Plasma organophosphate ester exposure-associated microRNA expression profiles and their functional analysis in...

Organophosphate esters (OPEs) are pervasive environmental contaminants with potential health risks. Circulating microRNAs (miRNAs) may mediate the pathological effects of OPEs by regulating gene expression, but relevant human studies are limited. We investigated the associations between thirteen plasma OPEs and plasma miRNA profiles in a cross-sectional study conducted from June to July 2021 among 156 healthy adults recruited from a Health Examination Center in Shiyan, China (the Shiyan Multi-omics Study). The participants, aged 20 to 70 years, had no history of cardiovascular disease, cancer, acute infection, or recent use of anti-inflammatory medications. Using linear regression, Cresyl diphenyl phosphate (CDPP), Tris(2-chloroethyl) phosphate (TCEP), and Tri-iso-butyl phosphate (TiBP) were associated with 55, 10, and 9 plasma miRNAs, respectively. In the mixture model based on latent variable, the CDPP-TiBP-TCEP latent variable was associated with the downregulation of miR-449c-5p and miR-548e-5p, and the upregulation of miR-4433b-5p, let-7d-3p, let-7g-5p, let-7d-5p, miR-3140-3p, miR-223-5p, let-7b-3p, and miR-361-5p. Furthermore, we observed significant correlations between plasma and leukocyte levels of miR-223-5p, let-7b-3p, let-7d-5p, and miR-4433b-5p, supporting leukocytes as a potential biological source of plasma miRNAs. By integrating leukocyte mRNA sequencing data with the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) databases, and Hallmark gene set, functional annotation identified enrichment in pathways related to amyloid beta metabolic process, axon guidance, and glioma, suggesting potential neurotoxic mechanisms of OPEs in humans. This study is the first to identify plasma miRNA profiles associated with trace-level OPEs exposure, highlighting the potential public health significance of low-level OPE exposure in disrupting neural regulation.