Placental DNA methylation as a mediator in the association between maternal prenatal bisphenol analogue exposure and myopia in children: A long-term prospective cohort study.

Prenatal exposure to bisphenol analogs is becoming increasingly common and may affect the development of myopia in children. However, human evidence and mechanistic studies remain limited. In this study, 370 mother-child pairs from the Shanghai-Minhang Birth Cohort Study (S-MBCS) were analyzed. We measured the concentrations of five bisphenol analogs in maternal urine, quantified genome-wide DNA methylation (DNAm) in placental samples, and assessed the myopia status and spherical equivalent (SE) of school-aged children. Multiple CpG sites with methylation levels significantly associated with SE were identified, and Kyoto Encyclopedia of Genes and Genomes analysis identified cellular senescence as a pathway significantly associated with SE in the left eye. Dozens of differentially methylated regions are associated with the risk of myopia or SE. Prenatal exposure to bisphenol A and bisphenol AF increased the risk of myopia and decreased SE. Guided by a meet-in-the-middle approach, mediation analysis showed that the effects of bisphenol AF exposure on SE might be partially mediated by changes in methylation at the cg23146659 locus (mapping to TDRD3 in the left eye) and a differentially methylated region annotated as MROH1 (in the right eye). Our findings suggest that placental DNAm is associated with myopia development, and that specific DNAm changes may partially explain the association between prenatal chemical exposure and myopia. This study delineates how long-term prenatal exposure to environmental factors influences ocular development in children and informs early identification of myopia risk.