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.