Molecular evidence of epithelial cell damage caused by iqmik, an Alaska smokeless tobacco mixture

Abstract

The percentage of Alaska Natives who use smokeless tobacco (SLT) is 4 times that of non-Native Alaskans and 45 times higher for Alaska Native women than non-Native women. The use of SLT is concentrated in Southwest Alaska where 32% of all adult Alaska Natives use SLT. Out of those users, 35% use only iqmik, a unique form of SLT in Alaska, which is a combination of tobacco leaf mixed with Phellinus igniarius (punk fungus). There is little evidence of the pathological effects of iqmik to assist in the development of an evidenced-based intervention regarding the harmful effects of iqmik. The current lack of evidence reinforces a belief that iqmik is less harmful than other tobacco alternatives. The overall objective of this thesis is to elucidate the effect of iqmik and iqmik-mediated metal exposure on oxidative stress and nuclear factor- κB (NF-κB) induced inflammation in human gingival epithelial cells. The central hypothesis of this thesis is that cadmium (Cd), cobalt (Co) and nickel (Ni) accumulate in human gingival epithelial cells from iqmik treatments, inducing oxidative stress and promoting an intracellular environment that alters NF-κB proinflammatory signaling targets. Our findings indicate that iqmik is a greater source of heavy metals, such as Cd, Co and Ni, than air-cured tobacco leaf. Human gingival epithelial cells accumulate more Cd, Co and Ni from the punk ash component of iqmik than from the air-cured tobacco. These metals have the capacity to accumulate in cells from iqmik treatments and generate and propagate the production of endogenous reactive oxygen species (ROS), which activates NF-κB significantly altering its signaling targets, more so than tobacco alone. The results of this thesis identify iqmik as a unique health hazard compared to other tobacco products and enhances our understanding of how iqmik may contribute to oral pathologies.