Superfund Research Program
Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
Project Leader: Sanjay Srivastava
Co-Investigator: Daniel J. Conklin
Grant Number: P42ES023716
Funding Period: 2017-2022
- Project Summary
Project Summary (2017-2022)
Exposure to toxicants has been linked to the development or exacerbation of chronic disease. While the health of effects of ubiquitous environmental substances such as tobacco smoke and particulate matter are more well-studied, less 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). Understanding how VOC affect CMD is important because obesity and T2D are rapidly growing global health crises.
As part of this University of Louisville Superfund Research Program (UL SRP) Center project, researchers are determining the mechanisms by which VOCs negatively impact cardiovascular health and metabolism, identifying biomarkers for VOC exposure and vascular injury, and test therapeutic strategies to minimize VOC-induced cardiometabolic effects. Preliminary data suggests that VOCs such as acrolein promote endoplasmic reticulum (ER) stress and trigger the unfolded protein response (UPR) in endothelial cells, resulting in insulin resistance. In addition, they found that individuals exposed to VOC such a vinyl chloride develop symptoms of CMD that could be instigated at the molecular level by VOC-induced ER stress.
The research team is investigating the hypothesis that, in the mouse model, VOCs diminish insulin sensitivity in vascular tissues by inducing ER stress, which triggers a series of metabolic changes that accelerate ectopic lipid deposition and cardiometabolic dysfunction. To test this hypothesis, the researchers are examining the effects of VOC exposure on endothelial function and insulin resistance, and delineating the contribution of endothelial UPR to the cardiometabolic toxicity of VOCs. 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. Successful completion of this project will lead to identification of the underlying cellular and molecular mechanisms by which VOC affect insulin sensitivity and cardiometabolic function.