Placental DNA methylation at thyroid hormone-related genes mediates the association between prenatal exposure to bisphenol analogues and increased offspring obesity risk.

Prenatal exposure to bisphenol analogues (BPs) has been suggested to impair fetal growth and increase obesity risk in future life. However, the mechanisms remain unclear. Based on the Shanghai-Minhang Birth Cohort Study, this study aimed to investigate the associations between prenatal exposure to BPs and placental DNA methylation (DNAm) at thyroid hormone (TH)-related genes and explore whether these epigenetic modifications mediated the effects of BPs on offspring adiposity. The participants were recruited between April and December 2012 from the Minhang Maternal and Child Health Hospital in Shanghai, China. The study included 205 mother-child pairs with complete data on exposure, DNAm, and infant skinfold thickness. Maternal BPs concentrations were measured using a single spot urine sample collected in late pregnancy. Placental DNAm levels in the promoter regions were analyzed using bisulfite amplicon sequencing for five TH-related genes: SLC16A2, SLCO1C1, TTR, DIO3 and TRH. We found that prenatal exposure to BPA, BPF and BPS was associated with increased DNAm at SLC16A2, which mediated the associations between these BPs and increased infant skinfold thickness, accounting for 10-16% of the total effects. Additional associations were found between BPS and BPAF and higher methylation levels of SLCO1C1 and TTR. TCBPA was linked to increased DNAm at SLCO1C1 but decreased DNAm at DIO3. These findings suggest that placental DNAm at TH-related genes may serve as a mechanism underlying the effects of prenatal exposure to BPs and a potential mediator linking this exposure to offspring growth.