Abstract
BackgroundIt has been estimated that more than 1 million workers in the United States are exposed to cobalt. Occupational exposure to 59 Co occurs mainly via inhalation and leads to various lung diseases. Cobalt is classified by the IARC as a possible human carcinogen (group 2B). Although there is evidence for in vivo and in vitro toxicity, the mechanisms of cobalt-induced lung toxicity are not fully known. The purpose of this work was to identify potential signatures of acute cobalt exposure using a toxicogenomic approach. Data analysis focused on some cellular processes and protein targets that are thought to be relevant for carcinogenesis, transport and biomarker research.ResultsA time course transcriptome analysis was performed on A549 human pulmonary cells, leading to the identification of 85 genes which are repressed or induced in response to soluble 59 Co. A group of 29 of these genes, representing the main biological functions, was assessed by quantitative RT-PCR. The expression profiles of six of them were then tested by quantitative RT-PCR in a time-dependent manner and three modulations were confirmed by Western blotting. The 85 modulated genes include potential cobalt carriers (FBXL2, ZNT1, SLC12A5), tumor suppressors or transcription factors (MAZ, DLG1, MYC, AXL) and genes linked to the stress response (UBC, HSPCB, BNIP3L). We also identified nine genes coding for secreted proteins as candidates for biomarker research. Of those, TIMP2 was found to be down-regulated and this modulation was confirmed, in a dose-dependent manner, at protein level in the supernatant of exposed cells.ConclusionMost of these genes have never been described as related to cobalt stress and provide original hypotheses for further study of the effects of this metal ion on human lung epithelial cells. A putative biomarker of cobalt toxicity was identified.
Highlights
It has been estimated that more than 1 million workers in the United States are exposed to cobalt
For genes displaying temporal modulation, down-fluctuation quickly followed by up-regulation, as with AXL, a slight difference in the kinetics of different exposures could explain the opposing results we found between microarray and quantitative RT-PCR (qRT-PCR) ratios, because RNAs from different exposures were used to perform the microarray experiments and qRT-PCR
The results show that ubiquitin genes were up-regulated after 24 h of toxic exposure while UBC gene induction was observed in the kinetics from 4 h with qRT-PCR, showing that it is not an early event in cell response
Summary
It has been estimated that more than 1 million workers in the United States are exposed to cobalt. Occupational exposure to 59 Co occurs mainly via inhalation and leads to various lung diseases. The purpose of this work was to identify potential signatures of acute cobalt exposure using a toxicogenomic approach. In the United States, more than a million workers are potentially exposed to cobalt or its compounds [1]. Occupational exposure to Co occurs mainly via inhalation leading to various lung diseases, such as pneumonitis, fibrosis and asthma [7,8]. Lethal cardiomyopathy was reported in people who consumed large quantities of beer containing cobalt as a foam stabilizer (0.04–0.14 mg cobalt/kg/day), and acute mortality accounted for 18% of the deaths [12]. A 19-month-old boy who swallowed an unknown amount of cobalt chloride solution died 6.5 hours after ingestion [13]
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