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INVESTIGATIONS INTO AGE-RELATED SUSCEPTIBILITY TO ARSENIC CARCONOGENICITY
Citation:
AHLBORN, G., R. GRINDSTAFF, B. ROOP, J. W. ALLEN, G. M. NELSON, K. T. KITCHIN, D. J. THOMAS, C. J. WOLF, A. D. KLIGERMAN, A. H. TENNANT, G. W. KNAPP, J. PRESTON, W. M. WINNIK, AND D. A. DELKER. INVESTIGATIONS INTO AGE-RELATED SUSCEPTIBILITY TO ARSENIC CARCONOGENICITY. Presented at EPA Science Forum, Washington, DC, DC, May 15 - 18, 2006.
Description:
Environmental Issue. Arsenic compounds are ubiquitous throughout the environment and are a major health problem in many parts of the world. Human exposure to arsenic has been identified from both natural and anthropogenic sources. Most chronic exposure comes from drinking water, particularly in underdeveloped regions of the world like India and Bangladesh, and other Asian countries. Epidemiology studies suggest that chronic exposure to inorganic arsenic and its metabolites are associated with large increases in cancer of the skin, bladder and lung as well as more moderate increases in the kidney and liver. However, until recently few useful animal models have been developed to study arsenic carcinogenesis experimentally. Recent findings suggest that in utero exposure to inorganic arsenic increases the susceptibility of mice to cancer. The data suggest that investigation into age-related susceptibility to arsenic carcinogenicity is necessary for accurate estimation of human cancer risk.
Approach. This NHEERL multi-divisional (ECD, ETD and RTD) research study is designed to fill known data gaps in human health research, particularly the influence of age on cancer susceptibility to environmental chemicals. Needed expertise for this research project includes toxicogenomics, gene methylation, genetic toxicology, molecular pathology, and oxidative stress signaling and risk assessment.
Results. C3H mice were exposed to inorganic arsenic in their drinking water for eleven days during three stages of development; in utero (gestation day 8-18), pre-pubescence (postnatal day 22-32) and post-pubescence (postnatal day 57-67). Target tissues were taken and fractionated for analysis of protein profiles by 2-D gel electrophoresis and mass spectrometry, gene regulation by DNA methylation analysis, and genetic toxicology by micronuclei induction. Additional groups of animals are currently being exposed for an additional 52 weeks to determine the tumor yield. Preliminary results suggest that differential susceptibility to general arsenic toxicity (decreased body weight) is observed with mice exposed pre-pubescence vs. mice exposed post-pubescence. Treatment-related changes in protein profiles and DNA methylation were observed at all three life-stages examined. To date, micronucleus induction proved insensitive to arsenic dosing.
Conclusions. We have developed the necessary multidisciplinary technology/methods for assessing age-related differences in arsenic toxicity following acute and chronic exposures. Preliminary results show that age-related differences in toxicity are observed and may be related to increased cell proliferation during high growth periods.
Future Directions. Characterize protein profiles associated with arsenic carcinogenicity and how these profiles are affected by age. Evaluate the levels of biomarker proteins in lesions/tumors that develop after chronic exposure.
Impact. These studies fulfill regulatory human health requirements to characterize age-related susceptibilities to environmentally linked cancers. Results of these studies may be used to more accurately set environmental exposure standards that do not rely on default correction factors.