The environmental pollutant, polychlorinated biphenyl 126, alters liver function in a rodent model of alcohol‐associated liver disease

• Published in: Alcohol, clinical & experimental research clinical & experimental research, 2023-01, Vol.47 (1), p.60-75
• Main Authors: Gripshover, Tyler C., Wahlang, Banrida, Head, Kimberly Z., Young, Jamie L., Luo, Jianzhu, Mustafa, Muhammad T., Kirpich, Irina A., Cave, Matthew C.
• Format: Article
• Language: English
• Subjects: Albumin; Alcohol; alcohol‐associated liver disease (ALD); Animals; Carbohydrates; Diet, High-Fat; Dioxins; Environmental Pollutants - metabolism; Environmental Pollutants - pharmacology; Ethanol; Ethanol - pharmacology; Fatty liver; Gene expression; Glycogen; High fat diet; Humans; Immune clearance; lifestyle factors; Lipid peroxidation; Lipids; Lipids - pharmacology; Liver - metabolism; Liver diseases; Liver Diseases, Alcoholic - metabolism; Macromolecules; Male; Malnutrition; Malnutrition - metabolism; Malnutrition - pathology; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - metabolism; PCB; Plasma levels; Pollutants; polychlorinated biphenyl 126 (PCB 126); Polychlorinated biphenyls; Polychlorinated Biphenyls - metabolism; Polychlorinated Biphenyls - pharmacology; Rodentia; Steatosis; Toxicants; toxicant‐associated steatohepatitis (TASH)
• ISSN: 0145-6008; 2993-7175; 1530-0277; 2993-7175
• DOI: 10.1111/acer.14976

Background The prevalence of alcohol‐associated liver disease (ALD), a subtype of fatty liver disease (FLD), continues to rise. ALD is a major cause of preventable death. Polychlorinated biphenyl (PCB) 126 is an environmentally relevant, dioxin‐like pollutant whose negative metabolic effects have been well documented. In human and animal studies, PCB has been associated with the severity of nonalcoholic fatty liver disease (NAFLD). However, few studies have investigated whether exposures to environmental toxicants can worsen ALD. Thus, the objective of the current study was to develop an alcohol‐plus‐toxicant model to study how an environmental pollutant, PCB 126, impacts rodent ALD pathology. Methods Briefly, male C57BL/6J mice were exposed to 0.2 mg/kg PCB 126 or corn oil vehicle four days prior to ethanol feeding using the chronic‐binge (10‐plus‐one) model. Results Concentrations of macromolecules, including hepatic lipids, carbohydrates, and protein (albumin) were impacted. Exposure to PCB 126 exacerbated hepatic steatosis and hepatomegaly in mice exposed to the chemical and fed an ethanol diet. Gene expression and the analysis of blood chemistry showed a potential net increase and retention of hepatic lipids and reductions in lipid oxidation and clearance capabilities. Depletion of glycogen and glucose was evident, which contributes to disease progression by generating systemic malnutrition. Granulocytic immune infiltrates were present but driven solely by ethanol feeding. Hepatic albumin gene expression and plasma levels were decreased by ~50% indicating a potential compromise of liver function. Finally, gene expression analyses indicated that the aryl hydrocarbon receptor and constitutive androstane receptor were activated by PCB 126 and ethanol, respectively. Conclusions Various environmental toxicants are known to modify or enhance FLD in high‐fat diet models. Findings from the present study suggest that they interact with other lifestyle factors such as alcohol consumption to reprogram intermediary metabolism resulting in exacerbated ethanol‐associated systemic malnutrition in ALD. The current study evaluates how environmental pollutant, Polychlorinated Biphenyl (PCB) 126, can enhance alcohol‐associated liver disease (ALD). Here, we characterize a multi‐hit, alcoholassociated hepatitis (chronic‐binge) model where PCB 126 promotes ALD by reprograming intermediary metabolism to alter liver function. Environmental pollutants have been demonstrated t