Although arsenic is a well-established human carcinogen and induces cancers the skin, liver, bladder, and lung, the underlying carcinogenic mechanism(s) for arsenic is unknown. Although arsenic induces chromosomal aberrations and sister chromatid exchanges in cultured mammalian cells it has not been shown to be active as a gene mutagen. Using the human-hamster hybrid (A/L) cells that are sensitive in detecting multilocus deletions, the applicant has obtained preliminary data suggesting that arsenic is mutagenic in mammalian cells. The first objective of this proposal is to examine the quantitative mutagenic yield and the spectrum of mutations induced by graded doses of the trivalent sodium arsenite and the pentavalent sodium arsenate. Specifically, the quantitative mutagenic data will be used to obtain dose response relationship for the mutagenicity of arsenic. The molecular spectrum will be used to ascertain qualitatively the presence or absence of specific signature changes at the gene level. The second and third objectives are to examine the underlying mechanisms for the observed mutagenic events induced by arsenic compounds, particularly, the roles of reactive oxygen species and cellular glutathione levels. Mutations will be scored at both the S1 and HGPRT loci using the A/L cells. The A/L cells contain only one copy of human chromosome 11 and mutations on marker genes located on this chromosome can be readily scored using an antibody complement lysis technique. Since the A/L cell also contain the HGPRT gene located on the hamster X chromosome, mutations induced by arsenic on an essential (-X) versus a non-essential chromosome (human chromosome 11) will provide useful information on the types and sizes of the induced molecular alterations. By using specific DNA probes of other genes that have been regionally mapped to various sites on chromosome 11, the molecular mechanisms of mutation in A/L cells will also be examined.
| Kessel, Maris; Liu, Su Xian; Xu, An et al. (2002) Arsenic induces oxidative DNA damage in mammalian cells. Mol Cell Biochem 234-235:301-8 |
| Hei, T K; Liu, S X; Waldren, C (1998) Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species. Proc Natl Acad Sci U S A 95:8103-7 |
