Center investigators are collaborating with scientists at NIEHS on investigation of the mechanism of arsenic carcinogenicity. The hypothesis is that there is increased susceptibility to arsenic tumorigenesis from genetic limitations in methylation capacity or as a result of nutritional deficiencies. A murine model for the induction of cancer in methyl-deficient C57Bl/6 mice is being developed. A subchronic study (funded by an SCEHSC pilot project grant) included mice fed methyl sufficient diets, methyl-deficient diets, and 4 concentrations of arsenic in methyl deficient animals. NIEHS pathologists have completed the histopathology on the animals from the subchronic study and there is evidence of hyperplasia of the bladder in the methyl-deficient, arsenic exposed mice.

A chronic bioassay is underway with 400 animals, facilitated by collaboration with Dr. Louis Dubeau of the Molecular Biology Facility Core. Dr. Dubeau has provided training to a Ph.D.-level student conducting molecular biology studies on the effects of diet and arsenic on methylation status on global and gene specific methylation. Interaction with the Adult cancer core is also an element of this research since the staff of Professor Peter Jones, an authority on the genetic and epigenetic aspects of DNA methylation on genome expression, mutation and carcinogenesis, has assisted the laboratory aspects of the investigation.

This research is an outgrowth of an earlier project which sought to characterize the mechanism of arsenic metabolism in a population currently drinking arsenic-contaminated water in Taiwan. There were three parts to the study, a cohort study, a case control study for skin cancer, and a study of intra-individual variability associated with chronic arsenic exposure. The latter three research projects are complete and being submitted for publication. The results of this research are highly relevant since they indicate that alterations in methylation capacity may affect arsenic carcinogenesis.