In Utero Dioxin Exposure and Age at Menarche in the Seveso Second Generation

Abstract

Introduction: In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant and potent endocrine disrupting compound, is associated with delayed pubertal development in animal studies. On July 10, 1976, an explosion at a chemical plant near Seveso, Italy exposed nearby residents to high levels of TCDD. The Seveso Women’s Health Study (SWHS), initiated in 1996, is the only study to date of TCDD’s health effects in a female population with the unique benefit of individual TCDD measured in blood collected near the time of the explosion. In 2014, we enrolled SWHS offspring (those exposed in utero to TCDD) in the Seveso Second Generation study. We examined the relationship of in utero TCDD exposure with reported age at onset of menarche among SWHS daughters.Methods: Age at onset of menarche (in years) was collected by maternal or self-report at interview in 341 SWHS daughters. We defined in utero TCDD exposure as initial (1976) maternal serum TCDD level and TCDD extrapolated to pregnancy. Data were analyzed using Cox proportional hazards models.Results: At interview, 287 daughters were postmenarche, averaging 25.6 (±8.0) years of age. The mean reported age at menarche was 12.1 (±1.3) years. Overall, we found no change in risk of menarche onset with a 10-fold increase in initial maternal TCDD (Hazard Ratio (HR) = 0.91, 95% CI 0.79, 1.06) or TCDD estimated at pregnancy (HR = 0.86, 95% CI 0.72, 1.03). When we considered maternal menarche status at explosion as a potentially sensitive developmental exposure window, TCDD estimated at pregnancy (log10) was associated with later age at menarche among daughters whose mothers were premenarche at explosion (HR = 0.71, 95% CI 0.50, 1.00) but not postmenarche at explosion (HR = 0.87, 95% CI 0.71, 1.07).Conclusions: These results suggest in utero exposure to TCDD may alter pubertal timing among daughters of women who were prepubescent at the time of the Seveso accident.