Prenatal exposure to synthetic phenolic antioxidants and cognitive development in preschool children: Identification of sex-specific susceptibility and critical windows

Synthetic phenolic antioxidants (SPAs) are suspected neurodevelopmental toxicants. This study investigated associations between prenatal exposure to individual and mixed SPAs and cognitive development in preschool children. Based on the China National Birth Cohort, 1239 mother-child pairs were included. We quantified urinary concentrations of nine SPAs across all three trimesters using UPLC-MS/MS and assessed children's cognitive development at age 3 using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-Ⅲ) by trained professionals. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to examine associations between urinary SPAs and children's cognitive development. The detection frequencies of the nine SPAs in maternal urine ranged from 1.33% to 95.83%. Linear regression showed that second-trimester exposure to AO3114 and BHT-CHO were associated with lower cognitive scores (β = -0.222, 95% CI: -0.358, -0.085; β = -0.080, 95% CI: -0.149, -0.012; respectively). In the third trimester, BHT-OH was associated with reduced cognitive and fine motor scores (β = -0.059, 95% CI: -0.112, -0.007; β = -0.052, 95% CI: -0.096, -0.009; respectively). Sex-stratified analyses showed that these associations were primarily observed in boys. BKMR analysis similarly showed that co-exposure to SPAs in the second and third trimesters correlated with decreased cognitive and expressive language scores. This first epidemiological study reports sex-specific associations between prenatal SPA exposure and preschool children's cognitive development, and identifies the second trimester as a potential susceptible period.