Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, PhD
States, J. Christopher
arsenic; EGFR; lung; chronic exposure
Chronic arsenic exposure is a risk factor for the development of pulmonary diseases, including lung cancer, but the exact mechanism is not yet fully understood. Many previous studies have relied on acute arsenic exposure (i.e. 1-10 uM arsenic for 24 hours) to study arsenic toxicological effects. However, acute exposure does not reflect the levels or duration of arsenic associated with environmental exposure, or drinking of contaminated well water. This dissertation differentiates the effects of acute versus chronic arsenic exposures on the EGFR signaling axis and suggests possible mechanisms for chronic arsenic-induced pulmonary diseases. The EGFR is a receptor tyrosine kinase localized on the cell surface. Overexpression of the EGFR has been used as biomarkers for many different types of cancers, including lung cancer. There is a strong association between arsenic and lung cancer development, although the clear mechanism is still elusive. I hypothesized that chronic exposure of an environmentally relevant level of arsenic disrupts the EGFR signaling axis. To test this, a non-malignant human bronchial epithelial cell line (BEAS-2B) was exposed to 100 nM arsenite for 24 weeks. I first differentiated the impact of acute versus chronic arsenic exposure on the EGFR signaling axis. Both acute and chronic arsenic exposure increased EGFR protein expression level, but only chronic exposure increased EGFR activity, increased transcription and protein levels of TGFα. Next, I assessed the functional effects of chronic arsenic exposure in BEAS-2B cells and measured EGFR dependency in chronic arsenic exposure-induced increased cell migratory ability, which may contribute to identifying a novel therapeutic target for arsenic-induced lung carcinogenesis. The dissertation proposes novel roles of acute and chronic arsenic on the EGFR signaling axis and potential mechanisms of chronic arsenic-induced lung diseases, such as lung cancer. It concludes that acute and chronic arsenic exposure impact the EGFR signaling axis in different mechanistic pathways, and chronic arsenic exposure increases cell migration in both EGFR-dependent and independent mechanisms.
Kim, Christine, "Assessing the role of chronic arsenite exposure in disrupting the EGFR signaling axis." (2021). Electronic Theses and Dissertations. Paper 3581.
Retrieved from https://ir.library.louisville.edu/etd/3581