyphosphateNo association with miscarriage rate or time to pregnancy (8Williams A.L. Watson R.E. DeSesso J.M. Developmental and reproductive outcomes in humans and animals after glyphosate exposure: a critical analysis.J Toxicol Environ Health B Crit Rev. 2012; 15: 39-96Crossref PubMed Scopus (99) Google Scholar)PlasticizersBPAContaminated food, consumer products, and packagingDecreased oocyte yield (9Mok-Lin E. Ehrlich S. Williams P.L. Petrozza J. Wright D.L. Calafat A.M. et al.Urinary bisphenol A concentrations and ovarian response among women undergoing IVF.Int J Androl. 2010; 33: 385-393Crossref PubMed Scopus (90) Google Scholar, 10Ehrlich S. Williams P.L. Missmer S.A. Flaws J.A. Ye X. Calafat A.M. et al.Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF.Hum Reprod. 2012; 27: 3583-3592Crossref PubMed Scopus (180) Google Scholar) and decreased normal fertilization (11Deng T. Du Y. Wang Y. Teng X. Hua X. Yuan X. et al.The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: a prospective single-center study.Ecotoxicol Environ Saf. 2020; 188: 109884Crossref PubMed Scopus (18) Google Scholar). Increased risk of miscarriage (12Lathi R.B. Liebert C.A. Brookfield K.F. Taylor J.A. vom Saal F.S. Fujimoto V.Y. et al.Conjugated bisphenol A in maternal serum in relation to miscarriage risk.Fertil Steril. 2014; 102: 123-128Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 13Shen Y. Zheng Y. Jiang J. Liu Y. Luo X. Shen Z. et al.Higher urinary bisphenol A concentration is associated with unexplained recurrent miscarriage risk: evidence from a case-control study in eastern China.PLoS One. 2015; 10e0127886Google Scholar, 14Sugiura-Ogasawara M. Ozaki Y. Sonta S. Makino T. Suzumori K. Exposure to bisphenol A is associated with recurrent miscarriage.Hum Reprod. 2005; 20: 2325-2329Crossref PubMed Scopus (329) Google Scholar)No association with decreased fecundity (15Buck Louis G.M. Sundaram R. Sweeney A.M. Schisterman E.F. Maisog J. Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) study.Fertil Steril. 2014; 101: 1359-1366Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 16Vélez M.P. Arbuckle T.E. Fraser W.D. Female exposure to phenols and phthalates and time to pregnancy: the Maternal-Infant Research on Environmental Chemicals (MIREC) study.Fertil Steril. 2015; 103: 1011-1020.e2Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). No association with fertilization rates, proportion of high-quality embryos, embryo implantation, clinical pregnancy, or live birth rates (17Mínguez-Alarcón L. Gaskins A.J. Chiu Y.H. Williams P.L. Erlich S. Chavarro J.E. et al.Urinary bisphenol A concentrations and association with in vitro fertilization outcomes among women from a fertility clinic.Hum Reprod. 2015; 30: 2120-2128Crossref PubMed Scopus (55) Google Scholar)DEHPUsed in consumer goods such as medical devices, cleaning/building materials, personal care products, cosmetics, pharmaceuticals, food processing, and toysDecreased oocyte yield, clinical pregnancy rate, and live birth rate (18Hauser R. Gaskins A.J. Souter I. Smith K.W. Dodge L.E. Ehrich S. et al.Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study.Environ Health Perspect. 2016; 124: 831-839Crossref PubMed Scopus (122) Google Scholar)No effect on couple time to pregnancy (15Buck Louis G.M. Sundaram R. Sweeney A.M. Schisterman E.F. Maisog J. Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) study.Fertil Steril. 2014; 101: 1359-1366Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar)MEPDecreased odds of normal fertilization (11Deng T. Du Y. Wang Y. Teng X. Hua X. Yuan X. et al.The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: a prospective single-center study.Ecotoxicol Environ Saf. 2020; 188: 109884Crossref PubMed Scopus (18) Google Scholar). Decreased fecundity (19Thomsen A.M. Riis A.H. Olsen J. Jönsson B.A. Lindh C.H. Hjollund N.H. et al.Female exposure to phthalates and time to pregnancy: a first pregnancy planner study.Hum Reprod. 2017; 32: 232-238PubMed Google Scholar)No correlation between good-quality embryos on day 3 or blastocyst formation (11Deng T. Du Y. Wang Y. Teng X. Hua X. Yuan X. et al.The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: a prospective single-center study.Ecotoxicol Environ Saf. 2020; 188: 109884Crossref PubMed Scopus (18) Google Scholar). No effect on couple time to pregnancy (15Buck Louis G.M. Sundaram R. Sweeney A.M. Schisterman E.F. Maisog J. Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) study.Fertil Steril. 2014; 101: 1359-1366Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar)MBPDecreased odds of normal fertilization (20Malott K.F. Luderer U. Toxicant effects on mammalian oocyte mitochondria.Biol Reprod. 2021; 104: 784-793Crossref PubMed Scopus (10) Google Scholar)No correlation between good-quality embryos on day 3 or blastocyst formation (11Deng T. Du Y. Wang Y. Teng X. Hua X. Yuan X. et al.The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: a prospective single-center study.Ecotoxicol Environ Saf. 2020; 188: 109884Crossref PubMed Scopus (18) Google Scholar). No effect on couple time to pregnancy (15Buck Louis G.M. Sundaram R. Sweeney A.M. Schisterman E.F. Maisog J. Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) study.Fertil Steril. 2014; 101: 1359-1366Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar)mcPPShorter time to pregnancy (15Buck Louis G.M. Sundaram R. Sweeney A.M. Schisterman E.F. Maisog J. Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) study.Fertil Steril. 2014; 101: 1359-1366Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar)Note: DDE = dichlorodiphenyldichloroethylene; EDC = endocrine-disrupting chemical; HCB = hexachlorobenzene; ΗCΗ = hexachlorocyclohexane; DDT = dichlorodiphenyltrichloroethane; BPA = bisphenyl A; DEHP = di (2-ethylhexyl) phthalate; MEP = monoethylphthalate; MBP = monobutylphthalate; mcPP = mono (3-carboxypropyl) phthalate. Open table in a new tab Note: DDE = dichlorodiphenyldichloroethylene; EDC = endocrine-disrupting chemical; HCB = hexachlorobenzene; ΗCΗ = hexachlorocyclohexane; DDT = dichlorodiphenyltrichloroethane; BPA = bisphenyl A; DEHP = di (2-ethylhexyl) phthalate; MEP = monoethylphthalate; MBP = monobutylphthalate; mcPP = mono (3-carboxypropyl) phthalate. This review was conducted using a PubMed search for human studies published between 2001 and 2021 using the following keywords: pesticides, fertility, reproduction, plasticizers, bisphenol A, phthalate, miscarriage, and in vitro fertilization (IVF). In addition, reviews that cited original references were examined for relevant information. We included studies that looked specifically at reproductive outcomes in women, including time to pregnancy, pregnancy loss, and assisted reproductive technology (ART) outcomes, including oocyte yield, embryo development, clinical pregnancy rates, and live birth rates. We also included reviews of the mechanisms underlying the effects of EDCs in rodent models. Studies with primary outcomes of ovarian reserve testing that lacked reproductive outcome data were excluded from this review. We excluded studies focusing on the effects of EDC exposure on gynecologic diseases, such as polycystic ovary syndrome, endometriosis, and uterine leiomyomas, considered to be outside the scope of this mini-review. Pesticides are commonly used in agricultural and household settings. Pesticides are used in large quantities—more than 1 billion pounds are used annually in the United States (2Segal T.R. Giudice L.C. Before the beginning: environmental exposures and reproductive and obstetrical outcomes.Fertil Steril. 2019; 112: 613-621Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Sources of contamination can be through ingestion, inhalation, or skin absorption, and the pathways of exposure can include food, water, air, dust, and soil (2Segal T.R. Giudice L.C. Before the beginning: environmental exposures and reproductive and obstetrical outcomes.Fertil Steril. 2019; 112: 613-621Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Decreased fertility because of exposure to pesticides has been reported in several studies. Exposure to organochlorine pesticides was associated with decreased fecundability in 394 couples enrolled in a French birth cohort (4Chevrier C. Warembourg C. Gaudreau E. Monfort C. Le Blanc A. Guldner L. et al.Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy.Epidemiology. 2013; 24: 251-260Crossref PubMed Scopus (60) Google Scholar). Elevated cord blood levels of 3 organochlorine pesticides—dichlorodiphenyldichloroethylene (DDE), β-hexachlorocyclohexane (β-HCH), and hexachlorobenzene (HCB)—were associated with a longer time to pregnancy. After adjusting for maternal age, body mass index (BMI) and smoking status, fecundability was lower for the highest exposure levels of DDE (odds ratio [OR], 0.60 [0.42–0.84]; P=.003), β-HCH (OR, 0.49 [0.29–0.80]; P=.005), and HCB (OR, 0.67 [0.48–0.95]; P=.02) (4Chevrier C. Warembourg C. Gaudreau E. Monfort C. Le Blanc A. Guldner L. et al.Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy.Epidemiology. 2013; 24: 251-260Crossref PubMed Scopus (60) Google Scholar). Important limitations of this study include the use of cord blood as a surrogate for maternal exposure before pregnancy and reliance on subject recall for time to pregnancy. Additionally, the study design was limited to women who were already pregnant and, thus, likely underrepresented the less fertile couples. Exposure to pesticides has also been shown to impact ART outcomes. Normal ovulation, healthy oocyte quality, and subsequent embryo development are dependent on tightly regulated interactions between the oocyte and its surrounding somatic cells within the follicular microenvironment, which may be very sensitive to contaminant exposures. In women undergoing ART, higher follicular fluid DDE, HCB, and β-HCH levels were strongly negatively associated with fertilization rate (P<.00001) and the proportion of high-quality embryos relative to the number of oocytes retrieved (P<.05) (5Petro E.M. Leroy J.L. Covaci A. Fransen E. De Neubourg D. Dirtu A.C. et al.Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.Hum Reprod. 2012; 27: 1025-1033Crossref PubMed Scopus (79) Google Scholar). However, no associations were observed between follicular pesticide levels and clinical pregnancy or live birth rate, underscoring the importance of aspects other than the follicular microenvironment (e.g., uterine environment) in the establishment and maintenance of a healthy pregnancy. Although logistic regression analyses controlled for male subfertility as a confounder, paternal exposures were not assessed, and genetic testing of the embryos was not performed, which could have contributed to poorer quality embryos. A recent subanalysis of the Environment and Reproductive Health prospective cohort study found an association between pesticide residue intake from the consumption of fruits and vegetables and pregnancy outcomes in women undergoing ART (3Chiu Y.H. Williams P.L. Gillman M.W. Gaskins A.J. Mínguez-Alarcón L. Souter I. et al.Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology.J Am Med Assoc Intern Med. 2018; 178: 17-26Google Scholar). In a cohort of 325 women undergoing 541 ART cycles, greater intake of high-pesticide residue fruits and vegetables was associated with 18% lower probability of clinical pregnancy (95% confidence interval [CI], 5%–30%) and 26% lower probability of live birth (95% CI, 13%–37%) (3Chiu Y.H. Williams P.L. Gillman M.W. Gaskins A.J. Mínguez-Alarcón L. Souter I. et al.Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology.J Am Med Assoc Intern Med. 2018; 178: 17-26Google Scholar). Although multivariate analysis adjusted for multiple confounding variables (e.g., age, BMI, smoking status, infertility diagnosis, residential pesticide exposures), reliance on the subject’s self-reported food intake is an important limitation. On the contrary, a study of 99 women found no association between exposure to the insecticide dichlorodiphenyltrichloroethane (DDT) and adverse ART outcomes (7Jirsová S. Masata J. Jech L. Zvárová J. Effect of polychlorinated biphenyls (PCBs) and 1,1,1-trichloro-2,2,-bis (4-chlorophenyl)-ethane (DDT) in follicular fluid on the results of in vitro fertilization-embryo transfer (IVF-ET) programs.Fertil Steril. 2010; 93: 1831-1836Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Higher levels of DDT in the follicular fluid were not significantly associated with a decrease in the number or quality of oocytes retrieved, fertilization rate, embryo quality, or pregnancy rate (7Jirsová S. Masata J. Jech L. Zvárová J. Effect of polychlorinated biphenyls (PCBs) and 1,1,1-trichloro-2,2,-bis (4-chlorophenyl)-ethane (DDT) in follicular fluid on the results of in vitro fertilization-embryo transfer (IVF-ET) programs.Fertil Steril. 2010; 93: 1831-1836Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Similarly, a review of epidemiologic studies assessing exposure to glyphosate, a common herbicide, found no consistent effects of glyphosate on reproductive health (8Williams A.L. Watson R.E. DeSesso J.M. Developmental and reproductive outcomes in humans and animals after glyphosate exposure: a critical analysis.J Toxicol Environ Health B Crit Rev. 2012; 15: 39-96Crossref PubMed Scopus (99) Google Scholar). Specifically, some studies examined both male and female self-reported exposure, spontaneous abortion rate, and time to pregnancy and found no significant correlation (8Williams A.L. Watson R.E. DeSesso J.M. Developmental and reproductive outcomes in humans and animals after glyphosate exposure: a critical analysis.J Toxicol Environ Health B Crit Rev. 2012; 15: 39-96Crossref PubMed Scopus (99) Google Scholar). Overall, contradictory findings may be due to different study populations (e.g., race/ethnicity, concurrent unmeasured environmental exposures, fertile vs. infertile women/couples, infertility diagnoses), methods of exposure assessment (e.g., direct measurement vs. subject recall), and/or the study of different pesticide compounds. Multiple studies support an association between pesticides and early pregnancy loss but are limited by substantial delays (e.g., 2–6 years) between index pregnancies and measurement of serum pesticide levels (reviewed by Green et al. [1]). A more robust, prospective analysis measured the preconception serum DDT levels in Chinese textile workers between 1996 and 1998; after adjusting for age, BMI, and other occupational exposures, logistic regression revealed a 2.12 relative odds of early pregnancy loss (95% CI, 1.26–3.57) in the highest tertile serum DDT group compared with the lowest tertile (6Venners S.A. Korrick S. Xu X. Chen C. Guang W. Huang A. et al.Preconception serum DDT and pregnancy loss: a prospective study using a biomarker of pregnancy.Am J Epidemiol. 2005; 162: 709-716Crossref PubMed Scopus (76) Google Scholar). The particular strengths of this study include its prospective nature, recruitment of newly married nulliparous women actively trying to conceive, and use of daily urine human chorionic gonadotropin assays to prospectively detect conceptions, including early pregnancy losses occurring before clinical detection. Although human epidemiologic studies cannot provide information on the mechanisms, rodent studies indicate that exposure to pesticides adversely affects ovarian function. In vivo exposure of CD-1 mouse antral follicles to methoxychlor, a pesticide commonly found in insecticides, resulted in decreased expression of steroidogenic enzymes and decreased ovarian steroid biosynthesis (21Basavarajappa M.S. Craig Z.R. Hernández-Ochoa I. Paulose T. Leslie T.C. Flaws J.A. Methoxychlor reduces estradiol levels by altering steroidogenesis and metabolism in mouse antral follicles in vitro.Toxicol Appl Pharmacol. 2011; 253: 161-169Crossref PubMed Scopus (39) Google Scholar). In rats, exposure to methoxychlor during early development resulted in reduced expression of estrogen receptor β in preantral and antral follicles, important in the regulation of growth and maturation of ovarian follicles, granulosa cell differentiation, and luteinizing hormone responsiveness (22Zama A.M. Uzumcu M. Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective.Front Neuroendocrinol. 2010; 31: 420-439Crossref PubMed Scopus (115) Google Scholar). In vitro studies exposing mouse oocytes to methoxychlor demonstrated increased formation of reactive oxygen species, lipid peroxidation, and aberrant mitochondrial distribution (20Malott K.F. Luderer U. Toxicant effects on mammalian oocyte mitochondria.Biol Reprod. 2021; 104: 784-793Crossref PubMed Scopus (10) Google Scholar). A review of the mechanisms by which pesticides affect female reproductive function is provided by Zama and Uzumcu (22Zama A.M. Uzumcu M. Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective.Front Neuroendocrinol. 2010; 31: 420-439Crossref PubMed Scopus (115) Google Scholar). Plasticizers are substances added to a material to produce or promote flexibility and to reduce brittleness. The major plasticizers include phthalates and BPA, which are present in food, packaging, and consumer products such as medical devices, cosmetics, pharmaceuticals, and toys (2Segal T.R. Giudice L.C. Before the beginning: environmental exposures and reproductive and obstetrical outcomes.Fertil Steril. 2019; 112: 613-621Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Exposure can occur through ingestion, inhalation, and skin absorption, similar to the pathways seen for pesticide exposure (23Machtinger R. Orvieto R. Bisphenol A, oocyte maturation, implantation, and IVF outcome: review of animal and human data.Reprod Biomed Online. 2014; 29: 404-410Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Prospective cohort studies to determine the effect of plasticizer exposures on natural conception have yielded inconsistent results. A survey of 229 women who had been part of the Danish First Pregnancy Planner Study from 1992–1994 found an association between urinary monoethyl phthalate levels and a longer time to pregnancy, with a fecundability ratio of 0.79 (95% CI, 0.63–0.99) (19Thomsen A.M. Riis A.H. Olsen J. Jönsson B.A. Lindh C.H. Hjollund N.H. et al.Female exposure to phthalates and time to pregnancy: a first pregnancy planner study.Hum Reprod. 2017; 32: 232-238PubMed Google Scholar). However, Buck Louis et al. (15Buck Louis G.M. Sundaram R. Sweeney A.M. Schisterman E.F. Maisog J. Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) study.Fertil Steril. 2014; 101: 1359-1366Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar) found no significant association between female urinary BPA or phthalate concentrations and time to pregnancy. Of note, the latter study used only a single urine measurement, and participants were mostly white, college-educated patients, limiting generalizability. Similarly, in a cohort of 2,001 pregnant women, Vélez et al. (16Vélez M.P. Arbuckle T.E. Fraser W.D. Female exposure to phenols and phthalates and time to pregnancy: the Maternal-Infant Research on Environmental Chemicals (MIREC) study.Fertil Steril. 2015; 103: 1011-1020.e2Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar) found no association between urinary BPA or phthalate levels and time to pregnancy. However, this study relied on subject recall of time to pregnancy; further, the subjects had already achieved pregnancy, and the urinary BPA level was collected in the first trimester. Therefore, infertile women who may have had higher exposures to these chemicals were excluded (16Vélez M.P. Arbuckle T.E. Fraser W.D. Female exposure to phenols and phthalates and time to pregnancy: the Maternal-Infant Research on Environmental Chemicals (MIREC) study.Fertil Steril. 2015; 103: 1011-1020.e2Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). An association between plasticizers and infertility has been described in multiple studies primarily focusing on plasticizers’ effects on oocyte yield in women undergoing ART. Mok-lin et al. (9Mok-Lin E. Ehrlich S. Williams P.L. Petrozza J. Wright D.L. Calafat A.M. et al.Urinary bisphenol A concentrations and ovarian response among women undergoing IVF.Int J Androl. 2010; 33: 385-393Crossref PubMed Scopus (90) Google Scholar) found a negative correlation between urinary BPA levels and oocyte yield in 84 women undergoing ART, with an average 12% decrease in the number of oocytes retrieved per log unit increase in specific gravity of urinary BPA (95% CI, 4–23; P=.007). Similarly, in 174 women undergoing ART, Ehrlich et al. (10Ehrlich S. Williams P.L. Missmer S.A. Flaws J.A. Ye X. Calafat A.M. et al.Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF.Hum Reprod. 2012; 27: 3583-3592Crossref PubMed Scopus (180) Google Scholar) found a significant linear dose-response association between increased urinary BPA concentrations and decreased oocyte yield and normally fertilized oocytes (P=.001). In addition, Hauser et al. (18Hauser R. Gaskins A.J. Souter I. Smith K.W. Dodge L.E. Ehrich S. et al.Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study.Environ Health Perspect. 2016; 124: 831-839Crossref PubMed Scopus (122) Google Scholar) evaluated di (2-ethylhexyl) phthalate metabolites in 256 women undergoing IVF. After controlling for age, BMI, smoking status, and primary infertility diagnosis, the urinary di (2-ethylhexyl) phthalate metabolite concentrations were inversely associated with oocyte yield (P<.05), clinical pregnancy (P=.04), and live birth rate (P=.01) after ART (18Hauser R. Gaskins A.J. Souter I. Smith K.W. Dodge L.E. Ehrich S. et al.Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study.Environ Health Perspect. 2016; 124: 831-839Crossref PubMed Scopus (122) Google Scholar). On the contrary, Deng et al. (11Deng T. Du Y. Wang Y. Teng X. Hua X. Yuan X. et al.The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: a prospective single-center study.Ecotoxicol Environ Saf. 2020; 188: 109884Crossref PubMed Scopus (18) Google Scholar) measured urinary phthalate metabolites in 663 women undergoing IVF/intracytoplasmic sperm injection at a single center. Although increased urinary monobutylphthalate levels were negatively correlated with the odds of normal fertilization (P<.01), no significant correlation was found between any of the urinary phthalate concentrations and odds of a good-quality embryo on day 3 or blastocyst formation, clinical pregnancy rate, live birth rate, or early miscarriage rate (11Deng T. Du Y. Wang Y. Teng X. Hua X. Yuan X. et al.The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: a prospective single-center study.Ecotoxicol Environ Saf. 2020; 188: 109884Crossref PubMed Scopus (18) Google Scholar). Similarly, another prospective cohort study of 256 women undergoing IVF found no association between the urinary BPA levels (measured in up to 2 urine samples collected before oocyte retrieval) and proportion of high-quality embryos, fertilization rates, implantation rates, clinical pregnancy or live birth rates (17Mínguez-Alarcón L. Gaskins A.J. Chiu Y.H. Williams P.L. Erlich S. Chavarro J.E. et al.Urinary bisphenol A concentrations and association with in vitro fertilization outcomes among women from a fertility clinic.Hum Reprod. 2015; 30: 2120-2128Crossref PubMed Scopus (55) Google Scholar). Although multivariate models adjusted for confounders such as age, race, and BMI, a major caveat is the measurement of these short-lived compounds in 1–2 urine or serum samples at the time of the IVF cycle, which may not reflect the true window of exposure in relation to folliculogenesis, embryo implantation, or during pregnancy. In addition, whether the results can be generalizable to those conceiving naturally is unclear. With respect to miscarriage risk, Lathi et al. (12Lathi R.B. Liebert C.A. Brookfield K.F. Taylor J.A. vom Saal F.S. Fujimoto V.Y. et al.Conjugated bisphenol A in maternal serum in relation to miscarriage risk.Fertil Steril. 2014; 102: 123-128Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) conducted a prospective study of 115 women undergoing 68 clinical miscarriages. The median serum conjugated BPA concentrations measured during the missed menstrual cycle were significantly higher in women who had miscarriages than in those who had live births (P=.014) (12Lathi R.B. Liebert C.A. Brookfield K.F. Taylor J.A. vom Saal F.S. Fujimoto V.Y. et al.Conjugated bisphenol A in maternal serum in relation to miscarriage risk.Fertil Steril. 2014; 102: 123-128Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). A similar increased risk has been noted for both aneuploid and euploid miscarriages (12Lathi R.B. Liebert C.A. Brookfield K.F. Taylor J.A. vom Saal F.S. Fujimoto V.Y. et al.Conjugated bisphenol A in maternal serum in relation to miscarriage risk.Fertil Steril. 2014; 102: 123-128Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Unique to this study was the timing of serum conjugated BPA measurement, collected during early pregnancy shortly after implantation. In a subsequent case-control study including 102 patients with recurrent miscarriage, urinary BPA levels were correlated with an increased risk of recurrent miscarriage (P<.001) (13Shen Y. Zheng Y. Jiang J. Liu Y. Luo X. Shen Z. et al.Higher urinary bisphenol A concentration is associated with unexplained recurrent miscarriage risk: evidence from a case-control study in eastern China.PLoS One. 2015; 10e0127886Google Scholar). Although women with identifiable causes of recurrent miscarriage were excluded, embryo aneuploidy was not assessed. The study relied on subject recall of pregnancy history, and spot urine measurements were obtained after pregnancy, questioning the timing of exposure. A smaller study by Sugiura-Ogasawara et al. (14Sugiura-Ogasawara M. Ozaki Y. Sonta S. Makino T. Suzumori K. Exposure to bisphenol A is associated with recurrent miscarriage.Hum Reprod. 2005; 20: 2325-2329Crossref PubMed Scopus (329) Google Scholar) measured serum BPA levels in 45 women with a history of 3 or more consecutive first-trimester pregnancy losses and followed subsequent pregnancy outcomes over 16 months. The mean serum BPA levels were significantly higher in women with previous recurrent pregnancy loss (P=.024) compared with age-, BMI- and geographic location–matched controls, but higher serum BPA levels did not predict future miscarriage (14Sugiura-Ogasawara M. Ozaki Y. Sonta S. Makino T. Suzumori K. Exposure to bisphenol A is associated with recurrent miscarriage.Hum Reprod. 2005; 20: 2325-2329Crossref PubMed Scopus (329) Google Scholar). However, the timing of BPA exposure relative to subsequent miscarriage was unclear. Further, none of the above studies have taken into account the potential effects of male exposures on embryo quality and miscarriage risk. Studies in mice have elucidated the mechanisms by which plasticizers negatively impact female fertility and IVF outcomes. After Patricia Hunt serendipitously discovered an increase in mouse oocyte aneuploidy associated with damaged plastic cages and water bottles in 1998, her group later elucidated a dose-dependent increase in oocyte aneuploidy in mice treated with daily BPA (2Segal T.R. Giudice L.C. Before the beginning: environmental exposures and reproductive and obstetrical outcomes.Fertil Steril. 2019; 112: 613-621Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 22Zama A.M. Uzumcu M. Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective.Front Neuroendocrinol. 2010; 31: 420-439Crossref PubMed Scopus (115) Google Scholar). Mechanistic studies for BPA demonstrating adverse effects of BPA exposure on hypothalamic-pituitary signaling, folliculogenesis, oogenesis, estrous cyclicity, and embryo implantation have been reported (reviewed by Zama and Uzumcu [22] and Ziv-Gal and Flaws [24]). In utero exposures impaired uterine morphology and function in offspring (24Ziv-Gal A. Flaws J.A. Evidence for bisphenol A-induced female infertility: a review (2007-2016).Fertil Steril. 2016; 106: 827-856Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Human in vitro studies have also demonstrated adverse effects of BPA on oogenesis; exposure of fetal oocytes to BPA resulted in defects in synapsis and recombination of homologous chromosomes and increased oocyte degeneration (23Machtinger R. Orvieto R. Bisphenol A, oocyte maturation, implantation, and IVF outcome: review of animal and human data.Reprod Biomed Online. 2014; 29: 404-410Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). In adult oocytes, BPA exposure resulted in impairment of the cytoskeleton and incomplete meiosis (23Machtinger R. Orvieto R. Bisphenol A, oocyte maturation, implantation, and IVF outcome: review of animal and human data.Reprod Biomed Online. 2014; 29: 404-410Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Regarding phthalates, the mechanisms affecting female fertility in rodent studies include disruption of oogenesis and folliculogenesis, induction of deoxyribonucleic acid damage in oocytes, altered expression of gonadotropin and gonadotropin hormone-releasing hormone receptors, impaired steroidogenesis, and altered estrogen/androgen receptor signaling (reviewed in detail in the study by Hlisníková et al. [25Hlisníková H. Petrovičová I. Kolena B. Šidlovská M. Sirotkin A. Effects and mechanisms of phthalates’ action on reproductive processes and reproductive health: a literature review.Int J Environ Res Public Health. 2020; 17: 6811Crossref Scopus (50) Google Scholar]). Overall, these studies provide important insight into the mechanisms underlying decreased fertility after exposure to plasticizers. The data supporting the role of pesticides and plasticizers in female infertility and miscarriage continue to grow as more interest in the field arises. Much of the human literature is based on epidemiological studies lacking mechanistic information, and results are varied, in large part because of methodological differences, populations studied (e.g., fertile vs. infertile couples), and assessment of exposures (e.g., metabolites studied and frequency/timing of assessment). However, the data overwhelmingly support an overall negative effect of these EDCs on female fertility, reviewed in detail in the report by Green et al. (1Green M.P. Harvey A.J. Finger B.J. Tarulli G.A. Endocrine disrupting chemicals: impacts on human fertility and fecundity during the peri-conception period.Environ Res. 2021; 194: 110694Crossref PubMed Scopus (33) Google Scholar). Outside the scope of this review, but of equal importance, is the effect of male EDC exposures." @default.
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