Bisphenol A, oocyte maturation, implantation, and IVF outcome: review of animal and human data.

Recent data have raised concerns about the detrimental effect of chronic exposure to environmental chemicals. Some chemicals affect the endocrine system (endocrine disruptors) and have been linked to several diseases, including infertility. One such endocrine disruptor is bisphenol A (BPA), a monomer widely used in the plastic industry, with nearly ubiquitous exposure. In this review, data on the effects of BPA on female fertility are summarized. Specifically, its effect is considered on folliculogenesis, oocyte maturation, embryo quality, and implantation, both in animal and human models. Animal studies have shown that BPA might impair prophase I, follicular growth, and implantation, and may be associated with spindle abnormalities. In humans, while in-vitro studies have suggested an association between BPA exposure and impaired oocyte meiosis, clinical evidence indicate possible adverse effects of BPA exposure on IVF outcomes. As human clinical data are still scarce, larger studies are required to further elucidate the effects of BPA exposure on female fertility.

Machtinger R ，Orvieto R 《-》

Long-lasting effects of neonatal bisphenol A exposure on the implantation process.

Successful implantation is the result of complex molecular interactions between the hormonally primed uterus and a mature blastocyst. This very carefully synchronized interplay of hormonal signals and feedback loops is potentially vulnerable to chemicals such as endocrine disruptors that may disrupt endocrine signaling. Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide. This chapter describes the effects of brief postnatal exposure to BPA on female reproductive performance and specifically on the uterine adaptations during the preimplantation period. We propose that an early alteration in Hoxa10 gene expression affects the functional differentiation of the preimplantation uterus as part of an altered endocrine signal transduction pathway. These molecular alterations could explain, at least in part, the adverse effects of BPA on uterine implantation. Exposure to endocrine disruptors, such as BPA, could contribute to the impaired female fertility noted over the past decades.

Varayoud J ，Ramos JG ，Muñoz-de-Toro M ，Luque EH ... -  《Vitamins and Hormones》

Environmentally relevant levels of bisphenol A affect uterine decidualization and embryo implantation through the estrogen receptor/serum and glucocorticoid-regulated kinase 1/epithelial sodium ion channel α-subunit pathway in a mouse model.

To investigate whether bisphenol A (BPA) exposure is associated with uterine decidualization and embryo implantation failure in mice. Experimental animal study and in vitro study. University-based infertility center. ICR mice. Mice treated with different doses of BPA; Ishikawa cells cultured in medium of different concentrations of BPA. Embryo implantation sites, uterine weight, quantitative real-time reverse transcriptase-polymerase chain reaction, Western blot analysis, hematoxylin and eosin staining, and immunohistochemical, cell proliferation, and statistical analyses. In the experiment of mouse model, administration of 1-100 μg/kg/day of BPA by gavage led to reduction of the number of embryo implantation sites in a dose-dependent manner; 100 μg/kg/day of BPA statistically significantly reduced the number of implantation sites compared with the control group. The uterine weight change (the wet weight of the decidualized uterine horn divided by the wet weight of the undecidualized uterine horn of the mouse) in groups exposed to BPA (100-10,000 μg/kg/day) were statistically significantly lower compared with the control group. Immunohistochemical analysis demonstrated that administration of 100, 1,000, or 10,000 μg/kg/day of BPA by gavage statistically significantly down-regulated the expression of epithelial Na+ channel α-subunit (ENaCα) in the luminal epithelial cells and desmin in decidual cells of the oil-induced decidualized uterine horns. Administration of 100 μg/kg/day BPA on embryo days 0.5-3.5 by gavage statistically significantly decreased the level of uterine serum and glucocorticoid-regulated kinase 1 (SGK1) protein expression on embryo days 4 and 6. After treatment with 0.001, 0.01, 0.1, or 1.0 μg/mL of BPA for 48 hours, the SGK1, ENaCα, and phospho-SGK1 protein expression of Ishikawa cells was down-regulated, and the effect of BPA on SGK1 could be abrogated by fulvestrant. Our study provides the first indication that BPA exposure at levels as low as 100 μg/kg/day can impair embryo implantation in mice and BPA can affect decidualization of the uterus in mouse model. Our results suggest that BPA can down-regulate SGK1 and ENaCα protein expression through estrogen receptors in Ishikawa cells.

Yuan M ，Hu M ，Lou Y ，Wang Q ，Mao L ，Zhan Q ，Jin F ... -  《-》

Urinary bisphenol A concentrations and association with in vitro fertilization outcomes among women from a fertility clinic.

Are urinary BPA concentrations associated with in vitro fertilization (IVF) outcomes among women attending an academic fertility center? Urinary BPA concentrations were not associated with adverse reproductive and pregnancy outcomes among women from a fertility clinic. Bisphenol A (BPA), an endocrine disruptor, is detected in the urine of most Americans. Although animal studies have demonstrated that BPA reduces female fertility through effects on the ovarian follicle and uterus, data from human populations are scarce and equivocal. This prospective cohort study between 2004 and 2012 at the Massachusetts General Hospital Fertility Center included 256 women (n = 375 IVF cycles) who provided up to two urine samples prior to oocyte retrieval (total N = 673). Study participants were women enrolled in the Environment and Reproductive Health (EARTH) Study. Intermediate and clinical end-points of IVF treatments were abstracted from electronic medical records. We used generalized linear mixed models with random intercepts to evaluate the association between urinary BPA concentrations and IVF outcomes adjusted by age, race, body mass index, smoking status and infertility diagnosis. The specific gravity-adjusted geometric mean of BPA was 1.87 µg/l, which is comparable to that for female participants in the National Health and Nutrition Examination Survey, 2011-2012. Urinary BPA concentrations were not associated with endometrial wall thickness, peak estradiol levels, proportion of high quality embryos or fertilization rates. Furthermore, there were no associations between urinary BPA concentrations and implantation, clinical pregnancy or live birth rates per initiated cycle or per embryo transfer. Although we did not find any associations between urinary BPA concentrations and IVF outcomes, the relation between BPA and endometrial wall thickness was modified by age. Younger women (<37 years old) had thicker endometrial thickness across increasing quartiles of urinary BPA concentrations, while older women (≥37 years old) had thinner endometrial thickness across increasing quartiles of urinary BPA concentrations. Limitations to this study include a possible misclassification of BPA exposure and difficulties in extrapolating the findings to the general population. Data on the relation between urinary BPA concentrations and reproductive outcomes remain scarce and additional research is needed to clarify its role in human reproduction. This work was supported by NIH grants R01ES022955, R01ES009718 and R01ES000002 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32DK00770316 from the National Institute of Child Health and Human Development (NICHD). None of the authors has any conflicts of interest to declare. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Mínguez-Alarcón L ，Gaskins AJ ，Chiu YH ，Williams PL ，Ehrlich S ，Chavarro JE ，Petrozza JC ，Ford JB ，Calafat AM ，Hauser R ，EARTH Study Team ... -  《-》

Influence of N-acetyl-L-cysteine against bisphenol a on the maturation of mouse oocytes and embryo development: in vitro study.

Li Q ，Zhao Z 《-》