Mediation of the Association between Prenatal Arsenic Exposure and Infant Birth Outcomes by DNA Methylation of DNMT3A

摘要

Background: Prenatal arsenic (As) exposure is negatively associated with birth weight and gestational age. Epigenetic changes, including DNA methylation (DNAm) play a critical role in fetal development. DNA methyltransferase 3 alpha (DNMT3A) is a key enzyme responsible for de novo DNAm and genomic imprinting. Thus DNMT3A is a prime candidate gene as a mediator between the prenatal environment and adverse birth outcomes. We evaluated the relationships between prenatal As exposure, gestational age (GA), birth weight (BW), and DNAm of DNMT3A. Methods: In a prospective Bangladeshi birth cohort, cord blood DNAm of three DNMT3A CpGs was measured using bisulfite pyrosequencing. Maternal toenail As concentration at birth was measured using inductively coupled plasma mass spectrometry to estimate fetal exposure. Among vaginal births (N=415), structural equation models (SEMs) were used to evaluate mediation by DNMT3A DNAm for the association between log2-maternal toenail As concentration, GA, and BW. Results: DNAm of the three CpGs was used to define a latent variable representing DNMT3A. In an unadjusted SEM, the effect of As concentration on BW was mediated by GA (indirect effect β=-0.02 P=0.007). Arsenic concentration was positively associated with DNAm of DNMT3A (P=0.002). DNMT3A DNAm mediated the association between As concentration and GA (β=-0.05; P=0.02), but not the association with BW. Overall, results adjusted for infant sex and maternal weight gain and education were consistent. DNAm mediated the association between As concentration and GA (β=-0.04; P=0.02); mediation of the association between As concentration and BW by DNAm was borderline significant (β=-0.01; P=0.06). In both unadjusted and adjusted models, the total effect of a doubling in As concentration was a decrease in GA of 2 days. Conclusions: DNMT3A plays a critical role in fetal epigenetic programming and may mediate the association between prenatal As exposure and birth outcomes.