Superfund Research Program
An Integrated Experimental and Computational Approach to Understand the Effects of Population Variability on the Shape of the Dose-Response Curve
Project Leader: John J. LaPres
Grant Number: P42ES004911
Funding Period: 2006-2021
Individuals are exposed to a wide range of toxicants on a daily basis, including many chemicals that can activate the aryl hydrocarbon receptor (AHR). These chemicals include one of the most toxic compounds found at Superfund sites, 2,3,7,8-tetrachlorodibenoz-p-dioxin (TCDD). Exposure to TCDD and other AHR ligands can lead to chloracne, immune suppression, and metabolic dysfunction. During the course of these investigations, the team has shown that a threshold model more accurately predicts toxicity for these non-cancer endpoints than a linear model. This implies that regulators can now focus on refining the current models for risk assessments and this will have profound effects on people’s health and safety, especially those around sites contaminated with this class of chemicals. Researchers' most recent experiments have demonstrated a link between TCDD exposure and cholesterol homeostasis. Importantly, their recent published report suggests that co-exposure of TCDD and the cholesterol lowering drug, simvastatin, exacerbates AHR-mediated hepatotoxicity. The team is now exploring the direct link between AHR, cholesterol biogenesis, and specific inflammatory signals in the liver and the role they play in TCDD-induced liver pathology. These findings not only highlight the complex nature of AHR signaling, but also add insight to the understanding of metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD).