Human Cell Models for Arsenic Carcinogenicity and Toxicity: Transformation and Genetic Susceptibility

摘要

Humans are more sensitive to arsenic compounds than are rodents by at least an order of magnitude. This is also true on the cellular level. The lack of an arsenite-inducible tolerance mechanism in human cells may partly account for their sensitivity. In addition, inter-individual variability in sensitivity to arsenic is well known. It is therefore important to study the effects of arsenic compounds on human cells. We have found that extremely low and completely nontoxic concentrations of arsenite (0.1 nM) can transform human osteosarcoma (HOS) cells to anchorage-independence, a marker for tumorigenicity. The transformation is seen only after extensive growth (～8 weeks) in the presence of arsenite. HOS transformation will be an important system with which to study the mechanism of arsenite carcinogenicity. We have also started a study of genetic diversity by measuring the sensitivities of 14 lymphoblast lines derived from normal human donors. We show that growth inhibition by arsenite differs significantly in different lymphoblast lines, and that the differences are not related to the growth rates of the lymphoblasts. By comparing arsenite metabolism, uptake, efflux, and specific gene expression between the most sensitive and most resistant lines, we may be able to identify genes of importance in arsenic sensitivity.