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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES034407&format=word)
| Principal Investigator: Petriello, Michael Curtis | |
|---|---|
| Institute Receiving Award | Wayne State University |
| Location | Detroit, MI |
| Grant Number | R01ES034407 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 19 Sep 2023 to 31 Aug 2026 |
| DESCRIPTION (provided by applicant): | PROJECT SUMMARY Cardiovascular diseases are the leading cause of death in the United States and worldwide, and atherosclerotic heart disease is particular burdensome. Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitous man-made chemicals that have been associated with increased risk factors for cardiometabolic disease (i.e., increased circulating cholesterol), or major outcomes related to atherosclerosis including stroke/heart attacks in epidemiological studies. No studies have reported on PFAS accelerated atherosclerosis using rodent models. Recent rodent studies have shown PFAS can increase circulating cholesterol, but these studies have relied primarily on wildtype mice which display lipoprotein cholesterol fraction patterns (VLDL, LDL, HDL) that are opposite of humans, and which do not develop lesions within the aorta. To circumvent this problem and to have an experimental model from which results can be directly extrapolated to humans, we will use Low Density Lipoprotein Receptor deficient mice (Ldlr -/-), which have lipid profiles like humans, to determine if PFAS- mediated increases in cholesterol levels lead to pathological atherosclerosis. Recently, we published that wildtype mice fed an atherogenic diet and exposed to a simple mixture of 5 environmentally relevant PFAS (PFOS, PFOA, PFNA, PFHxS, and GenX) for 12 weeks resulted in increased circulating cholesterol and bile acids. In preliminary studies, we followed the same exposure paradigm and observed increased circulating cholesterol in Ldlr -/- mice. Here, we propose to extend our initial observations using a simple PFAS mixture to a full factorial design and examine atherosclerotic lesion formation. Circulating cholesterol levels can be modulated through mechanisms related to dietary cholesterol absorption, de-novo cholesterol synthesis, and fecal excretion. Our preliminary studies show that Ldlr -/- mice exposed to the mixture show decreased bile acid excretion and induction of reuptake transporters in the ileum (especially apical sodium dependent bile acid transporter; ASBT). Our proposed studies will use pharmaceuticals selective for ASBT and mass labeled sterols to confirm ASBT induction is critical. Finally, to validate some of these observations in a human cohort, we recently measured PFAS in serum from the Anniston Community Health Surveys (ACHS) and we reported that residents were highly exposed to PFOS, and we now propose to measure bile acids in stored samples. We will use mixture methods to show 1) PFAS mixtures statistically correlate with increased cholesterol, and 2) these associations are mediated through increases in circulating bile acids. We hypothesize that PFAS accelerate atherosclerosis by altering cholesterol excretion as bile acids. Our specific aims are: 1) To test the hypothesis that mixtures of environmentally relevant PFAS accelerate atherosclerosis in Ldlr -/- mice. 2) To test the hypothesis that PFAS disrupts bile acid reuptake leading to increases in circulating cholesterol through ASBT- related mechanisms. 3) To examine the association between PFAS mixtures and circulating bile acids and test if that the association between PFAS mixtures and cholesterol can be explained by increases in these. |
| Science Code(s)/Area of Science(s) |
Primary: 41 - Cardiovascular System Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Danielle Carlin |