Revisão Acesso aberto Revisado por pares

Evidence for bisphenol A-induced female infertility: a review (2007–2016)

2016; Elsevier BV; Volume: 106; Issue: 4 Linguagem: Inglês

10.1016/j.fertnstert.2016.06.027

ISSN

1556-5653

Autores

Ayelet Ziv‐Gal, Jodi A. Flaws,

Tópico(s)

Effects and risks of endocrine disrupting chemicals

Resumo

We summarized the scientific literature published from 2007 to 2016 on the potential effects of bisphenol A (BPA) on female fertility. We focused on overall fertility outcomes (e.g., ability to become pregnant, number of offspring), organs that are important for female reproduction (i.e., oviduct, uterus, ovary, hypothalamus, and pituitary), and reproductive-related processes (i.e., estrous cyclicity, implantation, and hormonal secretion). The reviewed literature indicates that BPA may be associated with infertility in women. Potential explanations for this association can be generated from experimental studies. Specifically, BPA may alter overall female reproductive capacity by affecting the morphology and function of the oviduct, uterus, ovary, and hypothalamus-pituitary-ovarian axis in animal models. In addition, BPA may disrupt estrous cyclicity and implantation. Nevertheless, further studies are needed to better understand the exact mechanisms of action and to detect potential reproductive toxicity at earlier stages. We summarized the scientific literature published from 2007 to 2016 on the potential effects of bisphenol A (BPA) on female fertility. We focused on overall fertility outcomes (e.g., ability to become pregnant, number of offspring), organs that are important for female reproduction (i.e., oviduct, uterus, ovary, hypothalamus, and pituitary), and reproductive-related processes (i.e., estrous cyclicity, implantation, and hormonal secretion). The reviewed literature indicates that BPA may be associated with infertility in women. Potential explanations for this association can be generated from experimental studies. Specifically, BPA may alter overall female reproductive capacity by affecting the morphology and function of the oviduct, uterus, ovary, and hypothalamus-pituitary-ovarian axis in animal models. In addition, BPA may disrupt estrous cyclicity and implantation. Nevertheless, further studies are needed to better understand the exact mechanisms of action and to detect potential reproductive toxicity at earlier stages. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/10958-evidence-for-bisphenol-a-induced-female-infertility-review-2007-2016 Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/10958-evidence-for-bisphenol-a-induced-female-infertility-review-2007-2016 Female infertility is generally defined as the inability to get pregnant naturally and to deliver a live healthy newborn. According to the Centers for Disease Control and Prevention (CDC; http://www.cdc.gov/nchs/nsfg/key_statistics/i.htm#infertility), between 2011 and 2013, 6.1% of married women were considered to be infertile in the United States alone. The percentage of infertile women can reach 30% worldwide (1Inhorn M.C. Patrizio P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century.Hum Reprod Update. 2015; 21: 411-426Crossref PubMed Scopus (18) Google Scholar). Infertility in women can be the result of various factors, including physical problems, endocrine problems, lifestyle habits, and environmental factors. Environmental factors, such as exposure to chemicals with endocrine disrupting properties, can mimic or block the endocrine activity of endogenous hormones and thus adversely affect reproduction. One of the most extensively studied endocrine disrupting chemicals is bisphenol A (BPA). Bisphenol A is incorporated in many daily used products; it is used by the manufacturers of polycarbonate plastics and epoxy resins. Despite the relatively short half-life of BPA (6–24 hours) (2Volkel W. Colnot T. Csanady G.A. Filser J.G. Dekant W. Metabolism and kinetics of bisphenol a in humans at low doses following oral administration.Chem Res Toxicol. 2002; 15: 1281-1287Crossref PubMed Scopus (389) Google Scholar), it was measured in various reproductive tissues (3Vandenberg L.N. Hauser R. Marcus M. Olea N. Welshons W.V. Human exposure to bisphenol A (BPA).Reprod Toxicol. 2007; 24: 139-177Crossref PubMed Scopus (830) Google Scholar), including ovarian follicular fluid, placenta, breast milk, and colostrum. Findings from previous publications suggest that BPA is a reproductive toxicant (4Peretz J. Vrooman L. Ricke W.A. Hunt P.A. Ehrlich S. Hauser R. et al.Bisphenol a and reproductive health: update of experimental and human evidence, 2007–2013.Environ Health Perspect. 2014; 122: 775-786PubMed Google Scholar, 5Vandenberg L.N. Ehrlich S. Belcher S.M. Ben-Jonathan N. Dolinoy D.C. Hugo E.R. et al.Low dose effects of bisphenol A.Endocrine Disruptors. 2013; 1: e26490Crossref Google Scholar, 6Maffini M.V. Rubin B.S. Sonnenschein C. Soto A.M. Endocrine disruptors and reproductive health: the case of bisphenol-A.Mol Cell Endocrinol. 2006; 254-255: 179-186Crossref PubMed Scopus (273) Google Scholar). The current review focuses on the scientific evidence for BPA-induced fertility problems in females. We summarized the main findings of epidemiological and experimental studies that examined the potential effects of BPA on female fertility and that were published between 2007 and 2016. We included the morphological and mechanistic findings reported in the reviewed articles. We focused on the reported outcomes of BPA exposure on overall: [1] fertility, [2] reproductive-related processes including the ovarian cycle, and [3] reproductive tissues. PubMed (http://www.ncbi.nlm.nih.gov/pubmed) searches for the years 2007–2016 were conducted using the following key words: BPA, bisphenol A, fertility, female, reproduction, ovary, pregnancy, oviduct, ovulation, fertilization, uterus, implantation, hypothalamus, and pituitary. We focused on articles published in 2007–2016 to expand on previous review reports on the same topic (4Peretz J. Vrooman L. Ricke W.A. Hunt P.A. Ehrlich S. Hauser R. et al.Bisphenol a and reproductive health: update of experimental and human evidence, 2007–2013.Environ Health Perspect. 2014; 122: 775-786PubMed Google Scholar, 5Vandenberg L.N. Ehrlich S. Belcher S.M. Ben-Jonathan N. Dolinoy D.C. Hugo E.R. et al.Low dose effects of bisphenol A.Endocrine Disruptors. 2013; 1: e26490Crossref Google Scholar, 7Fowler P.A. Bellingham M. Sinclair K.D. Evans N.P. Pocar P. Fischer B. et al.Impact of endocrine-disrupting compounds (EDCs) on female reproductive health.Mol Cell Endocrinol. 2012; 355: 231-239Crossref PubMed Scopus (70) Google Scholar, 8Caserta D. Di Segni N. Mallozzi M. Giovanale V. Mantovani A. Marci R. et al.Bisphenol A and the female reproductive tract: an overview of recent laboratory evidence and epidemiological studies.Reprod Biol Endocrinol. 2014; 12: 37Crossref PubMed Scopus (16) Google Scholar, 9Aghajanova L. Giudice L.C. Effect of bisphenol A on human endometrial stromal fibroblasts in vitro.Reprod Biomed Online. 2011; 22: 249-256Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 10Machtinger 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 (0) Google Scholar, 11Gore A.C. Chappell V.A. Fenton S.E. Flaws J.A. Nadal A. Prins G.S. et al.EDC-2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.Endocrinol Rev. 2015; 36: E1-E150Crossref PubMed Scopus (0) Google Scholar). In addition, references included in other review articles were examined for relevant information. We included articles that dealt with fertility/infertility outcomes related to overall fertility, implantation, uterine morphology and function, estrous cyclicity, hypothalamus-pituitary, hormone levels (luteinizing hormone [LH], follicular stimulating hormone [FSH], and prolactin [PRL]), oviduct, and ovary. We excluded articles about topics that were out of the scope of this review or ones that will be reviewed by other investigators in this special issue (e.g., sexual maturation/behavior, oocyte quality and maturation, ovarian steroidogenesis, pregnancy, miscarriage, endometriosis, polycystic ovarian syndrome [PCOS], and uterine fibroids/leiomyoma). The BPA studies have used various study designs and included a wide range of doses. Based on the definitions in other studies, we considered a "low dose" of BPA as follows: a dose below the lowest observable adverse effect level of 50 mg/kg/d in animal models (4Peretz J. Vrooman L. Ricke W.A. Hunt P.A. Ehrlich S. Hauser R. et al.Bisphenol a and reproductive health: update of experimental and human evidence, 2007–2013.Environ Health Perspect. 2014; 122: 775-786PubMed Google Scholar, 5Vandenberg L.N. Ehrlich S. Belcher S.M. Ben-Jonathan N. Dolinoy D.C. Hugo E.R. et al.Low dose effects of bisphenol A.Endocrine Disruptors. 2013; 1: e26490Crossref Google Scholar, 12Richter C.A. Birnbaum L.S. Farabollini F. Newbold R.R. Rubin B.S. Talsness C.E. et al.In vivo effects of bisphenol A in laboratory rodent studies.Reprod Toxicol. 2007; 24: 199-224Crossref PubMed Scopus (502) Google Scholar, 13Vom Saal F.S. Akingbemi B.T. Belcher S.M. Birnbaum L.S. Crain D.A. Eriksen M. et al.Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure.Reprod Toxicol. 2007; 24: 131-138Crossref PubMed Scopus (363) Google Scholar), 17.2 mg/L for aquatic animals (5Vandenberg L.N. Ehrlich S. Belcher S.M. Ben-Jonathan N. Dolinoy D.C. Hugo E.R. et al.Low dose effects of bisphenol A.Endocrine Disruptors. 2013; 1: e26490Crossref Google Scholar, 14Crain D.A. Eriksen M. Iguchi T. Jobling S. Laufer H. LeBlanc G.A. et al.An ecological assessment of bisphenol-A: evidence from comparative biology.Reprod Toxicol. 2007; 24: 225-239Crossref PubMed Scopus (120) Google Scholar), 1 × 10−7 M for cell culture experiments (5Vandenberg L.N. Ehrlich S. Belcher S.M. Ben-Jonathan N. Dolinoy D.C. Hugo E.R. et al.Low dose effects of bisphenol A.Endocrine Disruptors. 2013; 1: e26490Crossref Google Scholar, 15Wetherill Y.B. Akingbemi B.T. Kanno J. McLachlan J.A. Nadal A. Sonnenschein C. et al.In vitro molecular mechanisms of bisphenol A action.Reprod Toxicol. 2007; 24: 178-198Crossref PubMed Scopus (339) Google Scholar), and a dose in the range of typical (not occupational) human exposures for epidemiological studies (5Vandenberg L.N. Ehrlich S. Belcher S.M. Ben-Jonathan N. Dolinoy D.C. Hugo E.R. et al.Low dose effects of bisphenol A.Endocrine Disruptors. 2013; 1: e26490Crossref Google Scholar, 16Vandenberg L.N. Colborn T. Hayes T.B. Heindel J.J. Jacobs Jr., D.R. Lee D.H. et al.Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.Endocrinol Rev. 2012; 33: 378-455Crossref PubMed Scopus (0) Google Scholar). Most studies described in this review used doses that are within the category of low dose. Throughout the text of this review, we indicated if the doses were considered low or high based on these categories. In the Tables, the specific doses that were used in each study are described in detail. Last, similar to Peretz et al. (4Peretz J. Vrooman L. Ricke W.A. Hunt P.A. Ehrlich S. Hauser R. et al.Bisphenol a and reproductive health: update of experimental and human evidence, 2007–2013.Environ Health Perspect. 2014; 122: 775-786PubMed Google Scholar), we defined exposure time during pregnancy as in utero; exposure after birth that ended before weaning as neonatal; and exposure any time after weaning as postnatal or adult exposure. In recent years, several research groups have examined the effects of BPA on overall fertility. Epidemiological studies examined whether BPA levels are higher in infertile women than in fertile women (Table 1). Findings from these studies (19Caserta D. Bordi G. Ciardo F. Marci R. La Rocca C. Tait S. et al.The influence of endocrine disruptors in a selected population of infertile women.Gynecol Endocrinol. 2013; 29: 444-447Crossref PubMed Scopus (24) Google Scholar, 26La Rocca C. Tait S. Guerranti C. Busani L. Ciardo F. Bergamasco B. et al.Exposure to endocrine disrupters and nuclear receptor gene expression in infertile and fertile women from different Italian areas.Int J Environ Res Public Health. 2014; 11: 10146-10164Crossref PubMed Scopus (4) Google Scholar) indicate that infertile women have higher serum BPA levels compared with fertile women. Furthermore, studies (17Bloom M.S. Kim D. Vom Saal F.S. Taylor J.A. Cheng G. Lamb J.D. et al.Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization.Fertil Steril. 2011; 96: 672-677.e2Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 21Ehrlich 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 (52) Google Scholar, 22Fujimoto V.Y. Kim D. vom Saal F.S. Lamb J.D. Taylor J.A. Bloom M.S. Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization.Fertil Steril. 2011; 95: 1816-1819Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 28Mok-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 (80) Google Scholar, 29Bloom M.S. Vom Saal F.S. Kim D. Taylor J.A. Lamb J.D. Fujimoto V.Y. Serum unconjugated bisphenol A concentrations in men may influence embryo quality indicators during in vitro fertilization.Environ Toxicol Pharmacol. 2011; 32: 319-323Crossref PubMed Scopus (21) Google Scholar) conducted in women undergoing IVF treatments show that BPA levels (total or unconjugated BPA) were inversely associated with peak E2 levels, number of oocytes retrieved, oocyte maturation, fertilization rates, and embryo quality. Thus, increased levels of BPA may decrease the success rate of IVF treatments. Nevertheless, these studies did not take into account potential modifying factors such as co-exposure to other chemicals and the location of sample collection as pointed out by Teeguarden et al. (30Teeguarden J.G. Waechter Jr., J.M. Clewell 3rd, H.J. Covington T.R. Barton H.A. Evaluation of oral and intravenous route pharmacokinetics, plasma protein binding, and uterine tissue dose metrics of bisphenol A: a physiologically based pharmacokinetic approach.Toxicol Sci. 2005; 85: 823-838Crossref PubMed Scopus (73) Google Scholar, 31Teeguarden J.G. Hanson-Drury S. A systematic review of Bisphenol A "low dose" studies in the context of human exposure: a case for establishing standards for reporting "low-dose" effects of chemicals.Food Chem Toxicol. 2013; 62: 935-948Crossref PubMed Scopus (38) Google Scholar). Thus, additional studies are needed to fully understand the associations between BPA exposure and fertility outcomes in women.Table 1BPA and fertility (epidemiological studies).Study designStudy populationSample sizeTime of BPA measurementBPA concentrationOutcomeReference no.Cross-sectionalWomen undergoing IVF44Day of oocyte retrievalMedian unconjugated serum BPA 2.53 ng/mL (range, 0.3–67.36 ng/mL)BPA inversely associated with peak estradiol; no association with number of oocytes retrieved17Bloom M.S. Kim D. Vom Saal F.S. Taylor J.A. Cheng G. Lamb J.D. et al.Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization.Fertil Steril. 2011; 96: 672-677.e2Abstract Full Text Full Text PDF PubMed Scopus (38) Google ScholarMatched cohortWomen discontinuing contraception210On the day of expectedmenstruationUrine (total BPA), mean (95% confidence interval): pregnant: 0.63 ng/mL (0.54–0.73); nonpregnant: 0.68 ng/mL (0.53–0.87)No association with impaired fecundity or time to pregnancy18Buck 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 (26) Google ScholarCross-sectionalFertile and infertile Italian women12 fertile35 infertileEnrollmentNot indicated; limit of detection 0.5 ng/mL (serum samples)Higher percentage of infertile women with detectable serum BPA levels19Caserta D. Bordi G. Ciardo F. Marci R. La Rocca C. Tait S. et al.The influence of endocrine disruptors in a selected population of infertile women.Gynecol Endocrinol. 2013; 29: 444-447Crossref PubMed Scopus (24) Google ScholarProspectiveWomen undergoing IVF239 (63 no soy food intake); 347 cyclesBetween days 3 and 9 of gonadotropin phase and on day of oocyte retrievalUrine (total BPA); Range, <0.4–16.6 μg/L; median, 1.3 μg/L (interquartile range, 0.9–1.9 μg/L)Soy food consumption modifies the correlation between BPA and infertility treatment outcomes20Chavarro J.E. Minguez-Alarcon L. Chiu Y.H. Gaskins A.J. Souter I. Williams P.L. et al.Soy intake modifies the relation between urinary bisphenol A concentrations and pregnancy outcomes among women undergoing assisted reproduction.J Clin Endocrinol Metab. 2016; 101: 1082-1090Crossref PubMed Scopus (2) Google ScholarProspectiveWomen undergoing IVF174 (237 cycles)Day of oocyte retrievalUrinary (total BPA) geometric mean 1.50 (SD 2.22) μg/LHigher BPA levels associated with lower serum peak estradiol, oocyte yield, MII oocyte count, and number of normally fertilizing oocytes21Ehrlich 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 (52) Google ScholarProspectiveWomen undergoing ICSI and IVF58Day of oocyte retrievalMedian unconjugated serum BPA 2.53 ng/mL (range, 0.0–67.4 ng/mL)Inverse associations between BPA and oocyte maturation (Asian women) and normal fertilization (all women)22Fujimoto V.Y. Kim D. vom Saal F.S. Lamb J.D. Taylor J.A. Bloom M.S. Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization.Fertil Steril. 2011; 95: 1816-1819Abstract Full Text Full Text PDF PubMed Scopus (37) Google ScholarPregnancy-based retrospectiveWomen in 1st trimester1,742Spot urine during the 1st trimester visitUrinary (total BPA) geometric mean 0.78 (0.73–0.82) ng/mLNo association with diminished fecundity23Velez 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 Google ScholarProspectiveWomen undergoing IVF35 of 58Day of oocyte retrievalMedian unconjugated serum BPA 2.4 μg/L serum (range, 0.0–67.4)Up-regulation of TSP50 with increased BPA levels due to a loss of methylation24Hanna C.W. Bloom M.S. Robinson W.P. Kim D. Parsons P.J. vom Saal F.S. et al.DNA methylation changes in whole blood is associated with exposure to the environmental contaminants, mercury, lead, cadmium and bisphenol A, in women undergoing ovarian stimulation for IVF.Hum Reprod. 2012; 27: 1401-1410Crossref PubMed Scopus (43) Google ScholarProspectiveFertile women that discontinued contraception221Pooled urine throughout menstrual cyclesUrinary (total BPA) median 2.7 ng/mL (interquartile range 1.8, 4.3), not adjustedBPA associated with shorter luteal phase; null associations with follicular-phase length, time to pregnancy, and early pregnancy loss25Jukic A.M. Calafat A.M. McConnaughey D.R. Longnecker M.P. Hoppin J.A. Weinberg C.R. et al.Urinary concentrations of phthalate metabolites and bisphenol A and associations with follicular-phase length, luteal-phase length, fecundability, and early pregnancy loss.Environ Health Perspect. 2016; 124: 321-328PubMed Google ScholarCross-sectionalWomen who volunteered110 infertile, 43 fertileWhole blood sample prior to any treatmentMean (total BPA, serum) (ng/mL): fertile 4.8 infertile 10.6BPA levels higher among infertile women (odds ratio 8.3) in metropolitan area26La Rocca C. Tait S. Guerranti C. Busani L. Ciardo F. Bergamasco B. et al.Exposure to endocrine disrupters and nuclear receptor gene expression in infertile and fertile women from different Italian areas.Int J Environ Res Public Health. 2014; 11: 10146-10164Crossref PubMed Scopus (4) Google ScholarProspectiveWomen undergoing IVF256 (375 cycles)Between days 3 and 9 of gonadotropin phase; and on day of oocyte retrievalUrinary (total BPA) geometric mean 1.87 μg/LNo associations with oocyte yield, endometrial thickness, embryo quality, fertilization rates, implantation, clinical pregnancy and live birth rates27Minguez-Alarcon L. Gaskins A.J. Chiu Y.H. Williams P.L. Ehrlich 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 (5) Google ScholarProspectiveWomen undergoing IVF84 (112 cycles)Day of oocyte retrievalUrinary (total BPA); Range, <0.4–25.5 μg/L; urinary geometric mean 2.52 μg/L (SD 3.2)BPA levels inversely associated with the number of oocytes retrieved and peak serum estradiol levels28Mok-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 (80) Google ScholarProspectiveWomen undergoing IVF36Day of oocyte retrievalMedian unconjugated serum BPA 3.3 ng/mL (range, 0.0–67.4 ng/mL)No association with embryo quality29Bloom M.S. Vom Saal F.S. Kim D. Taylor J.A. Lamb J.D. Fujimoto V.Y. Serum unconjugated bisphenol A concentrations in men may influence embryo quality indicators during in vitro fertilization.Environ Toxicol Pharmacol. 2011; 32: 319-323Crossref PubMed Scopus (21) Google ScholarNote: BPA = bisphenol A; ICSI = intracytoplasmic sperm injection. Open table in a new tab Note: BPA = bisphenol A; ICSI = intracytoplasmic sperm injection. Limited information is available on the potential molecular targets of BPA in infertile women. Hanna et al. (24Hanna C.W. Bloom M.S. Robinson W.P. Kim D. Parsons P.J. vom Saal F.S. et al.DNA methylation changes in whole blood is associated with exposure to the environmental contaminants, mercury, lead, cadmium and bisphenol A, in women undergoing ovarian stimulation for IVF.Hum Reprod. 2012; 27: 1401-1410Crossref PubMed Scopus (43) Google Scholar) reported an association between higher serum levels of unconjugated BPA and decreased methylation within the TSP50 gene promoter in whole blood samples of women undergoing IVF treatments. However, the researchers did not provide any mechanistic explanations of these findings other than to indicate that TSP50 may be an oncogene based on previous research by other groups (32Shan J. Yuan L. Xiao Q. Chiorazzi N. Budman D. Teichberg S. et al.TSP50, a possible protease in human testes, is activated in breast cancer epithelial cells.Cancer Res. 2002; 62: 290-294PubMed Google Scholar, 33Yuan L. Shan J. de Risi D. Broome J. Lovecchio J. Gal D. et al.Isolation of a novel gene, TSP50, by a hypomethylated DNA fragment in human breast cancer.Cancer Res. 1999; 59: 3215-3221PubMed Google Scholar). Interesting findings reported by Chavarro et al. (20Chavarro J.E. Minguez-Alarcon L. Chiu Y.H. Gaskins A.J. Souter I. Williams P.L. et al.Soy intake modifies the relation between urinary bisphenol A concentrations and pregnancy outcomes among women undergoing assisted reproduction.J Clin Endocrinol Metab. 2016; 101: 1082-1090Crossref PubMed Scopus (2) Google Scholar) suggest a potential modifying effect of soy food consumption on the inverse correlations between urinary total BPA concentrations and fertility treatment outcomes. Overall, these studies are suggestive for potential associations between BPA and infertility. However, additional studies are needed to determine a possible cause and effect relationship and the mechanism of action of BPA-mediated effects on fertility in healthy women. Not all epidemiological studies found an association between BPA exposure and fertility outcomes. Null associations were reported between urinary total BPA concentrations and impaired fecundity or time to pregnancy in generally healthy women (18Buck 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 (26) Google Scholar, 23Velez 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 Google Scholar, 25Jukic A.M. Calafat A.M. McConnaughey D.R. Longnecker M.P. Hoppin J.A. Weinberg C.R. et al.Urinary concentrations of phthalate metabolites and bisphenol A and associations with follicular-phase length, luteal-phase length, fecundability, and early pregnancy loss.Environ Health Perspect. 2016; 124: 321-328PubMed Google Scholar). In another study (27Minguez-Alarcon L. Gaskins A.J. Chiu Y.H. Williams P.L. Ehrlich 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 (5) Google Scholar), null associations between urinary total BPA concentrations and number of oocytes retrieved, embryo quality, and fertilization rates were reported in women undergoing IVF treatments. The differences in the results may be explained by differences in sample characteristics (i.e., generally healthy women without any reported infertility issues vs. women undergoing IVF treatments) and by differences in sample size. Studies using animal models provide further insights on the effects of BPA exposure on female fertility (Table 2). In mice, Berger et al. (34Berger R.G. Hancock T. deCatanzaro D. Influence of oral and subcutaneous bisphenol-A on intrauterine implantation of fertilized ova in inseminated female mice.Reprod Toxicol. 2007; 23: 138-144Crossref PubMed Scopus (31) Google Scholar) reported that low dose BPA exposure of pregnant dams during the preimplantation period significantly reduced the number of litters and litter size compared with controls. Furthermore, in utero low dose BPA exposure after implantation affected the fertility of the females in the subsequent generations (45Wang W. Hafner K.S. Flaws J.A. In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse.Toxicol Appl Pharmacol. 2014; 276: 157-164Crossref PubMed Scopus (15) Google Scholar, 49Ziv-Gal A. Wang W. Zhou C. Flaws J.A. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice.Toxicol Appl Pharmacol. 2015; 284: 354-362Crossref PubMed Scopus (4) Google Scholar). Cabaton et al. (35Cabaton N.J. Wadia P.R. Rubin B.S. Zalko D. Schaeberle C.M. Askenase M.H. et al.Perinatal exposure to environmentally relevant levels of bisphenol A decreases fertility and fecundity in CD-1 mice.Environ Health Perspect. 2011; 119: 547-552Crossref PubMed Scopus (0) Google Scholar) performed a forced breeding study and found that low dose BPA-exposed females had fewer pregnancies and overall reduced cumulative number of pups compared with controls. Moore-Ambriz et al. (40Moore-Ambriz T.R. Acuna-Hernandez D.G. Ramos-Robles B. Sanchez-Gutierrez M. Santacruz-Marquez R. Sierra-Santoyo A. et al.Exposure to bisphenol A in young adult mice does not alter ovulation but does alter the fertilization ability of oocytes.Toxicol Appl Pharmacol. 2015; 289: 507-514Crossref PubMed Google Scholar) examined the effects of BPA exposure in young adult mice on fertilization capacity later in adult life. The fertilization rate of BPA exposed females was reduced compared with controls. Furthermore, impaired fertility was also reported in a study that examined the effects of in utero low dose BPA exposure in three subsequent generations of mice (45Wang W. Hafner K.S. Flaws J.A. In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse.Toxicol Appl Pharmacol. 2014; 276: 157-164Crossref PubMed Scopus (15) Google Scholar, 49Ziv-Gal A. Wang W. Zhou C. Flaws J.A. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice.Toxicol Appl Pharmacol. 2015; 284: 354-362Crossref PubMed Scopus (4) Google Scholar). Specifically, F1 females that were gestationally exposed to BPA had reduced fertility, reduced litter size (45Wang W. Hafner K.S. Flaws J.A. In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse.Toxicol Appl Pharmacol. 2014; 276: 157-164Crossref PubMed Scopus (15) Google Scholar), and reduced ability to maintain pregnancy to term (i.e., reduced gestational index) compared with controls (49Ziv-Gal A. Wang W. Zhou C. Flaws J.A. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice.Toxicol Appl Pharmacol. 2015; 284: 354-362Crossref PubMed Scopus (4) Google Scholar). Furthermore, F2 females had a reduced gestational index compared with controls (49Ziv-Gal A. Wang W. Zhou C. Flaws J.A. The effects of in utero bisphenol A exposure on reproductive capacity in several

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