Superfund Research Program
Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
Project Leader: Sanjay Srivastava
Grant Number: P42ES023716
Funding Period: 2022-2027
- Project Summary
Project Summary (2022-2027)
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. The team’s 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, they 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 the researchers:
- Examine the effects of VOC exposure on endothelial function and insulin resistance.
- 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 the Cardiometabolic Injury due to VOCs project. 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.