Prenatal exposure to pesticide mixtures and the placental transcriptome: Insights from trimester-specific, sex-specific and metabolite-scaled analyses in the SAWASDEE cohort

We investigated the effect of exposure to pesticide mixtures during pregnancy on the placental transcriptome, to link these exposures and placental functions. The Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE) enrolled pregnant farmworkers from Thailand (n = 248), who were primarily exposed to organophosphate (OP) and pyrethroid pesticides. We measured maternal urinary levels of six non-specific OP metabolites expressed as three summary measures (dimethylalkylphosphates (DMAP), diethylalkylphosphates (DEAP), and dialkylphosphates (DAP) and three pyrethroid metabolites (3-phenoxybenzoic acid (3-PBA), cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA, trans-DCCA) during early, middle, and late pregnancy, and adjusted for urine dilution using creatinine. RNAsequencing was used to profile the placental transcriptome from which 21 co-expression network modules were identified by Weighted Gene Co-expression Network Analysis. Quantile g-computation analysis identified a positive mixture exposure effect on the E2f Target Module ((3 = 0.013 per SD, p = 0.012) and a negative mixture exposure effect ((3 = -0.016 per SD, p = 0.008) on the Myogenesis Module. The pesticide metabolites driving the associations differed for each module on each module varied, highlighting differential susceptibilities within the placental transcriptome to various pesticides. The Myogenesis Module exhibited a consistently significant negative association in both the second trimester ((3 = -0.013 per SD, p = 0.015) and the third trimester ((3 = -0.012 per SD, p = 0.028). When stratifying by infant sex, the mixture exhibited a significant negative effect ((3 = -0.018 per SD, P = 0.016) on the Myogenesis Module only in females. Other modules, such as epithelialmesenchymal transition, though not demonstrating an overall mixture effect, did demonstrate differential impacts of the mixture by sex. These findings underscore the importance of considering the prenatal environment more holistically, understanding the placenta's susceptibility to contaminants, and incorporating sex-specific analyses to understand differential impacts.