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 (<i>p</i> < 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.