Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4189-E4198. doi: 10.1073/pnas.1719010115. Epub 2018 Apr 16.
Early transient developmental exposure to an endocrine active compound, diethylstilbestrol (DES), a synthetic estrogen, causes late-stage effects in the reproductive tract of adult mice. Estrogen receptor alpha (ERα) plays a role in mediating these developmental effects. However, the developmental mechanism is not well known in male tissues. Here, we present genome-wide transcriptome and DNA methylation profiling of the seminal vesicles (SVs) during normal development and after DES exposure. ERα mediates aberrations of the mRNA transcriptome in SVs of adult mice following neonatal DES exposure. This developmental exposure impacts differential diseases between male (SVs) and female (uterus) tissues when mice reach adulthood due to most DES-altered genes that appear to be tissue specific during mouse development. Certain estrogen-responsive gene changes in SVs are cell-type specific. DNA methylation dynamically changes during development in the SVs of wild-type (WT) and ERα-knockout (αERKO) mice, which increases both the loss and gain of differentially methylated regions (DMRs). There are more gains of DMRs in αERKO compared with WT. Interestingly, the methylation changes between the two genotypes are in different genomic loci. Additionally, the expression levels of a subset of DES-altered genes are associated with their DNA methylation status following developmental DES exposure. Taken together, these findings provide an important basis for understanding the molecular and cellular mechanism of endocrine-disrupting chemicals (EDCs), such as DES, during development in the male mouse tissues. This unique evidence contributes to our understanding of developmental actions of EDCs in human health.
早期短暂的发育暴露于内分泌活性化合物己烯雌酚（DES），一种合成雌激素，会导致成年小鼠生殖道的晚期效应。雌激素受体α（ERα）在介导这些发育效应中起作用。然而，在男性组织中，其发育机制尚不清楚。在这里，我们展示了正常发育过程中和 DES 暴露后精囊（SVs）的全基因组转录组和 DNA 甲基化谱。ERα 介导了新生期 DES 暴露后成年小鼠 SVs 中 mRNA 转录组的异常。由于在小鼠发育过程中大多数 DES 改变的基因似乎是组织特异性的，因此这种发育暴露会导致成年雄性（SVs）和雌性（子宫）组织之间出现不同的疾病。SVs 中某些雌激素反应基因的变化是细胞类型特异性的。在野生型（WT）和 ERα 敲除（αERKO）小鼠的 SVs 中，DNA 甲基化在发育过程中动态变化，这增加了差异甲基化区域（DMRs）的丢失和获得。与 WT 相比，αERKO 中 DMR 的获得更多。有趣的是，两种基因型之间的甲基化变化位于不同的基因组位置。此外，DES 改变的基因子集的表达水平与发育性 DES 暴露后它们的 DNA 甲基化状态相关。综上所述，这些发现为理解内分泌干扰化学物质（如 DES）在雄性小鼠组织发育过程中的分子和细胞机制提供了重要基础。这一独特的证据有助于我们了解人类健康中 EDCs 的发育作用。
