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In utero bisphenol A exposure is linked with sex specific changes in the transcriptome and methylome of human amniocytes.

CONTEXT
Prenatal exposure to bisphenol A (BPA) is linked to obesity and diabetes, but the molecular mechanisms driving these phenomena are not known. Alterations in DNA methylation in amniocytes exposed to BPA in utero represent a potential mechanism leading to metabolic dysfunction later in life.


OBJECTIVE
To profile changes in genome-wide DNA methylation and expression in second trimester human amniocytes exposed to BPA in utero.


DESIGN
A nested case-control study was performed in amniocytes matched for offspring sex, maternal race/ethnicity, maternal age, gestational age at amniocentesis and gestational age at birth. Cases had amniotic fluid BPA measuring 0.251-23.74 ng/mL. Sex-specific genome-wide DNA methylation analysis and RNA-sequencing were performed to determine differentially methylation regions (DMRs) and gene expression changes associated with BPA exposure. Ingenuity pathway analysis was performed to identify biologically relevant pathways enriched after BPA exposure. In silico Hi-C analysis identified potential chromatin interactions with DMRs.


RESULTS
There were 101 genes with altered expression in male amniocytes exposed to BPA (q<0.05) in utero, with enrichment of pathways critical to hepatic dysfunction, collagen signaling and adipogenesis. Thirty-six differentially methylated regions (DMRs) were identified in male BPA exposed amniocytes and 14 in female amniocyte analysis (q<0.05). Hi-C analysis identified interactions between DMRs and 24 genes with expression changes in male amniocytes and 12 in female amniocytes (p<0.05).


CONCLUSION
In a unique repository of human amniocytes exposed to BPA in utero, sex-specific analyses identified gene expression changes in pathways associated with metabolic disease and novel DMRs with potential distal regulatory functions.