Prenatal OPEs Trimester- and Sex-Specifically Linked to Trajectories of Preschoolers’ Emotional and Behavioral Problems: Insights from Cord Blood Metabolomics

Organophosphate esters (OPEs) are neurotoxic, yet their impact on children's emotional and behavioral problems (EBPs) trajectories remains understudied, and biological mechanisms are unclear. In a prospective cohort of 2227 mother–child pairs, maternal urinary concentrations of the tris(2-chloroethyl) phosphate (TCEP) and six OPE metabolites were measured across three trimesters. EBPs were assessed at ages 4–6 using the Strengths and Difficulties Questionnaire, with trajectories modeled via latent class growth analysis. The results showed that bis (2-ethylhexyl) phosphate (BEHP) was associated with elevated hyperactivity and total difficulties score trajectories in both sexes. In girls, diphenyl phosphate (DPHP) was positively associated with higher trajectories of emotional problems (OR = 1.39) and bis(1-chloro-2-propyl) phosphate (BCIPP) was associated with higher trajectories of total difficulties score (OR = 1.25), prosocial behavior (OR = 1.45), hyperactivity (OR = 1.80) and peer problems (OR = 1.45). BBOEP showed negative associations with several EBPs trajectories in boys. The second-to-third trimester emerged as a sensitive window. No mixture effects were observed. Exploratory metabolomics analysis of cord blood (p < 0.05) linked DPHP, BEHP and BCIPP to metabolic disturbance, especially lipid-related pathways. In girls, several polyunsaturated fatty acid (PUFA) pathways─linoleic acid, arachidonic acid, and α-linolenic acid metabolism─were key mediators of OPE-induced EBPs trajectories impairments. This study highlights sex- and trimester-specific neurotoxicity of OPEs and provides mechanistic insight from cord blood metabolomics.