Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, PhD
Cave, Matthew C.
Committee Co-Chair (if applicable)
Beier, Juliane I.
Beier, Juliane I.
Prough, Russell A.
States, J. Christopher
Non-alcoholic fatty liver disease; polychlorinated biphenyls; aryl hydrocarbon receptor; liver-pancreas axis; hepatokine; relative potency values
Polychlorinated biphenyls (PCBs) are detectable in serum of 100% of adults in US, and has been associated with fatty liver disease in epidemiological studies. PCBs are classified as either dioxin-like (DL) or non-dioxin-like (NDL) PCB based on their ability to activate the aryl hydrocarbon receptor (AhR). We used exposures that reflect human bioaccumulation patterns, which resembles Aroclor 1260 with a low level of the DL-PCB, PCB 126. Our aim was to determine if this exposure will activate the human and mouse AhR and examine if receptor activation influences these steatotic responses due to PCB exposures. DL-PCBs exposure-induced AhR activation in luciferase assays and induction of AhR target gene expression demonstrated that the Mouse AhR was much more sensitive than human AhR to activation by DL-PCBs. Our PCB mixture reflected this by activating the mouse AhR, but not human AhR in vivo. The ability of PCBs to activate the AhR would be predicted to be WHO toxicity equivalency = rat >mouse >>human. Mice were exposed to either PCB 126 (20 μg/kg), Aroclor 1260 (20 mg/kg) or both, for 2 weeks. PCB 126 or Aroclor 1260/PCB 126 significantly activated AhR, but only PCB 126 exposure alone induced mild hepatic steatosis. AhR activation suppressed the induction of CAR and PXR targets. More complex patterns of attenuation were observed with genes involved in lipid metabolism. PCB exposures require a hypercaloric diet to transition steatosis to steatohepatitis in murine models. Mice were fed high fat diet and received the same treatments as the 2-week study for 12 weeks. Our PCBs mixture exposure did not induce wasting syndrome, and failed to exacerbate steatosis. In addition, PCB 126 exposure activated AhR. Aroclor 1260 exposure drove hepatic steatosis to steatohepatitis. Either PCB 126 or the Aroclor 1260/PCB 126 mixture protected against high fat diet induced liver injury and liver fibrosis. All PCB exposures affected hepatic lipid metabolism.
Shi, Hongxue, "The effects of polychlorinated biphenyls exposure on non-alcoholic fatty liver disease : role of aryl hydrocarbon receptor." (2018). Electronic Theses and Dissertations. Paper 2947.