Project 2 - Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs

SUMMARY Exposure to toxicants has been linked to the development or exacerbation of chronic disease. However, little is known about how volatile organic chemicals (VOC)—a class of toxicants associated with higher prevalence of type 2 diabetes (T2D) and stroke—promote the development of cardiometabolic disease (CMD). Accordingly, the overarching goals of this Superfund project are to determine the mechanisms by which VOCs negatively impact cardiovascular health and metabolism, identify biomarkers for VOC exposure and vascular injury, and test therapeutic strategies to minimize VOC-induced CMD. Our studies in the current funding cycle and preliminary data suggest that VOC such as benzene, vinyl chloride, and crotonaldehyde promote endoplasmic reticulum (ER) stress and trigger the unfolded protein response (UPR) in endothelial cells. Specifically, we hypothesize that aldehyde metabolites of VOC, which are generally more toxic than their parent compound, diminish endothelial toxicity by inducing ER stress, which triggers metabolic changes that accelerate ectopic lipid deposition and promote cardiometabolic dysfunction. To test this hypothesis we will: (1) examine the effects of VOC exposure on endothelial function and insulin resistance; (2) delineate the contribution of protein misfolding to the cardiometabolic toxicity of VOC. The design of these studies includes molecular and pharmacological interventions designed to detoxify or quench the reactive intermediates evoked by VOC exposure as well as studies that could lead to the identification of novel, sensitive and robust biomarkers of both VOC exposure and vascular injury. These studies were designed to synergize with and provide biological plausibility for the associations identified in Project 1. Successful completion of this project will lead to identification of the underlying cellular and molecular mechanisms by which VOC affect cardiometabolic function and provide insights into how VOC toxicity could be prevented or therapeutically minimized by targeting aldehydes or protein- folding pathways.