Haloacetamides exacerbate non-alcoholic fatty liver disease induced by a high-fat diet in C57BL/6J mice

Abstract

Obesity, a significant global health issue, heightens the risk of non-alcoholic fatty liver disease (NAFLD). Its interaction with environmental pollutants might exacerbate NAFLD's severity. Haloacetamides (HAcAms), a group of emerging nitrogenous disinfection byproducts (DBPs) and potent oxidative stressors, are found in chlorinated drinking water. Since oxidative stress is associated with HAcAms-DBP cytotoxicity and a key factor in NAFLD pathogenesis, we hypothesize that HAcAms-DBPs could exacerbate liver injury and NAFLD, particularly with high-fat diets. This study examined HAcAms-DBPs' impact on liver lipid metabolism in mice treated with 1 to 100 times the background drinking water level (13.05 µg/L) for up to 16 weeks of oral administration. Compared to a high-fat-only group, mice co-exposed to a high-fat diet and HAcAms-DBPs for 16 weeks had elevated serum alanine transaminase, aspartate transaminase, triglyceride, hepatic lipid aggregation, and inflammation response. Under high-fat conditions, background drinking water levels of HAcAms significantly upregulated liver Acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor gamma (PPARγ), PPARγ coactivator-1α, glucose transporter 1 and 4 protein expression in C57BL/6J mice; 10 times background significantly increased expression of inflammatory marker tumor necrosis factor and liver fibrosis marker protein alpha-smooth muscle actin; 100 times further increased both liver damage and markers of early non-alcoholic steatohepatitis phenotypes like steatosis and lobular inflammation. HAcAms-DBPs plus high-fat conditions worsened liver damage. The possible health risks of NAFLD induced by HAcAms in obese individuals deserve further study.

Keywords: de novo lipogenesis; fibrosis; haloacetamides; inflammation; non-alcoholic fatty liver disease.