Gestational Joint Exposure to Air Pollutants and Intrauterine Skeletal Development: Mediating Effect of Placental Metabolome in a Chinese Birth Cohort

Evidence from both epidemiology and toxicology suggests that exposure to individual air pollutant during pregnancy can impair intrauterine skeletal development, but the joint effects of pollutant mixtures and the mediating biological pathways are poorly understood. Within a Chinese birth cohort comprising 470 mother-infant pairs, we investigated the associations between joint exposure to six common air pollutants (fine particulate matter and inhalable particulate matter, nitrogen dioxide, sulfur dioxide, carbon monoxide, and ozone) and markers of intrauterine skeletal development (intrauterine femur length and birth length). We further explored the potential mediating role of placental metabolites in these observed associations. Our results show that joint exposure to air pollutants during the third trimester was inversely associated with femur length in utero and birth length, in which PM_2.5 was the primary contributor. Specifically, each quintile increase in the mixture was linked to decreases in femur length (β = -0.08 SD; 95% CI: -0.16, -0.01) and birth length (β = -0.11 SD; 95% CI: -0.19, -0.03). Placental metabolomic analysis identified that arachidonic acid metabolism was significantly linked to both air pollutants and intrauterine skeletal development. Specifically, arachidonic acid-metabolomic score was positively associated with joint exposure to air pollutants but negatively associated with birth length. Prostaglandins, including prostaglandin E2 and prostaglandin F2α mediated 4.16-7.24% of the observed inverse associations. Our findings suggest that maternal third trimester joint exposure to air pollutants may adversely affect intrauterine skeletal growth, potentially through disrupting placental arachidonic acid metabolism.