Liver and Systemic Effects of Toxic Exposures
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the major cause of liver disease worldwide, including among U.S. military personnel and Veterans. Indeed, about 25% of Americans have NAFLD. It is closely associated with systemic diseases like obesity, diabetes, and metabolic syndrome. Indeed, NAFLD is increasingly recognized as the liver component of the metabolic syndrome. NAFLD comprises of a spectrum of changes on liver biopsy tissue, ranging from simple steatosis to steatohepatitis (NASH) to advanced fibrosis (liver scarring) and cirrhosis. In early NAFLD, associated cardio-vascular disease (heart attack) is the greatest cause of death. However, the development of fibrosis during the course of the NAFLD increases the risk for liver-related mortality secondary to hepatic decompensation from portal hypertension or liver cancer. Importantly, toxic industrial chemicals are increasingly recognized as novel contributors to fatty liver pathogenesis (termed, toxicant-associated steatohepatitis—TASH), and this is highly relevant to the military. Many of the toxic chemicals listed in the TERP funding announcement have been associated with NAFLD. Most are also considered endocrine disrupting chemicals (EDCs) with broad effects. EDCs can be loosely defined as any substance that interferes with the endocrine system. The endocrine system is made up of glands located throughout the body, hormones that are made by those glands and released into the bloodstream, and tissues that recognize and respond to those hormones. Thus, alteration in insulin metabolism and subsequent diabetes is a potential effect of some EDCs. The mechanisms by which military chemical exposures cause liver are unknown. We hypothesize that certain military chemical exposures specifically harm the liver and are associated with liver and systemic metabolic disruption to promote NAFLD. Discovery of new mechanisms and effective therapies for NAFLD are critical unmet needs. Importantly, the prevalence of NAFLD is increasing at alarming rates in active-duty personnel and Veterans, and this is a highly military-relevant topic. As a chemical class, solvents have the longest history of military exposure-related liver toxicity. This was first reported in aircraft degreasers during World Wars I and II, and these types of exposures continued throughout the Vietnam Era, including the contamination of drinking water at USMC Base Camp Lejeune, which was associated with excess NAFLD and liver cancer risk. In this application, the hepatotoxic solvent, trichloroethylene (TCE), will be tested as a relevant model compound. It is well known to cause liver disease. Importantly, many of these liver toxins have a long lag time between exposure and disease development. Indeed, we have shown that a toxicant similar to TCE (vinyl chloride) can cause liver cancer in humans 30+ years after the toxicant exposure. We have also shown that vinyl chloride can interact in a synergistic fashion with a high-fat diet to produce liver injury. Thus, a high-fat diet in combination with low-dose exposure to vinyl chloride can cause much worse liver injury than exposure to either one alone. This proposed research will extend some of these observations related to vinyl chloride liver toxicity to TCE exposure as it relates to Veterans. Our research team has a long record of performing studies in Veterans, and the communicating PI is a liver doctor at the Robley Rex VAMC. Our proposal is highly translational, studying both relevant animal models and Veterans. We evaluate both modifying factors, such as diet and sex, and a mechanistic therapeutic intervention. Thus, recommendations could be made concerning diet interventions and/or prophylactic/therapeutic drug strategies. Results of this research could impact the health and wellbeing of military personnel and Veterans who are known to be at high risk for NAFLD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311056
Entities
People
- Matthew Cave
Organizations
- United States Army
- University of Louisville