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

> **NIH NIH P42** · UNIVERSITY OF LOUISVILLE · 2024 · $322,849

## Abstract

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.

## Key facts

- **NIH application ID:** 10914083
- **Project number:** 5P42ES023716-08
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Sanjay Srivastava
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $322,849
- **Award type:** 5
- **Project period:** 2017-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914083

## Citation

> US National Institutes of Health, RePORTER application 10914083, Project 2 - Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs (5P42ES023716-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10914083. Licensed CC0.

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