Human CYP1A1, diet and dioxin-induced hypertension

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DESCRIPTION (provided by applicant): Considerable evidence demonstrates that dietary omega-3 polyunsaturated fatty acids (?-3 PUFAs) protect against cardiovascular morbidity and mortality. Although the American Heart Association recommends that all individuals consume ?-3 PUFAs from fish or fish oil supplements, many individuals avoid fish consumption due to concern about accumulated environmental pollutants. It is well known that halogenated aromatic hydrocarbon (HAH) pollutants bioaccumulate in fish and studies have linked human HAH exposure to an increased risk of cardiovascular disease. Exposure to HAHs highly induces cytochrome P4501A1 (CYP1A1) and notably, ?-3 PUFAs are the preferred endogenous fatty acid substrates for CYP1A1. Thus, sustained CYP1A1 induction could decrease ?-3 PUFAs, contributing to cardiovascular disease risk resulting from HAH exposure. Our research shows that exposure to a prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces vascular dysfunction and hypertension in mice and these effects require induction of CYP1A1. Our preliminary data show that TCDD exposure of mice for 2 wks (prior to an increase in blood pressure) highly induces CYP1A1 in resistance arteries and depletes hepatic ?-3 PUFAs. This exposure also induces vascular gene expression consistent with ?-3 PUFA depletion and production of endothelial-derived contracting factors in CYP1A1 wildtype (WT), but not knockout (KO) mice. Further, TCDD increases arachidonic acid (AA)-mediated vasoconstriction and an ?-3 PUFA-enriched diet normalizes this effect. We hypothesize that CYP1A1 mediates TCDD-induced vascular dysfunction and hypertension via ?-3 PUFA depletion. We further hypothesize that human CYP1A1 will be as effective as mouse CYP1A1 in mediating these responses in vivo. To test this, in Aim 1 we will establish the requirement for CYP1A1 in TCDD-induced changes in vascular fatty acids and gene/protein expression, using CYP1A1 WT and KO mice, as well as mice where the mouse CYP1A1 and 1A2 genes have been replaced with the human CYP1A1/1A2 orthologs (hCYP1A). We will investigate the time course and magnitude of changes and the ability of ?-3 PUFAs to prevent them. The humanized CYP1A mouse will significantly improve our ability to extrapolate from mice to humans. In Aim 2 we will determine the mechanism by which CYP1A1 mediates TCDD-induced vascular dysfunction, using CYP1A1 WT and hCYP1A mice, and studying the aorta and mesenteric vasoreactivity ? and ?-3 PUFAs. In Aim 3 we will determine the ability of human CYP1A1 to mediate TCDD-induced hypertension and dietary ?-3 PUFAs to prevent it, using radiotelemetry. If proven correct these studies would provide the first experimental evidence that benefits of ?-3 PUFAs can offset vascular disease risk posed by HAH pollutants accumulated in fish. These outcomes also have broader human health implications. In particular, cigarette smoke has high levels of HAHs that induce CYP1A1 potentially contributing to vascular disease. Thus, CY?P1A1 inhibition could be a novel drug target for reducing vascular disease risk as a consequence of sustained CYP1A1 induction. PUBLIC HEALTH RELEVANCE: The American Heart Association recognizes that eating fish provides significant protection from developing cardiovascular disease and these benefits are derived from the intake of omega-3 polyunsaturated fatty acids; however, many individuals avoid fish consumption due to concern about accumulated environmental pollutants. While attempts have been made to estimate a risk-benefit ratio for fish consumption, no studies have experimentally investigated the interaction between dietary omega-3 polyunsaturated fatty acids, pollutants, and cardiovascular disease. The proposed studies will use an animal model to investigate the ability of dietary omega-3 polyunsaturated fatty acids to protect against pollutant induced vascular disease and hypertension, testing the premise that benefits of fish-derived fatty acids offset cardiovascular risk from pollutants accumulated in fish.