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Bisphenol A (BPA) is commonly found in epoxy resins used in the manufacture of plastic coatings in food packaging and beverage cans. There is a growing concern about BPA as a weak estrogenic compound that can affect human endocrine function. Chemicals structurally similar to BPA, such as bisphenol F (BPF) and bisphenol S (BPS), have been developed as substitutes in the manufacturing industry. Whether these bisphenol substitutes have adverse effects on human endocrine and reproductive systems remains largely unknown. This study investigated the effects of BPA, BPF, and BPS on regulating the function of decidualized human primary endometrial stromal cells on trophoblast outgrowth and invasion by indirect and direct co-culture models. All three bisphenols did not affect the stromal cell decidualization process. However, BPA- and BPF-treated decidualized stromal cells stimulated trophoblastic spheroid invasion in the indirect coculture model. The BPA-treated decidualized stromal cells had upregulated expressions of several invasion-related molecules including leukemia inhibitory factor (LIF), whereas both BPA- and BPF-treated decidualized stromal cells had downregulated expressions of anti-invasion molecules including plasminogen activator inhibitor type 1 (PAI-1) and tumor necrosis factor (TNFα) . Taken together, BPA and BPF altered the expression of invasive and anti-invasive molecules in decidualized stromal cells modulating its function on trophoblast outgrowth and invasion, which could affect the implantation process and subsequent pregnancy outcome.

Subfertility affects 10-15 percent of couples worldwide, and male factor is one of the dominant causes accounted for one third of these cases. Notably 40-90 percent male subfertility is due to idiopathic defective sperm production. Today, hundreds of genes have been shown to be involved in the regulation of spermatogenesis. Previously, we identified from the rat testis a novel acrosome-specific gene Vad1.3in a retinol-treated Vitamin A-deficiency (VAD) model. VAD1.3 was expressed in the testes from postnatal day 25 and its immunoreactivity was localized to the acrosomal cap of the rat, mouse, human, monkey and porcine spermatids. To explore the functional role of VAD1.3 in spermatogenesis in vivo, we used the gene-targeting approach to generate Vad1.3knockout mice. Vad1.3targeted allele was germline transmitted. No gross defect in spermatogenesis was found in the heterozygous mice testes. Crossing of heterozygous mice produced wild-type and heterozygous offsprings in a ratio of 1 : 2.6 (n = 92), but no Vad1.3-/-offspring was found. There were no significant difference in corpus luteum numbers between the wild-type and heterozygous mice, suggesting these animals ovulated comparable number of oocytes. However, the number of implantation site on day 8 and 15 post coital (dpc) (n = 7) as well as the litter size (n = 9) was consistently lower in the crossing of the heterozygous (8.0 ± 0.8; 7.3 ± 0.8; 7.2 ± 0.6, respectively) than the wild-type (9.1 ± 0.4; 8.3 ± 0.3; 8.1 ± 0.6, respectively) mice. Since no resorption site was found on 8 dpc in both groups, the difference in implantation site may result from failure in fertilization, preimplantation embryonic development or implantation of homozygous knockout embryos. To study the time of loss of these homozygous embryos, genotyping of individual preimplantation embryos after whole genome amplification was performed. It was found that Vad1.3-/-embryos existed at the zygotic and 2-cell stages but was absent at the blastocyst stage, suggesting that the Vad1.3-/-embryos died before blastocyst formation. Interestingly, spermatogenesis in 9-14 months old heterozygous mice exhibited higher incidence of germ cell loss when compared with the control mice of the same ages (4/15 vs. 1/15, respectively). Yet, spermatogenesis were comparable between the wild-type and heterozygous mice on post-natal day 25, 35, 45 and 60. In sum, our results indicate that VAD1.3 is critical for early preimplantation embryo development and spermatogenesis in adult mice. The use of tissue-specific knockout approach may help to answer the functional role of VAD1.3 in fertility. This project is supported in part by an RCG grant HKU7537/05M to KFL.(poster)