Prenatal exposure to multiple insecticides and reduced birth weight: a possible mediating role of plasma metabolomic alterations.

Organophosphates (OPPs), pyrethroids (PYRs), and neonicotinoids (NNIs) represent three major classes of insecticides with potential developmental toxicity, yet their effects on fetal growth remain insufficiently characterized. This prospective cohort study examined 442 maternal-infant pairs from Jiangsu, China to assess the relationship between prenatal insecticide exposure and birth outcomes, while exploring underlying metabolomic mechanisms. Maternal fasting blood samples obtained during early pregnancy (<16 weeks) were analyzed for 15 insecticides/their metabolites (3 OPPs, 3 PYRs, and 9 NNIs) and 495 metabolomic features. Fetal growth parameters were assessed via ultrasound-estimated fetal weight and birth measurements from medical records. Multiple linear regression revealed that each natural log-unit rise in 3,5,6-trichloro-2-pyridinol (TCPy, an OPP metabolite) and desmethyl-clothianidin (DM-CLO, an NNI metabolite) concentrations was linked to a significant reduction in birth weight by 43.75 g (95% CI: 73.27, -14.23) and 68.45 g (95% CI: 121.98, -14.92), respectively. Mixture analysis through weighted quantile sum (WQS) regression demonstrated that exposure to insecticide mixture was related to a 122.15 g reduction in birth weight (95% CI: 187.83, -56.47), with TCPy and DM-CLO identified as primary contributors. Metabolomic analysis identified 14 metabolites significantly linked to both insecticide exposure and birth weight, and pathway analysis revealed significant enrichment in "Valine, leucine and isoleucine biosynthesis" (P < 0.001). Mediation analysis indicated that ketoleucine and 3-Methyl-2-oxovaleric acid mediated 9.86% and 6.78% of the insecticides-birth weight association, respectively. These findings suggest that prenatal exposure to specific OPP and NNI metabolites is associated with reduced birth weight, potentially mediated through disruption of branched-chain amino acid metabolism.