Additive interaction of maternal early pregnancy exposure to particulate matter and residential greenness on congenital heart disease in the Offspring: Mediation of DNA methylation in placental tissue.

We aim to assess the interactive effect of greenness with particulate matter(PM) on congenital heart disease(CHD), and estimate the mediation of DNA methylation in PM on CHD. A case-control study of 1540 CHD mother-child pairs and one-to-one, age±2 years and gravidity-matched controls was organized in Tianjin, China during 2018-2021. And we further collected placental tissue(30 CHD mother-child pairs and 30 controls). We calculated maternal average PM and normalized difference vegetation index(NDVI) exposure at 3-8 gestation weeks. Conditional logistic regressions were performed to test associations between PM and NDVI, and CHD. Additive interactions were used to examine interactive effects of PM and NDVI on CHD. Quantile-based g-computation was performed to identify the main contributors. We further estimated the mediation of DNA methylation in PM on CHD. High PM exposure at 3-8 weeks of gestation increased CHD risk, whereas high NDVI decreased CHD risk. Low NDVI greatly enhanced the OR(95 % CI) of PM1≥vs.<25 μg/m3 exposure for CHD from 4.479(2.933,6.841) to 7.335(4.888,11.006). Similar results were found in the additive interaction of NDVI with PM2.5 and PM10. PM2.5 mixture(OR: 2.022, 95 % CI: 1.788,2.289) increased CHD risk and sulfate(SO42-) was the main contributor(weight = 0.533). After further adjusting for methylation level of cg13438944/cg12145624 in addition to PM1/SO42- on CHD, the effects of PM1(OR:1.120, 95 % CI: 0.989, 1.269) and SO42-(OR:1.530, 95 % CI: 0.992, 2.362) on CHD were no longer significant, indicating DNA methylation potentially might mediate the effect of PM on CHD. We recommend strict control of PM, especially SO42-, and increase residential greenness.