Pilot: Center for Appalachian Research in Environmental Sciences: Mechanisms Linking Flame Retardant Exposure and Diabetes

Organophosphate flame retardants (OPFRs) are used in automobiles, mattresses, and upholstery to meet federal and state-mandated flammability standards. OPFR off-gassing contaminates indoor spaces, leading to ubiquitous human exposure through hand-to-mouth contact. Studies from the National Health and Nutrition Examination Survey (NHANES) indicate that >95% of the American population have detectable OPFR body burdens. In humans, exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is positively associated with metabolic syndrome, obesity, non-alcoholic fatty liver disease, and insulin resistance. These epidemiological data point to TDCPP exposure as a type 2 diabetes risk factor. Despite use of weighted quartile-sum regression to statistically parse adverse effects of specific chemicals, the high rate of chemical co-exposure and the inherent limitations of cross-sectional studies leave a critical knowledge gap regarding whether the specific chemical TDCPP causes metabolic disruption. A physiologically relevant mouse model is critical to establish causation related to TDCPP-associated metabolic disruption and to elucidate the mechanistic underpinnings. The objective of this proposal is to test for TDCPP-induced metabolic disruption at human exposure levels using a translationally relevant mouse model. Clinical translation will be achieved by using a chronic exposure paradigm in which mice are exposed to relevant concentrations of TDCPP for 20 weeks. This chronic exposure better models the duration of TDCPP exposure in humans and increases the probability of discovering TDCPP-induced metabolic maladies at levels relevant to humans. Lastly, we will use Diversity Outbred (DO) mice to maximize genetic diversity and allow for genetic mapping of metabolic phenotypes caused by TDCPP exposure. Implementing these strategies to enhance human relevancy, we will test the overall hypothesis that chronic TDCPP exposure at levels comparable to humans increases adiposity and impairs glucose homeostasis. We anticipate results from this proposal to uncover TDCPP-induced metabolic disruption at human exposure levels and elucidate quantitative trait loci responsible for the phenotype. This is a necessary step in developing strategies to mitigate the harmful effects of TDCPP. Moreover, the results may be generalizable to other xenobiotics in which our results can help screen for more safe industrial chemicals.