Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway
Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway
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邻苯二甲酸二正丁酯通过 PTEN/AKT 途径表观遗传诱导生殖毒性
DOI：
10.1038/s41419-019-1547-8
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发表时间：
2019-04-05
影响因子：
9
通讯作者：
Qin, Zhi-qiang
中科院分区：
文献类型：
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作者：
Li, Ran;Xing, Qian-wei;Qin, Zhi-qiang
邻苯二甲酸二丁酯（DBP）是一种普遍存在的化学物质，与影响男性生殖系统的激素干扰有关。然而，DBP诱导生殖细胞毒性的机制仍不清楚。在这里，我们表明，DBP诱导增殖的减少，凋亡和DNA损伤依赖于PTEN/AKT途径的增加。从机制上讲，DBP降低了PTEN启动子甲基化并增加了其转录活性，导致PTEN表达增加。值得注意的是，DNMT 3b被证实为miR-29 b的靶标，并且miR-29 b介导的PTEN甲基化状态参与DBP治疗的效果。同时，DBP通过增加PTEN表达来降低AKT通路的表达。此外，DBP降低精子数量和活动精子百分比的事实与AKT途径和精子鞭毛相关基因的下调有关。总的来说，这些发现表明DBP诱导异常的PTEN去甲基化，导致AKT通路的抑制，这有助于生殖毒性。
Di-n-butyl phthalate (DBP) is a kind of ubiquitous chemical linked to hormonal disruptions that affects male reproductive system. However, the mechanism of DBP-induced germ cells toxicity remains unclear. Here, we demonstrate that DBP induces reduction of proliferation, increase of apoptosis and DNA damage dependent on the PTEN/AKT pathway. Mechanistically, DBP decreases PTEN promoter methylation and increases its transcriptional activity, leading to increased PTEN expression. Notably, DNMT3b is confirmed as a target of miR-29b and miR-29b-mediated status of PTEN methylation is involved in the effects of DBP treatment. Meanwhile, DBP decreases AKT pathway expression via increasing PTEN expression. In addition, the fact that DBP decreases the sperm number and the percentage of motile and progressive sperm is associated with downregulated AKT pathway and sperm flagellum-related genes. Collectively, these findings indicate that DBP induces aberrant PTEN demethylation, leading to inhibition of the AKT pathway, which contributes to the reproductive toxicity.