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Your Environment. Your Health.

TMAO IS A BIOMARKER OF DIOXIN-LIKE POLLUTANT EXPOSURE AND CARDIOMETABOLIC DISEASE

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Principal Investigator: Petriello, Michael Curtis
Institute Receiving Award Wayne State University
Location Detroit, MI
Grant Number R00ES028734
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Sep 2019 to 31 Jul 2022
DESCRIPTION (provided by applicant): Dioxin-like organic pollutants persist in the environment and, because of their bioaccumulation in adipose tissue can be detected in the blood of most individuals. Exposure to these pollutants causes diabetes and its complications of obesity and cardiovascular disease in animal models. These observations can likely be translated to humans because several large longitudinal epidemiological studies have associated serum levels of these pollutants, for example polychlorinated biphenyls (PCBs) with an increased risk of cardiovascular disease and type 2 diabetes. The variability in inter-individual responses to increased body burdens of these pollutants observed in these epidemiological studies can likely be explained by the additional contributions of genetic and other environmental risk factors, the most powerful of which is clearly the diet. The goal of this proposal is to provide the applicant with mentored training and early career research support to become an independent investigator studying interactions between diet, nutrition and environmental exposures as determinants of human disease. To accomplish this the candidate will be mentored by an interactive group of established investigators with complementary expertise in analytical chemistry, multivariate statistics, and preclinical models of cardiovascular and metabolic disease. This training will be accomplished through participation in an original research project studying a mechanism that could link diet and exposure to dioxin- like persistent organic pollutants to cardiovascular disease risk. Increased circulating levels of a diet derived metabolite, trimethylamine N-oxide (TMAO) are associated with coronary artery disease and diabetes risk in humans. The precursor of TMAO, trimethylamine (TMA) is generated from dietary substrates (choline containing lipids and carnitines) by the gut microbiota. TMA is oxidized to TMAO by hepatic Flavin-containing monooxygenases, predominantly the FMO3 isoform. We have found that exposure to dioxin-like PCBs strongly increases FMO3 expression in the liver to amplify formation of TMAO from dietary sources in animal models and that exposure to dioxin like pollutants positively associates with circulating TMAO levels in a highly exposed human population. These observations lead us to propose our overarching hypothesis that induction of FMO3 expression is a mechanism linking coplanar PCB exposure to the development of cardiovascular and related metabolic diseases and that circulating TMAO levels are a biomarker of systemic dioxin-like pollutant exposure in humans. We will test this hypothesis in the following aims. 1: To test the hypothesis that a diet high in TMAO precursors can exacerbate dioxin-induced cardiometabolic disease in vivo. 2: To test the hypothesis that FMO3 and/or gut microbiota are required for dioxin-induced cardiometabolic disease in vivo. 3 To test the hypothesis that elevated TMAO levels in dioxin-like pollutant-exposed individuals result from increased FMO3 activity/expression.
Science Code(s)/Area of Science(s) Primary: 41 - Cardiovascular System
Publications See publications associated with this Grant.
Program Officer Thaddeus Schug
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