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BackgroundIn 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on reproduction.ObjectiveIn this review, we summarize data obtained since 2007, focusing on a) findings from human and animal studies, b) the effects of BPA on a variety of reproductive end points, and c) mechanisms of BPA action.MethodsWe reviewed the literature published from 2007 to 2013 using a PubMed search based on keywords related to BPA and male and female reproduction.DiscussionBecause BPA has been reported to affect the onset of meiosis in both animal and in vitro models, interfere with germ cell nest breakdown in animal models, accelerate follicle transition in several animal species, alter steroidogenesis in multiple animal models and women, and reduce oocyte quality in animal models and women undergoing in vitro fertilization (IVF), we consider it an ovarian toxicant. In addition, strong evidence suggests that BPA is a uterine toxicant because it impaired uterine endometrial proliferation, decreased uterine receptivity, and increased implantation failure in animal models. BPA exposure may be associated with adverse birth outcomes, hyperandrogenism, sexual dysfunction, and impaired implantation in humans, but additional studies are required to confirm these associations. Studies also suggest that BPA may be a testicular toxicant in animal models, but the data in humans are equivocal. Finally, insufficient evidence exists regarding effects of BPA on the oviduct, the placenta, and pubertal development.ConclusionBased on reports that BPA impacts female reproduction and has the potential to affect male reproductive systems in humans and animals, we conclude that BPA is a reproductive toxicant.

STUDY QUESTION Does trophectoderm biopsy (TEBx) of blastocysts for preimplantation genetic testing in the clinic affect normal placental and embryo development and offspring metabolic outcomes in a mouse model? SUMMARY ANSWER TEBx impacts placental and embryonic health during early development, with some alterations resolving and others worsening later in development and triggering metabolic changes in adult offspring. WHAT IS KNOWN ALREADY Previous studies have not assessed the epigenetic and morphological impacts of TEBx either in human populations or in animal models. STUDY DESIGN, SIZE, DURATION We employed a mouse model to identify the effects of TEBx during IVF. Three groups were assessed: naturally conceived (Naturals), IVF, and IVF + TEBx, at two developmental timepoints: embryonic day (E)12.5 (n = 40/Naturals, n = 36/IVF, and n = 36/IVF + TEBx) and E18.5 (n = 42/Naturals, n = 30/IVF, and n = 35/IVF + TEBx). Additionally, to mimic clinical practice, we assessed a fourth group: IVF + TEBx + Vitrification (Vit) at E12.5 (n = 29) that combines TEBx and vitrification. To assess the effect of TEBx in offspring health, we characterized a 12-week-old cohort (n = 24/Naturals, n = 25/IVF and n = 25/IVF + TEBx). PARTICIPANTS/MATERIALS, SETTING, METHODS Our mouse model used CF-1 females as egg donors and SJL/B6 males as sperm donors. IVF, TEBx, and vitrification were performed using standardized methods. Placenta morphology was evaluated by hematoxylin–eosin staining, in situ hybridization using Tpbpa as a junctional zone marker and immunohistochemistry using CD34 fetal endothelial cell markers. For molecular analysis of placentas and embryos, DNA methylation was analyzed using pyrosequencing, luminometric methylation assay, and chip array technology. Expression patterns were ascertained by RNA sequencing. Triglycerides, total cholesterol, high-, low-, and very low-density lipoprotein, insulin, and glucose were determined in the 12-week-old cohort using commercially available kits. MAIN RESULTS AND THE ROLE OF CHANCE We observed that at E12.5, IVF + TEBx had a worse outcome in terms of changes in DNA methylation and differential gene expression in placentas and whole embryos compared with IVF alone and compared with Naturals. These changes were reflected in alterations in placental morphology and blood vessel density. At E18.5, early molecular changes in fetuses were maintained or exacerbated. With respect to placentas, the molecular and morphological changes, although different compared to Naturals, were equivalent to the IVF group, except for changes in blood vessel density, which persisted. Of note is that most differences were sex specific. We conclude that TEBx has more detrimental effects in mid-gestation placental and embryonic tissues, with alterations in embryonic tissues persisting or worsening in later developmental stages compared to IVF alone, and the addition of vitrification after TEBx results in more pronounced and potentially detrimental epigenetic effects: these changes are significantly different compared to Naturals. Finally, we observed that 12-week IVF + TEBx offspring, regardless of sex, showed higher glucose, insulin, triglycerides, lower total cholesterol, and lower high-density lipoprotein compared to IVF and Naturals, with only males having higher body weight compared to IVF and Naturals. Our findings in a mouse model additionally support the need for more studies to assess the impact of new procedures in ART to ensure healthy pregnancies and offspring outcomes. LARGE SCALE DATA Data reported in this work have been deposited in the NCBI Gene Expression Omnibus under accession number GSE225318. LIMITATIONS, REASONS FOR CAUTION This study was performed using a mouse model that mimics many clinical IVF procedures and outcomes observed in humans, where studies on early embryos are not possible. WIDER IMPLICATIONS OF THE FINDINGS This study highlights the importance of assaying new procedures used in ART to assess their impact on placenta and embryo development, and offspring metabolic outcomes. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by a National Centers for Translational Research in Reproduction and Infertility grant P50 HD068157-06A1 (M.S.B. C.C. M.M.), Ruth L. Kirschstein National Service Award Individual Postdoctoral Fellowship F32 HD107914 (E.A.R.-C.) and F32 HD089623 (L.A.V.), and National Institutes of Health Training program in Cell and Molecular Biology T32 GM007229 (C.N.H.). No conflict of interest. [ABSTRACT FROM AUTHOR]

Abstract Background Matrix metalloproteinases (MMPs) are implicated as mediators for ovarian remodeling events, and are involved with ovarian recrudescence during seasonal breeding cycles in Siberian hamsters. However, involvement of these proteases as the photoinhibited ovary undergoes atrophy and regression had not been assessed. We hypothesized that 1) MMPs and their tissue inhibitors, the TIMPs would be present and differentially regulated during the normal estrous cycle in Siberian hamsters, and that 2) MMP/TIMP mRNA and protein levels would increase as inhibitory photoperiod induced ovarian degeneration. Methods MMP-2, -9, -14 and TIMP-1 and -2 mRNA and protein were examined in the stages of estrous (proestrus [P], estrus [E], diestrus I [DI], and diestrus II [DII]) in Siberian hamsters, as well as after exposure to 3, 6, 9, and 12 weeks of inhibitory short photoperiod (SD). Results MMP-9 exhibited a 1.6-1.8 fold decrease in mRNA expression in DII (p < 0.05), while all other MMPs and TIMPs tested showed no significant difference in mRNA expression in the estrous cycle. Extent of immunostaining for MMP-2 and -9 peaked in P and E then significantly declined in DI and DII (p < 0.05). Extent of immunostaining for MMP-14, TIMP-1, and TIMP-2 was significantly more abundant in P, E, and DI than in DII (p < 0.05). Localization of the MMPs and TIMPs had subtle differences, but immunostaining was predominant in granulosa and theca cells, with significant differences noted in staining intensity between preantral follicles, antral follicles, corpora lutea, and stroma classifications. No significant changes were observed in MMP and TIMP mRNA or extent of protein immunostaining with exposure to 3, 6, 9, or 12 weeks of SD, however protein was present and was localized to follicular and luteal steroidogenic cells. Conclusions Although MMPs appear to be involved in the normal ovarian estrus cycle at the protein level in hamsters, those examined in the present study are unlikely to be key players in the slow atrophy of tissue as seen in Siberian hamster ovarian regression.

Background: Matrix metalloproteinases (MMPs) are implicated as mediators for ovarian remodeling events, and are involved with ovarian recrudescence during seasonal breeding cycles in Siberian hamsters. However, involvement of these proteases as the photoinhibited ovary undergoes atrophy and regression had not been assessed. We hypothesized that 1) MMPs and their tissue inhibitors, the TIMPs would be present and differentially regulated during the normal estrous cycle in Siberian hamsters, and that 2) MMP/TIMP mRNA and protein levels would increase as inhibitory photoperiod induced ovarian degeneration. Methods: MMP-2, -9, -14 and TIMP-1 and -2 mRNA and protein were examined in the stages of estrous (proestrus [P], estrus [E], diestrus I [DI], and diestrus II [DII]) in Siberian hamsters, as well as after exposure to 3, 6, 9, and 12 weeks of inhibitory short photoperiod (SD). Results: MMP-9 exhibited a 1.6-1.8 fold decrease in mRNA expression in DII (p < 0.05), while all other MMPs and TIMPs tested showed no significant difference in mRNA expression in the estrous cycle. Extent of immunostaining for MMP-2 and -9 peaked in P and E then significantly declined in DI and DII (p < 0.05). Extent of immunostaining for MMP-14, TIMP-1, and TIMP-2 was significantly more abundant in P, E, and DI than in DII (p < 0.05). Localization of the MMPs and TIMPs had subtle differences, but immunostaining was predominant in granulosa and theca cells, with significant differences noted in staining intensity between preantral follicles, antral follicles, corpora lutea, and stroma classifications. No significant changes were observed in MMP and TIMP mRNA or extent of protein immunostaining with exposure to 3, 6, 9, or 12 weeks of SD, however protein was present and was localized to follicular and luteal steroidogenic cells. Conclusions: Although MMPs appear to be involved in the normal ovarian estrus cycle at the protein level in hamsters, those examined in the present study are unlikely to be key players in the slow atrophy of tissue as seen in Siberian hamster ovarian regression. [ABSTRACT FROM AUTHOR]