DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort

Abstract

Background: Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 μm or less (PM₁₀) was measured inside participants' homes during the second trimester of pregnancy.

Results: A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM₁₀ and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582.

Conclusions: Our findings suggest that DNAm may mediate the association between prenatal PM₁₀ exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.

Keywords: Cord blood; Epigenetics; Neurodevelopment; Newborn DNA methylation; Particulate matter.

Fig. 1

Directed acyclic graphs (DAGs) for exposure-mediator (A), mediator-outcome (B), and exposure-outcome (C) associations. Above are DAGs for each causal pathway relevant to our mediation analysis

Fig. 2

Causal mediation analysis for the association between PM₁₀ (exposure) and cognitive neurodevelopment (outcome) using CpG sites identified with high-dimensional mediation analysis methods. This figure presents estimates for indirect effect (IDE), direct effect (DE), total effect (TE), and proportion mediated (PM) for CpG sites with both significant IDE and TE. Significant total effects were found only for the cognitive neurodevelopmental domain (no significant total effects were identified for general adaptive behavior, language, or motor neurodevelopmental domains). IDE, DE, and TE effect estimates have been multiplied by the PM₁₀ interquartile range (IQR) (58.78 µg/m³) observed in this cohort and thus these effect estimates represent the estimated effects on BSID-III cognitive score per one IQR increase in prenatal PM₁₀ exposure