Arsenic is an environmental carcinogen and a major health hazard. Despite extensive efforts, the mechanism of arsenic induced toxicity and tumorigenicity in not yet clearly understood. Evidence suggests that arsenic exerts its chronic toxicity, by interacting with sulphydryl groups, and generating reactive oxygen species that cause damage to cellular macromolecules via oxidative stress. Of importance, exposure to pro-oxidants such as arsenic, also results in the induction of a gene expression program, whose primary function is to protect cells from oxidative stress. The broad, long-term goal of this proposal is to understand this protective program of adaptation and acquired tolerance that could open up new therapeutic avenues for prevention and intervention strategies, against the toxic effects of arsenic. We recently demonstrated that, the expression and function of the ABC transporter ABCB6 might be an important cellular mechanism to provide arsenite resistance. However, the mechanism by which ABCB6 protects against arsenic toxicity is not known, which forms the basis of this proposal. The proposal will test the hypothesis that Abcb6 expression regulates cellular arsenic content and promotes mitochondrial function to reduce arsenic mediated cellular oxidative stress. This hypothesis will be tested utilizing various molecular and biochemical strategies, and a combination of in vivo and in vitro approaches. We expect that a greater understanding of the endogenous protective mechanisms activated by pro-oxidants such as arsenic will lead to novel strategies to treat arsenic toxicity.
Arsenic is an environmental carcinogen and a major health hazard. Arsenic toxicity is associated with increased oxidative stress. The purpose of this project is to evaluate the role of endogenous protective mechanisms activated in response to arsenic and understand their role in protection against oxidative stress and arsenic toxicity.
| Chavan, Hemantkumar; Christudoss, Pamela; Mickey, Kristen et al. (2017) Arsenite Effects on Mitochondrial Bioenergetics in Human and Mouse Primary Hepatocytes Follow a Nonlinear Dose Response. Oxid Med Cell Longev 2017:9251303 |
