Prenatal and childhood exposure to mixtures of endocrine-disrupting chemicals in association with measures of adiposity in childhood and adolescence.
BACKGROUND Childhood obesity is a global public health crisis. Endocrine-disrupting chemicals (EDCs) - widespread pollutants that interfere with hormonal and metabolic systems - may contribute to excessive adiposity. The combined, long-term, and mechanistic effects of multi-class EDC mixtures remain unexplored. METHODS We analyzed 1301 mother-child pairs from the Human Early Life Exposome (HELIX) project, spanning six European cohorts. Prenatal and childhood exposures to 45 EDCs across nine chemical classes were measured in maternal and child biospecimens. Thirty-six plasma proteins were quantified in childhood using targeted proteomic panels. Adiposity outcomes in childhood (6-11 years) and adolescence (12-18 years) included BMI z-scores, waist circumference, and body fat percentage. We applied penalized Lasso-type Bayesian Weighted Quantile Sum Regression to assess mixtures, a signed iterative random forest for interactions, and mediation analyses for biological pathways. RESULTS Prenatal metal and organochlorine pesticide mixtures were associated with higher BMI z-scores in childhood and adolescence and 47-48 % higher odds of overweight. Prenatal PFAS exposure was associated with higher body-fat percentage in both periods. Childhood phenol and high-molecular-weight phthalate exposures were associated with higher adolescent zBMI, whereas parabens and persistent compounds showed inverse associations. Childhood metal exposures were associated with higher body-fat percentage and overweight odds. An inflammatory-metabolic protein pattern mediated ∼ 30 % of the prenatal metal-adolescent zBMI association. CONCLUSIONS Early-life exposure to EDC mixtures may reprogram metabolic and inflammatory pathways, predisposing children to obesity that persists into adolescence. These findings provide mechanistic evidence linking chemical exposures to the global obesity epidemic and underscore the urgent need for policies preventing EDC exposure during critical developmental periods.