Search

Hexavalent chromium [Cr(VI)] is an established human lung carcinogen, but the carcinogenesis mechanism is poorly understood. Chromosome instability, a hallmark of lung cancer, is considered a major driver of Cr(VI)-induced lung cancer. Unrepaired DNA double-strand breaks are the underlying cause, and homologous recombination repair is the primary mechanism preventing Cr(VI)-induced DNA breaks from causing chromosome instability. Cell culture studies show acute Cr(VI) exposure causes DNA double-strand breaks and increases homologous recombination repair activity. However, the ability of Cr(VI)-induced DNA breaks and repair impact has only been reported in cell culture studies. Therefore, we investigated whether acute Cr(VI) exposure could induce breaks and homologous recombination repair in rat lungs. Male and female Wistar rats were acutely exposed to either zinc chromate particles in a saline solution or saline alone by oropharyngeal aspiration. This exposure route resulted in increased Cr levels in each lobe of the lung. We found Cr(VI) induced DNA double-strand breaks in a concentration-dependent manner, with females being more susceptible than males, and induced homologous recombination repair at similar levels in both sexes. Thus, these data show this driving mechanism discovered in cell culture indeed translates to lung tissue in vivo. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death; however, the mechanisms of lung carcinogens are poorly understood. Metals, including hexavalent chromium [Cr(VI)], induce chromosome instability, an early event in lung cancer. Failure of homologous recombination repair is a key mechanism for chromosome instability. Particulate Cr(VI) causes DNA double-strand breaks and prolonged exposure impairs homologous recombination targeting a key effector protein in this pathway, RAD51. Reduced RAD51 protein is a key endpoint of particulate Cr(VI) exposure. It is currently unknown how Cr(VI) reduces RAD51 protein. E2F1 is the predominant transcription factor for RAD51. This study sought to identify if E2F1 modulates the RAD51 response to particulate Cr(VI). Particulate Cr(VI) reduced RAD51 protein and mRNA levels but had a minimal effect on RAD51 half-life. E2F1 protein and mRNA were also inhibited by particulate Cr(VI) exposure. To connect these two outcomes, we tested if modulating E2F1 affects RAD51 outcomes after particulate Cr(VI) exposure. E2F1 knockdown inhibited RAD51 nuclear foci formation after acute particulate Cr(VI) exposure. These data indicate reduced RAD51 protein levels after prolonged particulate Cr(VI) exposure are predominantly due to inhibited expression. Particulate Cr(VI) also inhibits E2F1 expression. However, although loss of E2F1 does not modulate RAD51 expression after particulate Cr(VI) exposure, RAD51 nuclear foci formation is inhibited. These findings suggest E2F1 is important for RAD51 localization to double-strand breaks, but not expression after particulate Cr(VI) exposure in human lung cells. [ABSTRACT FROM AUTHOR]