2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is a potent endocrine disruptor in animal studies. On July 10, 1976, as a result of a chemical plant explosion, residents of Seveso, Italy experienced the highest levels of TCDD exposure in a human population. In 1996, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort study of the health of 981 women who were newborn to 40 years at the time of the explosion, lived in the most contaminated areas, and had archived blood collected soon after the explosion. Individual TCDD level was measured in the 1976 archived serum, and for a subset, TCDD and total dioxin toxic equivalents (TEQ) were also measured in serum collected in 1996. In 2008, we followed-up the SWHS cohort to study potential longer-term health sequelae. The SWHS is the only comprehensive study to date of the health of a female population exposed to TCDD; it is unique in being a large cohort with a wide range of TCDD exposure, documented by individual serum TCDD measurements. Over the last 15 years, we have reported numerous findings on this 1st generation of TCDD-exposed women. We found that TCDD serum levels were associated with infertility and higher rates of cancer. However, some of the most profound associations were found among the women who were youngest at the time of the explosion. In this group, we found that TCDD serum levels were related to early menarche, increased menstrual cycle length, and increased risk of metabolic syndrome. Animal studies suggest those exposed in utero may be even more susceptible to the effects of TCDD, and that effects may persist through multiple generations. However, few human studies have examined 2nd generation health effects of TCDD. Now, nearly 40 years after the explosion, the SWHS cohort will have completed their families. We propose to re-contact the SWHS women and enumerate their children born after the explosion. We will invite all children 2 years to participate in a study of their health, and we will measure anthropometrics, blood pressure and clinical chemistries. We will also interview the mother and/or the child. For this initial 2nd generation study, we focus on the endpoints that were the most sensitive to exposure in the 1st generation; namely, we will determine whether in utero TCDD exposure is associated with obesity and metabolic syndrome, thyroid function, age at menarche, menstrual cycle characteristics, and infertility. We hypothesize that the 2nd generation will be as, if not more, susceptible than the 1st to the effects of TCDD exposure. This initial study will lay the foundation for the ongoing investigation of the long-term health of this 2nd generation and will begin to enumerate the 3rd generation. Although increasing animal evidence supports the hypothesis that in utero exposure to endocrine disrupting compounds can have a long-term impact on the health of the 2nd and subsequent generations, the evidence in humans is nearly non-existent. This study will be one of the first to examine the hypothesis of fetal origins of adult disease in a human population.

Public Health Relevance

In 1976, as a result of an explosion at a chemical plant near Seveso, Italy, the surrounding population was exposed to high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD, a potent endocrine disruptor and known human carcinogen. The Seveso Women's Health Study (SWHS), the only comprehensive study to date of the health of women exposed to TCDD, has provided evidence that TCDD exposure is associated with reproductive and chronic health outcomes. Now, almost 40 years after the explosion, we propose to examine the relation of maternal TCDD exposure with the health of the children of Seveso women, in particular, obesity, metabolic syndrome, thyroid hormone levels, menstrual cycle characteristics and fertility.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Gray, Kimberly A
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University of California Berkeley
Public Health & Prev Medicine
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Eskenazi, Brenda; Warner, Marcella; Brambilla, Paolo et al. (2018) The Seveso accident: A look at 40?years of health research and beyond. Environ Int 121:71-84
Ames, Jennifer; Warner, Marcella; Brambilla, Paolo et al. (2018) Neurocognitive and physical functioning in the Seveso Women's Health Study. Environ Res 162:55-62
Ye, Morgan; Warner, Marcella; Mocarelli, Paolo et al. (2018) Prenatal exposure to TCDD and atopic conditions in the Seveso second generation: a prospective cohort study. Environ Health 17:22
Emond, C; DeVito, M; Warner, M et al. (2016) An assessment of dioxin exposure across gestation and lactation using a PBPK model and new data from Seveso. Environ Int 92-93:23-32
Eskenazi, Brenda; Warner, Marcella; Sirtori, Marcella et al. (2014) Serum dioxin concentrations and bone density and structure in the Seveso Women's Health Study. Environ Health Perspect 122:51-7
Chevrier, Jonathan; Warner, Marcella; Gunier, Robert B et al. (2014) Serum dioxin concentrations and thyroid hormone levels in the Seveso Women's Health Study. Am J Epidemiol 180:490-8
Warner, Marcella; Mocarelli, Paolo; Brambilla, Paolo et al. (2014) Serum TCDD and TEQ concentrations among Seveso women, 20 years after the explosion. J Expo Sci Environ Epidemiol 24:588-94
Wesselink, Amelia; Warner, Marcella; Samuels, Steven et al. (2014) Maternal dioxin exposure and pregnancy outcomes over 30 years of follow-up in Seveso. Environ Int 63:143-8
Warner, Marcella; Mocarelli, Paolo; Brambilla, Paolo et al. (2013) Diabetes, metabolic syndrome, and obesity in relation to serum dioxin concentrations: the Seveso women's health study. Environ Health Perspect 121:906-11
Warner, Marcella; Mocarelli, Paolo; Samuels, Steven et al. (2011) Dioxin exposure and cancer risk in the Seveso Women's Health Study. Environ Health Perspect 119:1700-5

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