Sex-specific mediation of placental inflammatory biomarkers in the effects of prenatal phthalate coexposure on preschooler cognitive development

The objective of this study is to investigate the mediating effect of placental inflammatory biomarkers on the relationship between prenatal phthalate coexposure and cognitive development in preschoolers. A subgroup of 1660 mother-child pairs from the Ma’anshan Birth Cohort study were included. We measured the levels of phthalate metabolites of dibutyl phthalate (DBP), butyl benzyl phthalate (BBzP), and di (2-ethylhexyl) phthalate (DEHP) in all the women included in the study from three urine samples collected in each of the trimesters. A potency-weighted sum of coexposure to DBP, BBzP, and DEHP (indicator: ∑PAE) was calculated. The mRNA of the proinflammatory cytokine IL-6 and the classically activated macrophage (M1) biomarker CD68 was analyzed using placental tissues. The Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition-Chinese was used to evaluate the full-scale intelligence quotient (FSIQ) of children aged 2.5–6 years. Average ∑PAEs and ∑PAEs in each trimester were associated with IL-6 and CD68. ∑PAE in the first trimester was positively associated with IL-6 (β = 0.11, 95% CIs = 0.03–0.19) and CD68 (β = 0.16, 95% CIs = 0.04–0.28), and negatively associated with FSIQ (β =−0.06, 95% CIs = −0.11 to −0.02), verbal comprehension (β =−0.06, 95% CIs = −0.11 to −0.01), and processing speed (β =−0.07, 95% CIs = −0.12 to −0.01). Additionally, sex discrepancies were observed for the mediating effects of placental inflammation on the relationships between ∑PAE and children’s cognitive development. For instance, the association between ∑PAE in early pregnancy and FSIQ was partially mediated by IL-6 (estimated proportion mediated: 21.85%) and CD68 (estimated proportion mediated: 16.2%). Gender-specific associations and trimester-specific relationships of prenatal multiple phthalate coexposure were revealed. ∑PAE in the first trimester of pregnancy was associated with increased of placental inflammation, and a decrease in preschoolers’ cognitive development. In boys, placental IL-6 and CD68 elevation resulting from phthalates might be potential mechanisms of poor cognitive development.