In utero dioxin exposure and cardiometabolic risk in the Seveso Second Generation Study

In utero exposure to endocrine-disrupting compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may alter risk of obesity and related metabolic disease later in life. We examined the relationship of prenatal exposure to TCDD with obesity and metabolic syndrome (MetS) in children born to a unique cohort of TCDD-exposed women resulting from a 1976 explosion in Seveso, Italy.

In 2014, nearly 40 years after the explosion, we enrolled 611 post-explosion offspring, 2 to 39 years of age, in the Seveso Second Generation Study. In utero TCDD exposure was defined primarily as TCDD concentration measured in maternal serum collected soon after the explosion and alternately as TCDD estimated at pregnancy. We measured height, weight, waist circumference, body fat, blood pressure, and fasting blood levels of lipids and glucose, which were combined to assess body mass index (BMI) and MetS.

Children (314 female, 297 male) averaged 23.6 (±6.0) years of age. Among the 431 children ≥18 years, a 10-fold increase in initial maternal TCDD concentration was inversely associated with BMI in daughters (adj-β = -0.99 kg/m²; 95% CI -1.86, -0.12), but not sons (adj-β = 0.41 kg/m²; 95% CI -0.35, 1.18) (p-int = 0.02). A similar relationship was found in the younger children (2-17 years); a 10-fold increase in initial maternal TCDD was inversely associated with BMI z-score (adj-β = -0.59 kg/m²; 95% CI -1.12, -0.06) among daughters, but not sons (adj-β = 0.04 kg/m²; 95% CI -0.34, 0.41) (p-int = 0.03). In contrast, in sons only, initial maternal TCDD was associated with increased risk for MetS (adj-RR = 2.09, 95% CI 1.09, 4.02). Results for TCDD estimated at pregnancy were comparable.

These results suggest prenatal TCDD exposure alters cardiometabolic endpoints in a sex-specific manner. In daughters, in utero TCDD is inversely associated with adiposity measures. In sons, in utero TCDD is associated with increased risk for MetS.