PILOT: Center for Appalachian Research in Envrionmental Sciences: Arsenic Exposure and Cardiovascular Risk Markers In Obese Children

SPECIFIC AIMS: Childhood obesity and its associated cardiometabolic risk factors are alarmingly increasing nationwide. Currently 17% of children and adolescents are obese and 34% are overweight, with rates of obesity increasing in all age groups in the pediatric population. Kentucky ranks number one in the nation in the prevalence of overweight among high school- aged youth (12-19yr) and overweight and obese children are more likely to be diagnosed with several major morbidities (hypertension, hyperlipidemia, diabetes). Long-term health consequences of childhood obesity also include increased risk of myocardial infarction and stroke, as well as various cancers. Several environmental pollutants including arsenic have been linked to these same morbidities in adults but few studies have investigated the interactions of obesity and environmental exposures in children. Defining the contributions of environmental contaminants in high-risk pediatric populations, and clarifying the mechanisms involved are important research priorities of our translational research team. Exposure to inorganic arsenic has already been identified as a risk factor for elevated blood pressure and cardiometabolic disease but its impact in early life obesity has never been studied. Murine models have demonstrated a synergistic effect of high fat diet and arsenic exposure in the development of hypertension and cardiometabolic disease; however, there are few studies on arsenic and cardiometabolic risk in the setting of pediatric obesity. Such studies will provide the basis for early interventions and prevention strategies. The Kentucky Children’s Hospital is well positioned to develop a research program to address environmental contributions to childhood disease in our region and to develop a portfolio of research projects in ‘environmental pediatrics’. The specific project proposed here will test the hypothesis that arsenic, a highly toxic metal contaminant known to exist in Central and Appalachian KY is associated with cardiovascular risk markers in obese children. This study will allow for the identification of the most vulnerable patients due to arsenic exposure and obesity-related disease risks. We propose the following specific aims: AIM 1: Measure Arsenic blood levels in available samples from obese children who have been cared for by the KCH high-BMI clinic. We will determine the range of levels of arsenic in blood samples we have already obtained from 100 obese patients at the KCH High-BMI clinic as a cross-sectional study. This will be achieved via P30 core facility support (Dr. Jason Unrine). AIM 2: Investigate relationships between blood arsenic levels, blood pressure, and markers of cardiovascular risk in obese children (samples from Aim 1). We will conduct additional assays on the available blood samples described in AIM 1 with respect to markers of: inflammation (CRP, IL6,), vascular endothelial injury (soluble-ICAM), and glucose metabolism (glucose, insulin, HOMA-IR), and lipids. Additionally, we will investigate blood pressure in relation to arsenic levels and other risk markers. AIM 3: Develop additional infrastructure to conduct a prospective observational study linking arsenic levels to cardiovascular risk markers in obese pediatric patients. While we have established IRB approval for the Aims proposed, we will revise and expand our IRB to allow for recruitment of patients in a prospective study from the additional venue of Pediatric Nephrology Clinic. Prospective enrollment of 45 patients from our clinical site will include cardiac MRI imaging for detailed cardiovascular assessments. We will also develop a more expansive sample capture and management strategy to allow for more extensive patient capture from Appalachia. This project will help to establish momentum for the junior PI in this research area and will provide novel and useful preliminary data for one or more new R01 submissions (or a K-series proposal). Furthermore, the sample library and clinical research processes derived from this project will provide a basis for additional inquiry in regard to environmental contributors to child health in our region.