Tang Zonghao, Zhang Zhenghong, Tang Yedong, Qi Lingbin, Yang Fafu, Wang Zhengchao
Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350007, P.R. China.
College of Chemistry and Chemical Engineering, Fujian Normal University, Fuzhou, Fujian 350007, P.R. China.
Exp Ther Med. 2017 Dec;14(6):5981-5989. doi: 10.3892/etm.2017.5328. Epub 2017 Oct 18.
Dimethyl carbonate (DMC) is a widely used industrial chemical, which may be increasingly used in the future. However, its toxicity profile remains largely unknown. The present study was designed to investigate the effects of DMC exposure on the ovaries and the effect of autophagy activation on follicular development. Rats were randomly divided into a control group and low, medium and high dose DMC groups (all n=10). Histological analyses identified no marked differences in the rate of apoptosis between the control and low dose groups; however, marked apoptosis occurred in the medium and high dose groups. The expression of cleaved caspase-3 was significantly increased in the medium and high dose groups, which was consistent with changes observed in the expression of Bcl-2 and Bax. These results indicated that DMC exposure induces toxicity on ovarian function via the induction of apoptosis. The increased expression of the autophagy-related proteins light chain 3II, beclin-1 and p62 following exposure to DMC further indicated that autophagy was activated primarily in the granulosa cells of ovarian follicles in a dose-dependent manner. In addition, the changes in the expression of hypoxia inducible factor 1 α subunit (HIF-1α) and its target protein BCL2 interacting protein 3 (BNIP3) indicated that they may serve a role in the follicular development process induced by DMC. The results of the current study demonstrated that DMC exposure activated autophagy in the ovarian tissue. Furthermore, exposure to low doses of DMC may protect follicular development by activating the HIF-1α/BNIP3 signaling pathway. Taken together, these results indicate that exposure to medium and high doses of DMC induced follicular atresia by activating the apoptotic signaling pathway. This may be an important mechanism of regulating follicular development and ovarian function in mammals.
碳酸二甲酯（DMC）是一种广泛使用的工业化学品，未来其使用量可能会不断增加。然而，其毒性特征在很大程度上仍不为人知。本研究旨在调查DMC暴露对卵巢的影响以及自噬激活对卵泡发育的影响。将大鼠随机分为对照组以及低、中、高剂量DMC组（每组n = 10）。组织学分析表明，对照组和低剂量组之间的凋亡率无明显差异；然而，中剂量组和高剂量组出现了明显的凋亡。中剂量组和高剂量组中裂解的半胱天冬酶-3的表达显著增加，这与Bcl-2和Bax表达的变化一致。这些结果表明，DMC暴露通过诱导凋亡对卵巢功能产生毒性。暴露于DMC后，自噬相关蛋白轻链3II、贝林蛋白-1和p62的表达增加，进一步表明自噬主要在卵巢卵泡的颗粒细胞中以剂量依赖的方式被激活。此外，缺氧诱导因子1α亚基（HIF-1α）及其靶蛋白BCL2相互作用蛋白3（BNIP3）表达的变化表明，它们可能在DMC诱导的卵泡发育过程中发挥作用。本研究结果表明，DMC暴露激活了卵巢组织中的自噬。此外，低剂量DMC暴露可能通过激活HIF-1α/BNIP3信号通路来保护卵泡发育。综上所述，这些结果表明，中高剂量DMC暴露通过激活凋亡信号通路诱导卵泡闭锁。这可能是调节哺乳动物卵泡发育和卵巢功能的重要机制。
