Early-life lipid programming: Environmental and biological drivers of neonatal cholesterol

BACKGROUND: Cholesterol at birth influences development and long-term health, but its environmental and biological determinants remain understudied. METHODS: This study investigates associations between the prenatal exposome and cord blood lipid profiles in 1,732 mother-child pairs from the Belgian ENVIRONAGE cohort. An exposome-wide association study, a deletion/substitution/addition variable selection, and multi-exposure regressions were applied to assess 90 external exposures in relation to cord blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and low-density lipoprotein cholesterol (LDL-C). Partial correlations were used to assess relations between 14 internal exposures and cholesterol levels. Mediation of identified internal exposures was tested via an imputation-based approach. RESULTS: Greater sunshine duration and higher atmospheric pressure during pregnancy were inversely associated with TC. Exposure to black carbon, presence of a heating tank in the household, maternal smoking, and primiparity were associated with lower HDL-C, while folic acid supplementation was associated with higher HDL-C. Primiparity was also associated with higher non-HDL-C, and sunshine exposure with lower non-HDL-C. Several biomarkers, including ferritin, thyroid hormones, and inflammatory markers, were correlated with lipid profiles. Homocysteine mediated the effect of atmospheric pressure on TC. Triiodothyronine (fT3), insulin, estradiol, and IL-6 mediated the effect of smoking on HDL-C. fT3 mediated the effect of folic acid on HDL-C, while insulin mediated the effect of primiparity on HDL-C. These findings reveal complex interactions between prenatal environmental exposures, internal biomarkers, and newborn lipid profiles, underscoring the importance of early-life exposome research for preventive health strategies.