Sex-specific DNA methylation changes in placental thyroid hormone regulatory genes following prenatal exposure to flame retardants

Prenatal exposure to organophosphate esters (OPEs) and polybrominated diphenyl ethers (PBDEs) has been linked to disrupted fetal thyroid hormone (TH), though the underlying mechanisms remain unclear. Based on the S-MBCS cohort, we analyzed OPE metabolite concentrations in maternal urine during early pregnancy and PBDE levels in cord plasma. Methylation of five TH regulatory genes, namely deiodinase type 3 (DIO3), solute carrier family 16 member 2 (SLC16A2), solute carrier organic anion transporter family member 1C1 (SLCO1C1), thyrotropin-releasing hormone (TRH), and transthyretin (TTR), was quantified in the placenta. We investigated the associations between prenatal exposure to PBDEs and OPEs and DNA methylation of placental TH-related genes, using samples from 240 and 327 mother-newborn pairs, respectively. We further examined sex-specific differences in these associations and assessed whether the observed epigenetic alterations mediated the relationship between exposures and TH disruption. Mediation analyses were conducted in a subset of mother-newborn pairs with available TH measurements in cord plasma. BDE-47 and ΣPBDE showed sex-specific relationships with DIO3 and SLC16A2 methylation, with a significant positive association in females and a non-significant inverse association in males. Both BDE-47 and ΣPBDEs were linked to SLCO1C1 hypermethylation. OPE metabolites were positively associated with DIO3 and TTR methylation, predominantly in females. Mediation analyses suggested that SLCO1C1 hypermethylation mediated 6.5-7.0 % of the association between ΣPBDE exposure and reduced free triiodothyronine. These findings highlight sex-specific epigenetic changes in placental TH-related genes in relation to PBDE and OPE exposure, providing novel insights into fetal thyroid disruption pathways.