No difference was observed for seminal vesicle fat (Fig 8A) or serum testosterone (Fig 8B) after 5 weeks contact with 0.5 or 50 g/kg/d BPA weighed against vehicle-exposed control. Open in another window Fig 8 Aftereffect of BPA publicity on testosterone plasma level and seminal vesicle ELF2 fat in the web host mice carrying second trimester individual fetal testis xenografts.Individual fetal testes (14-18GW) xenografted into castrated Nude LGX 818 (Encorafenib) (web host) mice. 0.027).(TIF) pone.0191934.s001.TIF (29K) GUID:?F5F7085B-965E-4A5B-A64D-AE258A790571 Data Availability StatementAll relevant data are inside the paper and its own Supporting Information files. Abstract Background Using an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 M BPA decreases basal, but not LH-stimulated, testosterone secreted by the first trimester human fetal testis. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and also to study the effect of BPA on germ cell development using both the hFETA and xenograft models. Methods Using the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 M BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 M BPA (~ 500 g/kg/day) in their drinking water for 5 weeks. Plasma LGX 818 (Encorafenib) levels of total and unconjugated BPA were 0.10 M and 0.038 M respectively. Mice grafted with second trimester testes received 0.5 and 50 g/kg/day BPA by oral gavage for 5 weeks. Results With first trimester human testes, using the hFeTA model, 10 M BPA increased germ cell apoptosis. In xenografts, germ cell density was also reduced by BPA exposure. Importantly, BPA exposure significantly decreased the percentage of germ cells expressing the pluripotency marker AP-2, whilst the percentage of those expressing the pre-spermatogonial marker MAGE-A4 significantly increased. BPA exposure did not affect hCG-stimulated androgen production in first and second trimester xenografts as evaluated by both plasma testosterone level and seminal vesicle weight in host mice. Conclusions Exposure to BPA at environmentally relevant concentrations impairs germ cell development in first trimester human fetal testis, whilst gonadotrophin-stimulated testosterone production was unaffected in both first and second trimester testis. Studies using first trimester human fetal testis demonstrate the complementarity of the FeTA and xenograft models for determining the respective short-term and long term effects of environmental exposures. Introduction Over recent decades, the incidence of male reproductive disorders has been steadily increasing [1C4]. These disorders such as cryptorchidism, hypospadias, low sperm count and quality, and testicular cancer are hypothesized to arise from abnormal development of the fetal testis. These associated disorders have been collectively described as a testicular dysgenesis syndrome (TDS) [5C8]. In 1993, Sharpe and Skakkebaek hypothesized that endocrine disruptors (EDs), particularly EDs with an estrogenic effect, could be an explanation for the increase in male reproductive disorders [9] initiating a large number of studies in reproductive toxicology [4,10,11]. Among such EDs, bisphenol A (BPA; 4,4′-dihydroxy-2,2-diphenylpropane) has been the focus of considerable research [12C15]. BPA is one of the most frequently produced synthetic chemicals worldwide, with approximately LGX 818 (Encorafenib) 70% used to produce polycarbonate plastics for a variety of products, including housewares and appliances, opticals, construction materials and medical, packaging. A further 20% of BPA is used as an essential component of epoxy resins that are mainly used to coat the inner surface of metallic food and beverage cans. Finally, BPA is used as antioxidant or inhibitor of polymerization in some plasticizers, polyvinyl chloride, and thermal cash register paper. Many studies have shown that BPA exposure of rodents during intrauterine life can induce a range of adverse effects in adult testes. It has been shown that or perinatal BPA exposure induces a decrease in sperm quality and production and testosterone secretion in adults [14,16C21]. These results suggest that BPA potentially disturbs fetal testis development and future function. However, there is limited data and conflicting results concerning the direct immediate effect of BPA exposure on fetal testis development and function. In pregnant rats, exposure to high doses of BPA (876 M analyses have demonstrated the complexity of the potential effect of BPA on Leydig cell function and development. Using an organotypic culture system termed Fetal Testis Assay (FeTA) developed for rat fetal testis in 1990’s [28] and extended for mouse and human fetal testes thereafter [29,30], we demonstrated that BPA concentrations as low as 0.01 M (gene. As GC differentiate from gonocytes to pre-spermatogonia the expression of AP-2y is reduced and the cells begin to express Melanoma Associated Antigen A4 (MAGE-A4) a differentiation marker also expressed in adult spermatogonia [37C42]. In rodents, this transition from gonocyte to pre-spermatogonia occurs synchronously during late gestation, whereas in humans this transition occurs asynchronously over the.