UC Berkeley

Evidence of inter-individual differences in toxicant response has necessitated heavy editing of Paracelsus’ famous toxicological maxim “the dose makes the poison” to include factors such as age, sex, and timing of exposure. This dissertation takes advantage of a unique multigenerational, long-term cohort and advances in molecular technology to examine whether life stage and genetic factors also modify human sensitivity to toxic exposures, particularly with respect to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant with well-documented carcinogenic and endocrine-disrupting effects in humans. 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 limited. In addition, individuals may have differences in susceptibility to chemical exposure based on their genetic make-up.

On July 10, 1976, an explosion at a chemical plant near Seveso, Italy resulted in a toxic plume that exposed nearby residents to high levels of TCDD. The Seveso Women’s Health Study (SWHS), an ambidirectional cohort study, was initiated in 1996 to investigate the health of 981 women who were newborn to age 40 years in 1976, had resided in the immediate vicinity of the plant, and had archived samples of blood collected soon after the explosion. The SWHS is the only comprehensive study of the health effects of TCDD exposure in a female population, and has the unique benefit of measurements of individual-level TCDD in blood collected near the time of the explosion. In 2014, 611 offspring of the SWHS who were born after the accident, and potentially exposed to their mother’s TCDD body burdens in utero were enrolled.

The first two chapters examine the neurotoxic effects of TCDD during windows of susceptibility in utero and later in life when hormonal processes potentially sensitive to TCDD’s estrogenic influence are driving brain changes. In particular, chapter 1 investigates TCDD and cognitive and physical functioning in SWHS women decades after their direct exposure to the accident and the modifying effects of menarche and menopause. Chapter 2 addresses the relation between neuropsychological function in 7-17 year old offspring (n=161) with respect to their mother’s 1976 exposures and maternal levels estimated at the time of pregnancy. Lastly, Chapter 3 examines genetic susceptibility in the aryl hydrocarbon receptor (AhR), a key transcription factor in the metabolism of TCDD and other xenobiotics in humans. Specifically, we conducted a gene-by-environment (GxE) analysis to evaluate the modifying effect of genetic polymorphisms in maternal AhR on the relationship between maternal TCDD levels and child birthweight, an indicator of a restricted fetal environment. The SWHS Second Generation Study in conjunction with the parent SWHS offers a rich dataset in which to explore windows of neurotoxic and genetic susceptibility to TCDD across the lifecourse and test the fetal origins of disease hypothesis.