Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis
Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis
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DOI：
10.1371/journal.pone.0191934
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发表时间：
2018-01-31
期刊：
影响因子：
3.7
通讯作者：
Habert, Rene
中科院分区：
文献类型：
--
作者：
Eladak, Soria;Moison, Delphine;Habert, Rene
我们之前使用一种被称为人类胎儿睾丸试验（hFeTA）的器官型培养系统发现，0.01 μ M双酚a会降低早期妊娠人类胎儿睾丸分泌的基础睾酮，而不是lh刺激的睾酮。本研究旨在通过异种移植模型确定BPA长期抗雄激素作用的可能性，并通过hFETA和异种移植模型研究BPA对生殖细胞发育的影响。方法采用hFeTA系统，用0.01 ~ 10 μ M双酚a培养孕早期睾丸3 d。对于异种移植，给阉割的成年雄性裸鼠注射hCG，并移植妊娠早期的睾丸。小鼠饮水中添加10 μ M双酚a（相当于500 μ g/kg/天），连续5周。血浆总双酚a和非共轭双酚a水平分别为0.10 μ M和0.038 μ M。孕中期睾丸移植小鼠分别灌胃0.5、50 μ g/kg/d双酚a，灌胃5周。结果10 μ M双酚a可增加妊娠早期人睾丸生殖细胞凋亡。在异种移植物中，BPA暴露也降低了生殖细胞密度。重要的是，BPA暴露显著降低了表达多能性标记AP-2 γ的生殖细胞的百分比，而表达精原前标记MAGE-A4的生殖细胞的百分比显著增加。通过对宿主小鼠的血浆睾酮水平和精囊重量进行评估，BPA暴露对妊娠早期和中期异种移植物中hcg刺激的雄激素产生没有影响。结论暴露于环境相关浓度的双酚a会损害妊娠早期人类胎儿睾丸的生殖细胞发育，而促性腺激素刺激的睾酮生成在妊娠早期和中期均不受影响。使用妊娠早期人类胎儿睾丸的研究表明，FeTA和异种移植模型在确定环境暴露各自的短期和长期影响方面具有互补性。
BackgroundUsing an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 mu 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.MethodsUsing the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 mu M BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 mu M BPA (similar to 500 mu g/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 mu M and 0.038 mu M respectively. Mice grafted with second trimester testes received 0.5 and 50 mu g/kg/day BPA by oral gavage for 5 weeks.ResultsWith first trimester human testes, using the hFeTA model, 10 mu 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 gamma, 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.