Lifecourse Approach to Developmental Repercussions of Environmental Agents on MEtabolic and Respiratory health (LA DREAMERs)

Increasingly, scientific evidence in both humans and animal models suggests that prenatal and early life environmental exposures can result in life-long health consequences. In particular, exposures to elevated air pollution, heavy metals, and persistent organic pollutants (POPs) have been associated with respiratory and/or metabolic health outcomes in childhood. Ambient air pollution is associated with allergic, respiratory and metabolic disease. Regional and near-roadway pollutants have also been associated with childhood asthma, but the strength of association may depend on timing and duration of exposures. Air pollutant exposures early in life, particularly during the prenatal period, have been associated with asthma development by age 6 years in some but not all studies. Emerging evidence also suggests that early life exposures to POPs and some metals, such as As and Pb, may contribute to the development of obesity and metabolic dysregulation. Robust animal toxicological study demonstrates that ambient particulate matter causes obesity, accumulation of metabolic active visceral fat and insulin resistance; limited human data suggest that both regional ambient and near-roadway air pollution are associated with BMI trajectory and insulin resistance in childhood and with type 2 diabetes in adults. However, the epidemiological data supporting a causal role of these prenatal and early life exposures in the development of childhood obesity or respiratory health is generally quite limited, and there has been little systematic evaluation of effects across childhood, or of the biological mediators of effects, or of the effects of mixtures of these common exposures on childhood health outcomes. Therefore, the major goal of this proposal is to study the developmental origins of childhood and adult respiratory and metabolic health in 8931 subjects representing 2 different cohorts of children- the Maternal And Developmental Risks from Environmental and Social Stressors (MADRES) and Children’s Health Study (CHS). The proposed study will address the following key questions in the field: 1) Do prenatal and early childhood environmental exposures alter childhood and adult respiratory and metabolic health? If so, what are the underlying biological mechanisms? Are there critical periods of exposure across the lifecourse? 2) Does exposure to high levels of mixtures of pollutants in utero increase individual susceptibility to childhood respiratory and metabolic disease? 3) Do changes in epigenetic marks provide one biological mechanism driving the rise in rates of childhood obesity and asthma? 4) Can prenatal environmental exposures induce transgenerational epigenetic alterations that help explain increased risk of disease? 5) Can we devise statistical approaches most appropriate for untangling the health effects of exposure mixtures and/or multiple health outcomes, including integration of ‘omics’ data? We will address these important questions by pooling data from MADRES and CHS to focus on the health effects of the following common prenatal exposures: ambient and near-roadway air pollution, heavy metals (As, Pb, Cd, Hg) and POPs in a series of three distinct research projects focused on respiratory health, metabolic health and statistical methods. All three projects will be supported by administrative, exposure and population cores. Deeper mechanistic questions will be addressed in MADRES, since recruitment is ongoing and we can tailor sample collection to address the most pressing questions. CHS has been followed for more than 20 years, enablin