Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, PR China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, 400016, PR China.
Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, PR China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, 400016, PR China.
J Hazard Mater. 2018 Sep 15;358:101-112. doi: 10.1016/j.jhazmat.2018.06.042. Epub 2018 Jun 20.
The female reproductive lifespan is largely determined by the size of the primordial follicle pool, which is established early in life. We previously reported that Di (2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor and a widely-spreading plasticizer, impairs primordial folliculogenesis. In the present study, we found DEHP significantly altered the number and sex ratio of the offspring of neonatal-exposed mice. Furthermore, by a neonatal exposure model and an ovary culture model, it showed that DEHP activated autophagy in the ovary, with increased autophagy-related gene expression and recognizable autophagosomes, while inhibition of autophagy by 3-MA attenuated the adverse impact of DEHP on primordial folliculogenesis. Moreover, key components of AMPK-SKP2-CARM1 signalling were up-regulated by DEHP in the ovary, and AMPK inhibitor Compound C reduced autophagy-related gene expression and partially recovered primordial follicle assembly. Collectively, this study demonstrates that DEHP induces autophagy by activating AMPK-SKP2-CARM1 signalling in mice perinatal ovaries, which results in disrupted primordial folliculogenesis and reduced female fertility.
女性生殖寿命在很大程度上取决于原始卵泡池的大小，而原始卵泡池是在生命早期建立的。我们之前曾报道过，邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种环境内分泌干扰物和广泛传播的增塑剂，会损害原始卵泡发生。在本研究中，我们发现 DEHP 显著改变了新生期暴露小鼠后代的数量和性别比例。此外，通过新生期暴露模型和卵巢培养模型，结果表明 DEHP 在卵巢中激活了自噬，自噬相关基因表达增加，可识别自噬体，而 3-MA 抑制自噬则减弱了 DEHP 对原始卵泡发生的不良影响。此外，DEHP 在卵巢中上调了 AMPK-SKP2-CARM1 信号通路的关键组成部分，而 AMPK 抑制剂 Compound C 降低了自噬相关基因的表达，并部分恢复了原始卵泡的组装。总之，这项研究表明，DEHP 通过激活小鼠围产期卵巢中的 AMPK-SKP2-CARM1 信号通路诱导自噬，从而导致原始卵泡发生破坏和雌性生育力降低。
