Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis

<div><p>Background</p><p>Using 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.</p><p>Methods</p><p>Using 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.</p><p>Results</p><p>With 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.</p><p>Conclusions</p><p>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.</p></div

Epigenetic transgenerational inheritance

Endocrine disruptors are critical environmental exposures that influence health and can promote epigenetic transgenerational inheritance of disease and abnormal physiology. Advances in 2015 included analyses of the effects of endocrine disruptors on human disease, further examples of endocrine disruptors promoting transgenerational behavioural effects, insights into effects of endocrine disruptors on epigenetic programming of primordial germ cells and the finding that endocrine disruptors can transgenerationally promote genetic mutations

Decoding Lamarck-transgenerational control of metabolism by noncoding RNAs

The concept of epigenetic transgenerational inheritance (ETI) posits that lifetime experiences in parents, particularly fathers, alter the phenotypic trajectory of their progeny independently of Mendelian genetics. Based on evidence from population studies and laboratory-controlled studies in syngenic animals, this long-term discredited so-called Lamarckian inheritance gained prominent attention. This article aims to summarize the current knowledge about ETI in lower and in higher organisms as well as in human cohorts and elaborates on epigenetic principles potentially underlying this nongenetic mode of heredity. Special attention is given to-small and long-noncoding RNAs in male gametes that recently emerged as a molecular sensor of organismal metabolic states which can ultimately relay information across the germline barrier by translating environmental cues into (epigenetic) changes in zygotic gene expression