Sex-Specific Associations of Gestational OPE Exposure with Offspring Digit Ratio: A Birth Cohort Study

Abstract The effect of prenatal organophosphate esters (OPEs) exposure on offspring reproductive development and the potential role of the placenta remain unclear. We investigated the associations of prenatal OPE exposure with the second-to-fourth digit ratio (2D:4D) and the mediating role of placental DNA methylation (DNAm) levels of PPAR pathway genes. Maternal urine OPE metabolites at 12–16 gestational weeks were measured. Placental DNAm levels at birth and children’s 2D:4D at ages 4 and 6 years were assessed. Multiple linear regression, BKMR, and causal mediation analyses were applied. We observed associations between prenatal exposure to BBOEP, BEHP, DBP, and DPP and increased 2D:4D in boys, whereas DBP and DCP were associated with decreased 2D:4D in girls. BKMR identified alkyl-OPEs, particularly BBOEP, as the primary contributors in boys. Moreover, hypermethylation of RXRA, ACAA1, and ACADM was associated with decreased 2D:4D in all populations. In girls, the associations among higher OPE exposure, increased ACAA1 methylation, and lower 2D:4D suggested a potential mediation pathway, while the mediation effects were not statistically significant. These findings suggest sex-specific associations between prenatal OPE exposure and 2D:4D. The potential role of placental PPAR-related DNAm in these associations warrants further investigation.