Distinct Epigenetic Modulation of Differentially Expressed Genes in the Adult Brain Following Prenatal Exposure to Low-Dose Bisphenol A

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Abstract Bisphenol A (BPA) is a common component in the manufacture of daily plastic consumer goods. Recent studies have suggested that prenatal exposure to BPA can increase the susceptibility of offspring to mental illness, although the underlying mechanisms remain unclear. In this study, we performed transcriptomic and epigenomic profiling in the adult brain following prenatal exposure to low-dose BPA. We observed a sex-specific transcriptional dysregulation in the cortex, with males exhibiting more significant differentially expressed genes (DEGs). Gene ontology analysis revealed that the upregulated genes primarily influenced neuronal functions, while the downregulated genes were significantly enriched in the energy metabolism pathways. Further evidence supporting impaired mitochondrial function in the cortical neurons of the BPA group, including a decreased ATP level and a reduced number of mitochondria. We further investigated the higher-order chromatin regulatory patterns of DEGs by incorporating our previously published Hi-C data. Interestingly, we found that upregulated genes exhibited more distal interactions with multiple enhancers, while downregulated genes displayed relatively short-range interactions among adjacent genes. Our data further revealed decreased H3K9me3 signal on the distal enhancers of upregulated genes, whereas increased DNA methylation and H3K27me3 signals on the promoters of downregulated genes. In summary, our study provides compelling evidence for the potential health risks associated with prenatal exposure to BPA, and uncovers sex-specific transcriptional changes with a complex interplay of multiple epigenetic mechanisms.

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