DNA methylation and transcriptome aberrations mediated by ERα in mouse seminal vesicles following developmental DES exposure

Estrogen receptor alpha mediates aberrations of the mRNA transcriptome in seminal vesicles following neonatal Diethylstilbestrol exposure, 2018

Significance

Early developmental exposure to endocrine active compounds causes late-stage effects and alterations in the reproductive tract of adult mice. Unexpectedly, estrogen receptor alpha (ERα) plays a pivotal role in mediating these developmental effects. As a model outcome from these developmental effects, we present transcriptome and DNA methylation profiling of the seminal vesicles (SVs) following neonatal diethylstilbestrol (DES) exposure. ERα mediates transcriptome aberrations in SVs of adult mice that impact developmental reprogramming at adulthood. DNA methylation dynamically changes during development, and methylation is greater in ERα knockout mice compared with wild type. Expression levels of DES-altered genes are associated with their DNA methylation status. These findings provide unique evidence for understanding the developmental actions and mechanisms of endocrine-disrupting chemicals in human health.

Abstract

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.

Reference

  • Full text (free access) : DNA methylation and transcriptome aberrations mediated by ERα in mouse seminal vesicles following developmental DES exposure, Proceedings of the National Academy of Sciences of the United States of America, NCBI PubMed PMC5939078, 2018 May 1.
  • Featured image : ERα-mediated aberrations of the transcriptome in the SVs of adult mice following developmental DES exposure.
    • (A) Differentially expressed (DE) gene analysis for week 10 SVs RNA-Seq (n = 4 for each group). DE genes from the four comparisons are shown as fold change with a cutoff of >1.5-fold, fragments per kilobase million (FPKM) >1 and q < 0.05.
    • (B) Heatmap depicting 2,162 DE genes from comparison 1 WT-DES vs. WT-veh (1,678 induced and 484 reduced genes).
    • (C) IPA analysis of 1,678 induced or 484 reduced genes PMC5939078/figure/fig02.
DES DIETHYLSTILBESTROL RESOURCES

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