Hong Juan, Chen Fang, Wang Xiaoli, Bai Yinyang, Zhou Rong, Li Yingchun, Chen Ling
State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
Mol Cell Endocrinol. 2016 May 15;427:101-11. doi: 10.1016/j.mce.2016.03.009. Epub 2016 Mar 11.
Previous studies have shown that bisphenol A (BPA) is a potential endocrine disruptor and testicular toxicant. The present study focused on exploring the impact of exposure to low dose of BPA on male reproductive development during the early embryo stage and the underlying mechanisms. BPA (20 μg/kg/day) was orally administered to female mice on days 1-5 of gestation. The male offspring were euthanized at PND10, 20, 24, 35 or PND50. We found that the mice exposed to BPA before implantation (BPA-mice) displayed retardation of testicular development with reduction of testosterone level. The diameter and epithelium height of seminiferous tubules were reduced in BPA-mice at PND35. The numbers of spermatogenic cells at different stages were significantly reduced in BPA-mice at PND50. BPA-mice showed a persistent reduction in serum and testicular testosterone levels starting from PND24, whereas GnRH mRNA was significantly increased at PND35 and PND50. The expressions of testicular StAR and P450scc in BPA-mice also decreased relative to those of the controls at PND35 and PND50. Further analysis found that the levels of histone H3 and H3K14 acetylation (Ac-H3 and H3K14ac) in the promoter of StAR were decreased relative to those of control mice, whereas the level of Ac-H3 in the promoter of P450scc was not significantly different between the groups. These results provide evidence that exposure to BPA in preimplantation embryo retards the development of testes by reducing histone acetylation of the StAR promoter to disrupt the testicular testosterone synthesis.
先前的研究表明，双酚A（BPA）是一种潜在的内分泌干扰物和睾丸毒物。本研究聚焦于探讨低剂量BPA暴露对早期胚胎阶段雄性生殖发育的影响及其潜在机制。在妊娠第1 - 5天对雌性小鼠经口给予BPA（20μg/kg/天）。在出生后第10天、20天、24天、35天或出生后第50天对雄性后代实施安乐死。我们发现，在植入前暴露于BPA的小鼠（BPA小鼠）表现出睾丸发育迟缓，睾酮水平降低。在出生后第35天，BPA小鼠的生精小管直径和上皮高度减小。在出生后第50天，BPA小鼠不同阶段的生精细胞数量显著减少。从出生后第24天开始，BPA小鼠的血清和睾丸睾酮水平持续降低，而促性腺激素释放激素（GnRH）mRNA在出生后第35天和第50天显著增加。在出生后第35天和第50天，BPA小鼠睾丸中类固醇生成急性调节蛋白（StAR）和细胞色素P450侧链裂解酶（P450scc）的表达相对于对照组也有所降低。进一步分析发现，相对于对照小鼠，StAR启动子中组蛋白H3和H3K14乙酰化（Ac - H3和H3K14ac）水平降低，而P450scc启动子中Ac - H3水平在两组间无显著差异。这些结果证明，植入前胚胎暴露于BPA会通过降低StAR启动子的组蛋白乙酰化来破坏睾丸睾酮合成，从而延缓睾丸发育。
