An assessment of organophosphate ester mixtures and the placental transcriptome.

Prenatal exposure to organophosphate ester (OPE) chemicals, commonly used as flame retardants and plasticizers, has been associated with adverse birth outcomes. The placenta is a critical fetal organ and therefore may be involved in pathogenesis of birth outcomes. The goal of this study was to evaluate associations of 10 maternal urinary OPE metabolites, individually and as a mixture, with the placental transcriptome at birth in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Individual OPE metabolites were evaluated for associations with individual genes as well as co-expressed gene modules. Mixtures analysis was conducted using quantile g-computation. The analyses were performed with the entire data set (N = 737) as well as the sex-stratified subsets. Two genes (HAP1 and RAP1GAP) were associated with bis(1,3-dichloro-2-propyl) phosphate (BDCPP), and six genes were associated the mixture in the full data set. 3 genes were associated with diphenyl phosphate (DPHP) and 36 genes were associated with the mixture in a male stratified analysis. 2 genes were associated with DPHP, and 1 gene was associated with diethyl phosphate (DEP) in a female stratified analysis. Three gene modules were associated with BDCPP or diphenyl phosphate (DPHP) and one module was associated with the OPE mixture. 12 WGCNA modules were associated with individual OPE metabolites or the mixture in males, and 1 WGCNA module was associated with DEP in females. Five of the OPE-associated gene modules were enriched for a total of 17 KEGG pathways, and 11 modules were enriched with targets of 12 nuclear hormone receptor transcription factors. Overall, novel associations were identified between the placental transcriptome and OPE metabolites, individually and in mixture, including differences based on fetal sex. These findings highlight the need for additional research on mechanisms of OPE-associated gene expression changes in the placenta and associated health outcomes.