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. Opposing effects on DNA methylation of Esr1 have also been observed as a consequence of these exposures, with potentially broad transcriptional effects. 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. We administered either a bisphenol mixture (BPA, BPF, BPS), BPA only, or a corn oil control to pregnant rat dams. Postnatal maternal care was measured using home-cage videos. Brains from male and female pups were collected at postnatal day 10 and the transcriptome and DNA methylome were assessed in the MPOA. Our results indicated a significant interaction between prenatal bisphenol exposure and maternal postnatal licking/grooming on estrogen-related receptor gamma ( Esrrg ) expression, exclusively in female pups. These interactions 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. While these differentially methylated regions were not enriched for estrogen responsive elements, there were binding motifs 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.