Abstract
BackgroundUsing an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 μM 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.MethodsUsing the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 μM BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 μM BPA (~ 500 μg/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 μM and 0.038 μM respectively. Mice grafted with second trimester testes received 0.5 and 50 μg/kg/day BPA by oral gavage for 5 weeks.ResultsWith first trimester human testes, using the hFeTA model, 10 μM 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-2γ, 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.ConclusionsExposure 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.
Highlights
Over recent decades, the incidence of male reproductive disorders has been steadily increasing [1,2,3,4]
Germ cell density was reduced by bisphenol A (BPA) exposure
Studies using first trimester human fetal testis demonstrate the complementarity of the Fetal Testis Assay” (FeTA) and xenograft models for determining the respective short-term and long term effects of environmental exposures
Summary
The incidence of male reproductive disorders has been steadily increasing [1,2,3,4] 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. In 1993, Sharpe and Skakkebaek hypothesized that endocrine disruptors (EDs), 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]. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and to study the effect of BPA on germ cell development using both the hFETA and xenograft models
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