Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and diabetes. The development of the NAFLD has previously been assumed to be due to excess calorie intake and genetic predisposition, but our recent studies show that steatosis and steatohepatitis can be exacerbated upon exposure to polychlorinated biphenyls (PCBs). The Anniston, AL cohort, who have higher exposure to PCBs have significant increases in steatohepatitis biomarkers and a prevalence of diabetes relative to healthy populations. Currently there is no well-established mechanism for exacerbated metabolic diseases due to PCB exposure. The literature and our preliminary data characterize PCBs as epidermal growth factor receptor (EGFR) antagonists that diminish activity of downstream effector kinases and transcription factors implicated in NAFLD/Diabetes. The literature and our preliminary data urges us to evaluate PCB-mediated EGFR inhibition as a key feature in the progression of NAFLD/diabetes. As we hypothesize that genetic loss of EGFR function will make mice more susceptible to PCB-mediated NAFLD/diabetes and epidermal growth factor (EGF) supplementation will ablate PCB-driven NAFLD/diabetes. Current risk assessment for PCB- mediated NAFLD/diabetes is limited. We recently characterized PCBs as EGFR antagonists which urges us to evaluate the binding affinities of PCB congeners for the EGFR extracellular domain to develop a EGFR toxic equivalency quotient (TEQ). Our preliminary data suggests that PCBs may outcompete epidermal growth factor (EGF) for EGFR binding at environmental exposure concentrations. We hypothesize that PCB congeners found in human serum directly antagonize the EGFR promoting NAFLD/diabetes. Preliminary data demonstrates that many PCB congeners prevent EGF-mediated phosphorylation of EGFR but only the non-dioxin like (NDL) PCBs are found in human serum at high concentrations. Preliminary proteomic data indicate that while the EGFR pathway is highly affected so are other EGFR independent pathways. To elucidate other hepatic aberrations due to PCB exposure we propose conducting a kinetic phosphoproteomic study in vitro. This will characterize what other pathways are altered due to PCB exposure. The proposed research aims to elucidate signaling pathways altered due to PCB exposure and if those alterations contribute to the development of liver disease and diabetes observed in animals and human populations. I plan to address these questions through genetic loss of function EGFR animal models, therapeutic EGF animal studies, binding assays, and kinetic phosphoproteomic analysis. The proposed research will provide valuable information on altered cell signaling pathways due to PCB mediated NAFLD and elucidate potential therapeutic targets for treatment of organopollutant-induced liver disease.

Public Health Relevance

The progression of non-alcoholic fatty liver disease (NAFLD) hasn?t previously been associated with environmental stressors such as polychlorinated biphenyls (PCBs) until recently in our laboratory and others. This application investigates the altered cell signaling pathways due to PCB exposure in relation to liver disease and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31ES028982-02
Application #
9491591
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Schug, Thaddeus
Project Start
2017-06-01
Project End
2018-09-30
Budget Start
2018-06-01
Budget End
2018-09-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Hardesty, Josiah E; Al-Eryani, Laila; Wahlang, Banrida et al. (2018) Epidermal Growth Factor Receptor Signaling Disruption by Endocrine and Metabolic Disrupting Chemicals. Toxicol Sci 162:622-634
Hardesty, Josiah E; Wahlang, Banrida; Falkner, K Cameron et al. (2017) Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling. Xenobiotica 47:807-820
Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E et al. (2016) Nuclear receptors and nonalcoholic fatty liver disease. Biochim Biophys Acta 1859:1083-1099
Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron et al. (2016) Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis. Toxicol Sci 149:396-410