Effect of Brief Maternal Exposure to Bisphenol A on the Fetal Female Germline in a Mouse Model.

Abstract

Background: Environmental contamination by endocrine disrupting chemicals (EDCs) has created serious public health, ecological, and regulatory concerns. Prenatal exposures can affect a wide range of developing organ systems and are associated with adverse changes to behavior, metabolism, fertility, and disease risk in the adult. The most serious and puzzling observation for some EDC exposures is the transmission of effects to subsequent unexposed generations (transgenerational effects) in animal models. This requires the induction of epigenetic aberrations to the germline that are not subject to the normal processes of erasure and resetting in subsequent generations. Understanding when and how the germline is vulnerable to environmental contaminants is an essential first step in devising strategies to prevent and reverse their effects.

Methods: Fetal mouse oocytes were collected after exposure of the dam to various concentrations of bisphenol A (BPA) or placebo. Meiotic effects were assessed by immunostaining to visualize the synaptonemal complex and recombination sites, as well as whole chromosome fluorescence in situ hybridization probes. Enriched oocyte pools were analyzed by mass spectrometry and RNA sequencing to determine differences in histone post-translational modifications and gene expression, respectively.

Results: We found germline effects across a wide range of exposure levels, the severity of which was positively associated with BPA concentration. We identified the onset of meiotic prophase as the vulnerable window of exposure and found surprising exposure-related differences in chromatin. Oocyte analysis by mass spectrometry and immunofluorescence suggested H4K20me2, a histone posttranslational modification involved in DNA damage repair, was particularly affected. Subsequent RNA-seq analysis revealed a relatively small number of differentially expressed genes, but in addition to genes involved in chromatin dynamics, several with important roles in DNA repair/recombination and centromere stability were affected.

Discussion: Together, our data from a mouse model suggest BPA exposure induced complex molecular differences in the germline that dysregulated chromatin and affected several critical and interrelated meiotic pathways. https://doi.org/10.1289/EHP15046.