Epi-mutations for spermatogenic defects by maternal exposure to Di (2-ethylhexyl) phthalate-猫眼课题宝

DOI：

10.1101/2021.05.19.444770

发表时间：

2021-05

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Yukiko Tando;H. Hiura;Asuka Takehara;Yumi Ito-Matsuoka;T. Arima;Y. Matsui

在胎儿发育过程中暴露于环境因素可能导致胎儿生殖细胞的表观基因组修饰，改变基因表达并促进连续几代的疾病。在小鼠中，已知母体暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP）可诱导连续几代精子发生缺陷，但精子发生受损的机制尚不清楚。在这里，我们发现母体DEHP暴露导致F1小鼠胎儿睾丸生殖细胞中精子发生相关基因启动子的DNA超甲基化，以及对精子发生至关重要的Hist 1h 2ba，Sycp 1和Taf 7 l的超甲基化，从胎儿睾丸细胞持续到成年精原细胞，导致这些基因表达下调。这些基因启动子的强制甲基化在报告基因测定中沉默了这些位点的表达。在母体DEHP暴露后，F2精原细胞中这些基因的表达和甲基化倾向分别下调和增加。这些结果表明，DEHP诱导的胎儿生殖细胞中Hist 1h 2ba，Sycp 1和Taf 7 l的超甲基化导致精原细胞中这些基因的下调和随后的精子发生缺陷，至少在F1代。

Exposure to environmental factors during fetal development may lead to epigenomic modifications in fetal germ cells, altering gene expression and promoting diseases in successive generations. In mouse, maternal exposure to Di (2-ethylhexyl) phthalate (DEHP) is known to induce defects in spermatogenesis in successive generations, but the mechanism(s) of impaired spermatogenesis are unclear. Here, we showed that maternal DEHP exposure results in DNA hypermethylation of promoters of spermatogenesis-related genes in fetal testicular germ cells in F1 mice, and hypermethylation of Hist1h2ba, Sycp1 and Taf7l, which are crucial for spermatogenesis, persisted from fetal testicular cells to adult spermatogonia, resulting in the downregulation of expression of these genes. Forced methylation of these gene promoters silenced expression of these loci in a reporter assay. Expression and methylation of those genes tended to be downregulated and increased, respectively in F2 spermatogonia following maternal DEHP exposure. These results suggested that DEHP-induced hypermethylation of Hist1h2ba, Sycp1 and Taf7l in fetal germ cells results in downregulation of these genes in spermatogonia and subsequent defects in spermatogenesis, at least in the F1 generation.

Epi-mutations for spermatogenic defects by maternal exposure to Di (2-ethylhexyl) phthalate

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