Abstract

Fanconi anemia (FA) is an autosomal recessive disorder characterized by diverse developmental abnormalities, progressive bone marrow failure, and a markedly increased incidence of malignancy. FA cells are hypersensitive to DNA cross-linking agents, suggesting a general defect in the repair of DNA cross-links. Some forms of hexavalent chromium [Cr(VI) ] are implicated as respiratory carcinogens and induce several types of DNA lesions, including ternary DNA-Cr-DNA interstrand cross-links (Cr-DDC) . We hypothesized that human FA complementation group A (FA-A) cells would be hypersensitive to Cr(VI) and Cr(VI) -induced apoptosis. Using phosphatidylserine translocation and caspase-3 activation, human FA-A fibroblasts were found to be markedly hypersensitive to chromium-induced apoptosis compared with CRL-1634 cells, which are normal human foreskin fibroblasts (CRL) . The clonogenicity of FA-A cells was also significantly decreased compared with CRL cells after Cr(VI) treatment. There was no significant difference in either Cr(VI) uptake or Cr-DNA adduct formation between FA-A and CRL cells. These results show that FA-A cells are hypersensitive to Cr(VI) and Cr-induced apoptosis and that this hypersensitivity is not due to increased Cr(VI) uptake or increased Cr-DNA adduct formation. The results also suggest that Cr-DDC may be proapoptotic lesions. These results are the first to show that FA cells are hypersensitive to an environmentally relevant DNA cross-linking agent. Key words: apoptosis, carcinogen, caspase-3, clonogenicity, DNA adducts, genotoxin, phosphatidylserine translocation, sodium chromate, uptake. Environ Health Perspect 110(suppl 5) :773-777 (2002) .

http://ehpnet1.niehs.nih.gov/docs/2002/suppl-5/773-777vilcheck/abstract.html