Knowledge about influence of aging on the susceptibility of liver to chemical injury is of importance in geriatric medicine and public health. While a considerable age-dependent variation in the incidence of chemical-induced hepatotoxicity is known, the reasons for this variation remain unexplored. Among the different models used to study hepatotoxicity, chlordecone (Kepone) + CC14 interactive model is well known for its advantages like, toxicity occurring at environmentally relevant levels, extensive liver damage, known mechanism, etc. In adult rats this interactive toxicity results in 67-fold amplification of hepatotoxicity and lethality. However, preliminary studies indicate that aged rats (25 months) are completely resilient to the interactive toxicity of chlordecone + CC14. This is extremely surprising and it certainly contradicts common perception that elderly are more susceptible to toxicity. The biological effects of this interaction in adult rats include extensive hepatotoxicity characterized by histological alterations, perturbed biochemical parameters, compromised tissue repair, and hepatic failure and death In contrast, in aged rats only a transient hepatic injury, earlier onset of liver regeneration and complete recovery were evident. It is hypothesized that modulation of tissue repair plays an important role in the observed resiliency of the aged rats to hepatotoxicity. The working hypothesis is that modifications in production of pro- inflammatory cytokines and cellular responses to these cytokines are responsible for enhanced tissue repair and observed resiliency in aged rats.
The specific aims are: To study, (a) toxicodynamics of liver injury and repair during chlordecone + CC14 toxicity in 3 different age groups (3, 15 and 30 months of age i.e., young adult, middle age and old age); (b) if CC14 metabolism or bioactivation plays any role; and (c) age-related alterations in molecular signal mechanisms responsible for cell proliferation. Primary focus is to investigate the role of TNF-a, IL-6, TGF-a,, EGFR leading to MAPK-RAS pathway activation followed by protooncogene expression (c fos, c-myc, c jun and Ha-Ras) and cyclin- dependent kinase activities. It is anticipated that in response to injury cytokine production increases with age, and the augmented signal transduction is responsible for the resiliency of the aged rats to chlordecone + CC14 hepatotoxicity. These studies will help us understand age-associated changes in cellular functions that alter tissue sensitivity.
