Alterations of senescence biomarkers in human cells by exposure to CrVI in vivo and in vitro

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Abstract

Heavy metals like CrVI, CdII, PbII and SnII have many applications in industry. They also represent a group of labour pollutants, as they are involved in several physiological disorders, such as carcinogenesis and various tissue dysfunctions. However, limited knowledge exists regarding their effects on ageing. In the current work we provide evidence that workers chronically exposed to CrVI have considerably reduced serum levels of the biomarker of senescence and cell survival, Apolipoprotein J/Clusterin (ApoJ/CLU). Moreover, we have found that both the degree and the time of exposure to CrVI associate negatively with ApoJ/CLU serum levels. To further examine whether CrVI directly affects cellular senescence we treated for 10 weeks two adult skin fibroblasts cultures as well as embryonic fibroblasts with a range of CrVI concentrations that approximate the values recorded in the blood circulation of exposed workers. Cellular treatment with a CrVI concentration that approximates the highest concentration in the blood was extremely toxic and nearly all cells died immediately after the first treatment. Interestingly, continuous treatment with a 10-fold lower CrVI concentration resulted in the induction of premature senescence. More specifically, treated cells were growth arrested, acquired an irregular shape, were positive to β-galactosidase staining, accumulated oxidized proteins and over-expressed the cyclin-dependent kinase inhibitor p21 and ApoJ/CLU. Similar treatments with three additional labour pollutants resulted in the induction of premature senescence by CdII, but not by SnII or PbII. In summary, our results indicate that exposure to CrVI induces alterations of senescence biomarkers both in vivo and in vitro. They also provide new valuable tools for monitoring CrVI cytotoxic effects in vivo as well as for re-evaluating the maximum permissive values of some labour pollutants, like CrVI and CdII.

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