PCB126 Modifies the Murine Hepatic Transcriptome and Metallome to Promote Alcohol-associated Liver Disease Pathogenesis
Background: Environmental pollutants, including polychlorinated biphenyls (PCBs) have been shown to alter and promote the development of alcohol-associated liver disease (ALD). Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in an ALD rodent model. Objectives: To better understand how PCB126 promoted ALD, the current study adopts transcriptomic and metallomic approaches to identify mechanistic pathways involved in this promotion. Methods: Briefly, male C57BL/6J mice were exposed to 0.2 mg/kg PCB126 or corn oil vehicle prior to ethanol feeding in the chronic-binge model. Liver tissues were collected for RNA sequencing and ICP-MS metals quantification. Results: PCB126 uniquely modified the transcriptome in EtOH-fed mice in terms of variance. EtOH feeding alone resulting in >4000 differentially expressed genes (DEGs) and PCB126 exposure resulted in more DEGs in the EtOH-fed group over the pair-fed group. Top gene ontology (GO) biological processes indicated 'peptidyl tyrosine modifications' and GO molecular function processes showed a loss of 'metal, and ion, and zinc binding'. Western blot analysis depicted that the JAK2-STAT5 signaling axis was disrupted by the enhanced loss of phosphorylated JAK2 in EtOH+PCB126 mice. Quantified liver essential metal levels were overall depleted by EtOH feeding, and potassium, magnesium, cobalt, and zinc were further decreased by PCB126. Discussion: The results suggests that phosphorylation and metal binding are disrupted in EtOH+PCB126 mice, implying that evolutionarily conserved homeostatic signaling mechanisms are modified by pollutant exposure in EtOH-fed mice. The loss of phosphorylation and essential metals are two suggestive modes of action that may explain the promotion of disease by PCB126 in ALD. Overall design: C57BL/6J mice were orally gavaged 0.2 mg/kg polychlorinated biphenyl 126 (PCB 126). Mice were then placed on the chronic-binge (ten-plus-one) alcohol (ethanol) feeding model using the Lieber-DeCarli Diet. Mice were initially allowed to acclimate to the diet over 5 days where mice were given 1 day of 0% ethanol, 2 days of 2% ethanol, and 2 days of 4% ethanol. Mice were then fed a 5% ethanol diet for 10 days. The following day (11th day - binge) mice were orally gavaged 5g/kg ethanol, followed by euthanasia and tissue collection. This study is an exact repeat of our characterization study previously published (PMID: 36377258)