Several studies have shown that
hexavalent chromium [
Cr(VI)] induces apoptosis in a variety of in vitro test systems. We instilled intra-tracheally either saline or
sodium dichromate (0.25 mg/kg
body weight), for three consecutive days, to Sprague-Dawley rats. TUNEL analyses showed a marked increase of the apoptotic index in both bronchial epithelium and lung parenchyma of
Cr(VI)-treated rats, but no effect was detected in their liver. In parallel, the expression of 13 out of 18 apoptosis-related genes, evaluated by
cDNA array analysis, was significantly enhanced in rat lung. The overexpressed genes included c-Jun N-terminal
kinases 1, 2 and 3, bcl-x, bcl-2-associated death promoter and bcl-2-related ovarian killer
protein,
caspases 1, 3 and 6,
DNase I precursor,
DNA topoisomerases I and II alpha, and
poly(ADP-ribose) polymerase. The enhancement of p53 expression in the lung was borderline to statistical significance. Expressions of bcl-2, bax-alpha, mdm2 and
DNA topoisomerase IIB were not enhanced to a significant extent in lung. No induction of gene expression was observed in rat liver. RT-PCR analyses confirmed that
Cr(VI) enhances the expression of
c-Jun N-terminal kinase 1,
caspase 6, and
DNase I precursor but not that of bcl-2 in lung, while none of these genes was overexpressed in the liver of
Cr(VI)-treated rats. The lack of stimulation of apoptosis in the liver parallels the failure of
Cr(VI) to produce genotoxic damage, as we previously observed under identical experimental conditions. These negative findings may be ascribed to reduction of
Cr(VI) to Cr(III) when traveling from the respiratory tract to the liver. On the other hand, induction of apoptosis in the respiratory tract parallels the occurrence of genotoxic effects and oxidative DNA damage produced by
Cr(VI) in the same tissue. As previously shown in another laboratory,
Cr(VI) did not induce lung
tumors after 30 months of administration of the same daily dose. Therefore, apoptosis is likely to provide a protective mechanism at a post-genotoxic stage of
Cr(VI)
carcinogenesis.