| Summary: | <p> Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten, remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. This work demonstrates tungsten’s ability to induce carcinogenic-related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer related pathways in transformed clones as determined by RNA sequencing. Human bronchial epithelial cell line (BEAS-2B) exposed to tungsten developed carcinogenic properties. In a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. </p><p> In order to examine the epigenetic mechanisms that mediate tungsten’s tumorigenicity, we investigated if tungsten alters the levels of global histone methylation and if these changes are due to tungsten influencing the histone demethylases. We found that cells acutely treated with tungsten displayed significantly increased numbers of H34me3 and H3K9me2 histone marks on a global scale. This increase was due to down-regulation in the protein levels of the histone demethylases JMJD1A and JARID1A. The increase in global histone methylation remained when cellular SAM levels were depleted. The decrease in histone demethylase proteins was found to be due to a reduction in their gene expression. Epigenetic alterations induced by tungsten in the histone demethylase genes caused the repression. </p><p> We also evaluated insoluble tungsten, tungsten oxide (WO<sub>3</sub>). WO<sub>3</sub> is an occupational exposure hazard. The primary route of WO<sub> 3</sub> exposure is inhalation and WO<sub>3</sub> is known as a pulmonary irritant. WO<sub>3</sub> exposure led to stochastic results, which were likely due to the random effects of the particles. </p><p> Given the carcinogenic potential of other metals, it is likely that tungsten will exert carcinogenic outcomes. This study evaluates cancer-associated endpoints induced by tungsten exposure in both <i>in vitro</i> and <i> in vivo</i> models. To evaluate the mechanisms that underlie tungsten-induced carcinogenesis, alterations to the epigenome are assessed. Arsenic, cadmium, nickel, and chromium (VI) are poor mutagens; however, they exert their carcinogenic potential via epigenetic mechanisms. The literature is currently void of investigations examining the epigenetic effects of tungsten. Given the evidence characterizing metals as epimutagens, it is likely that tungsten toxicity and carcinogenesis is mediated via epigenetic mechanisms.</p>
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