Urbano, AM; Rodrigues, CFD; Alpoim, MC
World-wide, several million workers experience occupational exposure to different hexavalent chromium [Cr(VI)] compounds (chromates) which have long been recognized as human respiratory tract carcinogens through chronic exposure. Although the majority of lung cancers were found among Cr(VI)-exposed workers who smoked, smoking does not affect chromium accumulation in the lung and chromate exposure was clearly established as an independent risk factor for lung cancer. Compatible with the smoking-unrelated origin of the majority of chromate malignancies are the findings that the molecular features of chromate- and smoking-associated cancers are very different and that the location of chromate lung tumors, i.e. the bronchial bifurcations, corresponds to the sites of chromium accumulation in ex-chromate workers. More recent studies also revealed that environmental exposure to particulate Cr(VI) compounds is increasing due to chromium-containing dusts generated from industrial waste disposal, portland cement, concrete pavement, milling, demolition, cigarette smoke and fuel combustion. Experimentally, it has been demonstrated that Cr(VI) compounds can neoplastically transform cells in culture. They are also genotoxic and can induce a wide spectrum of DNA damage, gene mutations, sister chromatid exchanges and chromosomal aberrations. Albeit extensive information and studies on Cr(VI)-induced effects, the mechanisms mediating Cr(VI)-induced toxicity and carcinogenicity are still poorly understood. This happens mostly due to the use, in a vast majority of the studies, of inadequate model systems and exposure regimens, as well as to the restricted access to lung tumor tissues from Cr(VI)-exposed workers, critical for the identification of consistent cellular and molecular changes. Consequently, additional studies using adequate model systems and exposure regimens mimicking occupational exposure conditions will have to be performed in order to understand the signalling mechanisms involved in the cellular response to Cr(VI), as well as the role of genomic instability and of specific DNA repair pathways in the development of this pathology. Knowledge of these pertinent issues will be a step forward for the discovery of biomarkers of malignant transformation that might lead to new treatment approaches or new ways to prevent this particular subtype of lung cancer. This review will discuss several aspects underlying Cr(VI)-induced carcinogenicity. However, particular emphasis will be given to the recently identified roles of Cr(VI)-induced DNA lesions, particularly single- and double-strand breaks, on genomic instability, one of the hallmarks of lung cancer.
Hexavalent chromium; lung cancer; genomic instability; microsatellite; instability; double-strand breaks; lead chromate particles; protein cross-links; human bronchial cells; factor-kappa-b; genotoxic carcinogen; chromium(vi); induced chromosome instability; nucleotide; excision-repair; directed mismatch repair; dna-polymerase arrest