Postnatal maternal care impacts hypothalamic Esrrg gene expression, co-expression profiles, and the DNA methylome in prenatal bisphenol-exposed rats

Environmental exposures co-occurring during early life have a profound influence on neurodevelopment. Our previous work in rats suggests that postnatal maternal care modulates the effects of prenatal exposure to bisphenols, an estrogenic endocrine disrupting chemical, on offspring neurodevelopment. Elevated postnatal maternal licking/grooming and prenatal bisphenol exposure have known opposing effects on estrogen receptor alpha (Esr1) expression in the medial preoptic area (MPOA) of the hypothalamus, which could impact expression of estrogen-responsive genes. Based on this previous work, we hypothesized that postnatal maternal licking/grooming would mitigate the effects of prenatal bisphenol exposure on Esr1 expression and estrogen-responsive genes in the developing MPOA. In addition, we hypothesized that there would be interactive effects of prenatal bisphenol exposure and postnatal maternal licking/grooming on DNA methylation, particularly nearby estrogen responsive elements. Our results suggest that maternal postnatal licking/grooming normalized prenatal bisphenol-induced upregulation of estrogen-related receptor gamma (Esrrg) expression in female pups. These mitigating impacts were also evident in co-expression gene profiles in female pups; the majority of which were enriched for estrogen-responsive genes. Finally, DNA methylation analyses indicated that adding postnatal maternal licking/grooming as a covariate influenced the number of differentially methylated regions for prenatal bisphenol-exposed male and female pups. These differentially methylated regions were enriched for binding sites for transcription factors that are known to interact with estrogen receptors, suggesting some secondary effects on postnatal gene regulation. These results suggest a novel biological mechanism in which postnatal maternal care can mitigate the negative neurodevelopmental impacts of prenatal bisphenol exposure. These results also suggest that postnatal tactile stimulation might be a potential intervention strategy to mitigate the neurodevelopmental risks from prenatal endocrine disrupting chemical exposure. Author SummaryNeurodevelopment can be shaped by both aversive and positive experiences early in life, in part due to epigenetic mechanisms such as DNA methylation. Here, we follow up on our previous studies that suggest high levels of postnatal maternal care could mitigate the negative impacts of prenatal bisphenol exposure, an estrogenic endocrine disrupting chemical. We focused on gene expression and DNA methylation changes in the developing medial preoptic area, a brain area that is enriched in estrogen receptors and important for sex-specific social behaviors. We found that maternal postnatal licking/grooming normalized prenatal bisphenol-induced upregulation of estrogen-related receptor gamma (Esrrg) expression in female pups only. We find similar patterns in multiple co-expressed gene networks that are enriched in estrogen-responsive genes. Finally, postnatal maternal licking/grooming influenced DNA methylation patterns for prenatal bisphenol-exposed male and female pups. These results suggest a novel biological mechanism in which postnatal maternal care can mitigate the negative neurodevelopmental impacts of prenatal bisphenol exposure. This is important because it suggests that postnatal tactile stimulation could be an effective intervention against the negative neurodevelopmental impacts from prenatal endocrine disrupting chemical exposure.