Abstract
Despite a considerable amount of data, the molecular and cellular bases of the toxicity due to metal exposure remain unknown. Recent mechanistic models from radiobiology have emerged, pointing out that the radiation-induced nucleo-shuttling of the ATM protein (RIANS) initiates the recognition and the repair of DNA double-strand breaks (DSB) and the final response to genotoxic stress. In order to document the role of ATM-dependent DSB repair and signalling after metal exposure, we applied twelve different metal species representing nine elements (Al, Cu, Zn Ni, Pd, Cd, Pb, Cr, and Fe) to human skin, mammary, and brain cells. Our findings suggest that metals may directly or indirectly induce DSB at a rate that depends on the metal properties and concentration, and tissue type. At specific metal concentration ranges, the nucleo-shuttling of ATM can be delayed which impairs DSB recognition and repair and contributes to toxicity and carcinogenicity. Interestingly, as observed after low doses of ionizing radiation, some phenomena equivalent to the biological response observed at high metal concentrations may occur at lower concentrations. A general mechanistic model of the biological response to metal exposure based on the nucleo-shuttling of ATM is proposed to describe the metal-induced stress response and to define quantitative endpoints for toxicity and carcinogenicity.
Highlights
Metals are abundantly used and transformed by a number of industrial activities such as mining, metallurgy, production of fertilizers, paints, batteries, and more recently, hightech products
The exposure of human cells to metal results in the production of metalinduced (MI) double-strand breaks (DSB) whose occurrence may depend on the cellular model, the concentration, and the nature of the metallic species
Since the number of unrepaired RI DSB assessed at 24 h post-irradiation has been shown to be correlated with cellular death and with toxicity [13,24], the number of MI DSB revealed by the nuclear γH2AX foci was assessed in human fibroblasts for 24 h after the introduction of metal in the culture medium
Summary
Metals are abundantly used and transformed by a number of industrial activities such as mining, metallurgy, production of fertilizers, paints, batteries, and more recently, hightech products. Accidental, environmental occupational exposures to metals have increased our knowledge about their toxicity. This is notably the case for lead (Pb) with saturnism [1]. Copper (Cu) and Fe have been cited for their potential link to Parkinson’s disease [5,6]. In addition to their potential toxicity, chronic exposure to metals may increase cancer risk. Epidemiological studies of workers in chromium (Cr) production and occupational and environmental exposure to arsenic (As) and nickel (Ni) have documented the risk of lung and nasal cancers [7,8,9,10]
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