Prenatal Exposure to Organophosphate Esters and Infantile Neurobehavior: Integrating the Gut Microbiome and Metabolome.

Organophosphate esters (OPEs) are widely used flame retardants and plasticizers. Given their structural similarity to neurotoxic organophosphorus pesticides, concerns have been raised regarding their potential developmental neurotoxicity. However, epidemiologic evidence remains limited, and the roles of gut microbial and metabolic perturbations in these associations are not well characterized. We analyzed 404 mother-child pairs from the Shanghai Maternal-Child Pairs Cohort. OPE concentrations were quantified in cord serum. Meconium samples were profiled for gut microbiota and metabolomics, and behavioral development at 2 years was assessed using the Strengths and Difficulties Questionnaire. Generalized linear models, negative-binomial hurdle regression, SHapley Additive exPlanations, high-dimensional mediation analysis, metabolome-wide association analysis, meet-in-the-middle analysis, and pathway enrichment analysis were applied. A doubling of cord serum tris(2-butoxyethyl) phosphate (TBEP) concentration was associated with a 0.09-point increase in the conduct problem score at age 2 years (95% confidence interval [CI]: 0.02, 0.16). A doubling of TBEP concentration was also associated with 7.9% higher Chao1 richness (95% CI: 2.8%, 14.1%) and 8.7% higher ACE richness (95% CI: 3.5%, 14.1%). A doubling of Chao1 and ACE richness was associated with 0.27-point (95% CI: 0.12, 0.42) and 0.31-point (95% CI: 0.15, 0.46) increases in conduct problem scores, respectively. Alpha diversity indices and Collinsella were identified as potential mediators of the TBEP-conduct problem association. Integrated metabolomic analyses further implicated five pathways, particularly catecholamine biosynthesis and tyrosine metabolism. Enrichment scores for these pathways were positively associated with Chao1, ACE, and Collinsella. Prenatal TBEP exposure was associated with greater behavioral problems in early childhood. Altered neonatal gut microbiota and related metabolic pathways may partly underlie this association.