Gene Expression in Oogenesis and Implications for Transgenerational Effects of Environmental Toxicants

Evidence from experimental studies suggests that fetal exposure to the endocrine-disrupting chemical bisphenol A (BPA) has adverse reproductive effects in both males and females. Studies from our laboratory suggest that exposure to the developing female fetus produces a unique, multigenerational effect. Specifically, maternal exposure affects the earliest stages of oogenesis in the developing fetal ovary, and the resulting subtle meiotic defects increase the likelihood that embryos produced by the exposed female in adulthood (i.e., the grandchildren) will be chromosomally abnormal. To understand the impact of BPA on the developing ovary, we conducted expression studies to characterize gene expression changes in the fetal ovary that result from BPA exposure. We first tested the validity of the approach, asking whether we could reliably detect temporal changes in expression levels of meiotic genes in controls. As anticipated, we were able to identify appropriate increases in expression in meiotic, but in few other, genes. Intriguingly, this analysis provided data on a small set of genes for which timing and expression changes suggest that they may have important and heretofore unrecognized meiotic roles. After verifying the utility of our approach, we focused our analysis on BPA-exposed animals. We found modest, but significant, changes in gene expression in the fetal ovaries from exposed fetuses. The first changes were evident within 24 h of exposure, and the most extensive changes correlated with the onset of meiosis. Furthermore, gene ontology analysis suggested that BPA acts to down-regulate mitotic cell-cycle genes, raising the possibility that fetal BPA exposure may act to limit expansion of the primordial germ cell population.