Chromium genotoxicity: A double-edged sword

Abstract

Certain forms of hexavalent chromium [Cr(VI)] are known respiratory carcinogens that induce a broad spectrum of DNA damage. Cr(VI)-carcinogenesis may be initiated or promoted through several mechanistic processes including, the intracellular metabolic reduction of Cr(VI) producing chromium species capable of interacting with DNA to yield genotoxic and mutagenic effects, Cr(VI)-induced inflammatory/immunological responses, and alteration of survival signaling pathways. Cr(VI) enters the cell through non-specific anion channels, and is metabolically reduced by agents including ascorbate, glutathione, and cysteine to Cr(V), Cr(IV), and Cr(III). Cr(III) has a weak membrane permeability capacity and is unable to cross the cell membrane, thereby trapping it within the cell where it can bind to DNA and produce genetic damage leading to genomic instability. Structural genetic lesions produced by the intracellular reduction of Cr(VI) include DNA adducts, DNA-strand breaks, DNA-protein crosslinks, oxidized bases, abasic sites, and DNA inter- and intrastrand crosslinks. The damage induced by Cr(VI) can lead to dysfunctional DNA replication and transcription, aberrant cell cycle checkpoints, dysregulated DNA repair mechanisms, microsatelite instability, inflammatory responses, and the disruption of key regulatory gene networks responsible for the balance of cell survival and cell death, which may all play an important role in Cr(VI) carcinogenesis. Several lines of evidence have indicated that neoplastic progression is a result of consecutive genetic/epigenetic changes that provide cellular survival advantages, and ultimately lead to the conversion of normal human cells to malignant cancer cells. This review is based on studies that provide a glimpse into Cr(VI) carcinogenicity via mechanisms including Cr(VI)-induced death-resistance, the involvement of DNA repair mechanisms in survival after chromium exposure, and the activation of survival signaling cascades in response to Cr(VI) genotoxicity.

Figure 1

Cellular resistance to Cr(VI)-induced death and early stage carcinogenesis. Upon exposure to relevant doses of Cr(VI), a normal cell will undergo a transient checkpoint arrest in an attempt to repair damaged DNA. Cells that are unable to repair the damage will undergo apoptosis or terminal growth arrest (replicative death); however a small population of cells may survive. These survivors may have acquired an intrinsic mechanism(s) of death resistance through dysregulated DNA repair mechanisms and/or dysregulated survival signaling and transcriptional repatterning. Direct damage to the cells from Cr(VI) exposure can led to tissue injury and severe inflammatory responses, which may further contribute to the micro-environmental milieu potentiating the death resistant phenotype. Cells that are phenotypically resistant to Cr(VI)-induced death may be predisposed to pre-malignant progression thereby propagating early stage carcinogenesis, which may over time lead to the malignant conversion of the predisposed precursor cells to tumor cells.