Joint trajectories of ADHD and autistic traits in preschoolers linked to prenatal phthalate exposure: insights from the cord blood metabolome

This study explored the association between prenatal phthalate exposure and the joint trajectories of ADHD and autism traits, as well as potential mechanisms. We measured seven phthalate metabolites in urine samples from 3,083 mother-child pairs and assessed the joint neurodevelopmental trajectories of preschool. The results demonstrated time-, sex-, and metabolite-specific associations between prenatal phthalate exposure and the joint trajectories of ADHD and autistic traits. Higher concentrations of DEHP (OR: 1.922, 95 %CI: 0.928, 3.979, per log10 unit increase) and high-molecular-weight phthalates (HMWP) (OR: 1.897, 95 %CI: 0.917, 3.921) were linked to an elevated risk of the high-coexistence trajectory, particularly in girls. Trimester-specific positive associations were observed: first-trimester MBP (OR: 1.292, 95 %CI: 0.998, 1.672) and low-molecular-weight phthalates (LMWP) (OR: 1.360, 95 %CI: 0.996, 1.855) increased the risk of low-coexistence trajectory in girls, while MBzP (OR: 0.817, 95 %CI: 0.682, 0.977) exposure unexpectedly showed protective effects in boys; third-trimester MBzP (OR: 1.232, 95 %CI: 0.970, 1.565) increased low-coexistence risks in boys. Notably, MEHP (OR: 0.677, 95 %CI: 0.510, 0.897), MEHHP (OR: 0.701, 95 %CI: 0.501, 0.981), DEHP (OR: 0.647, 95 %CI: 0.440, 0.950) and HMWP (OR: 0.656, 95 %CI: 0.447, 0.964) appeared to have protective effects in girls. Sex-specific dose-response relationships were evident. Mechanistically, in boys, DEHP and its metabolites were linked to the high-coexistence trajectory through cord blood metabolites involved in lipid and amino acid metabolism. In girls, early high MBP exposure influenced this outcome via metabolites associated with immune regulation and retinol metabolism. Prenatal phthalate exposure may affect neurodevelopmental trajectories through a complex interplay. This study highlights the importance of considering co-occurring neurodevelopmental patterns in environmental risk assessment.