Date on Master's Thesis/Doctoral Dissertation

12-2023

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Cave, Matthew

Committee Co-Chair (if applicable)

Clark, Barbara

Committee Member

Clark, Barbara

Committee Member

Hood, Joshua

Committee Member

Kirpich, Irina

Committee Member

Rai, Shesh

Committee Member

Wahlang, Banrida

Author's Keywords

PCB126; alcohol-associated liver disease; lifestyle factors; environmental liver disease; interactions

Abstract

Steatotic liver disease is brought upon by differing etiologies and its global prevalence is expected to keep increasing over the next several decades. Particularly, alcohol-associated liver disease (ALD) manifests from excessive alcohol consumption where the liver retains lipids and progresses with metabolic dysfunction. Previous studies have demonstrated that environmental pollutants, polychlorinated biphenyls (PCBs) promote metabolic dysfunction associated steatotic liver disease (MASLD), in diet-induced obesity models. However, it is unknown if environmental pollutants may also promote ALD pathogenesis. Thus, this dissertation focuses on characterizing the effects of PCB126 in a rodent ALD model followed by multiple ‘Omics approaches to identify mechanisms for modified disease pathogenesis. C57BL/6J mice were orally gavaged 0.2mg/kg PCB126 or vehicle prior to the chronic-binge alcohol feeding model. Mice were then provided a 5% EtOH or control diet for ten days. The following day, mice were provided 5 g/kg EtOH bolus, prior to euthanasia and tissue collection. PCB126 exposure significantly enhanced hepatomegaly in EtOH-fed mice as observed by increased liver weight and steatosis. Carbohydrate metabolism was disrupted wherein blood glucose and hepatic glycogen were significantly reduced. Gene expression analyses supported both endpoints by suggesting a net retention of hepatic lipids and general loss of glycolysis and gluconeogenesis functionality. Albumin levels were reduced ~50% at the transcriptional and protein level by PCB126 in EtOH-fed mice. Finally, differential aryl hydrocarbon receptor activation was observed by PCB126 exposure and EtOH feeding. RNA sequencing reveals that PCB126 uniquely alters the transcriptome in EtOH-fed mice. Significant gene ontology (GO) biological processes suggested “peptidyl tyrosine modifications” are prevalent. Western blotting revealed PCB126 further decreasing phosphorylated JAK2. Significant GO Molecular Function processes suggested metal ion binding is deficient, and metallomic analyses show decreased hepatic metals, supporting this observation. Phosphoproteomics demonstrated that phospho-peptide levels were reduced in EtOH+PCB126 mice. The phosphoproteome was globally impacted by EtOH feeding; however, PCB126 altered specific phospho-peptides. Particularly, PCB126 increased the phosphorylation of progesterone receptor membrane component 1 (PGRMC1) at serine-181 which may conformationally inhibit other phosphoacceptor residues. Overall, the findings implicated that PCB126 promoted ALD pathogenesis and reprogramed intermediary metabolism at all macromolecule levels. Multiple ‘Omics suggest that signaling is disrupted by altered protein phosphorylation and loss of essential metal levels. Future studies must consider the disease modifying effects toxicants have on ALD.

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