Particulate hexavalent chromium exposure induces DNA double-strand breaks and inhibits homologous recombination repair in rat and human lung tissues

Abstract

Lung cancer is an important human health concern because of its high mortality rate, with many cases caused by environmental chemicals other than tobacco. Particulate hexavalent chromium [Cr(VI)] is a well-established human lung carcinogen, but how Cr(VI) induces lung cancer is poorly understood. Chromosome instability, a hallmark of lung cancer, is considered a major driving factor in Cr(VI)-induced lung cancer. Our previous studies in cultured human lung cells showed that particulate Cr(VI) induces DNA double-strand breaks during the late S and G2 phases of the cell cycle, which are repaired by homologous recombination, one of the main repair pathways of DNA double-strand breaks. Our previous data showed that prolonged exposure to Cr(VI) inhibits homologous recombination repair by targeting RAD51, a key protein that mediates homologous recombination. Therefore, particulate Cr(VI)-induced DNA damage combined with failure of DNA repair can lead to chromosome instability. In this study we translated these results to rat lung tissue and lung tumor tissue from Cr(VI)-exposed workers. Wistar rats were exposed to zinc chromate in a saline solution or saline alone by oropharyngeal aspiration with a single dose repeated weekly for 90 days. We observed DNA double-strand breaks increased in a concentration-dependent manner, but homologous recombination repair decreased in rat lungs after 90 days of exposure. Notably, these effects were more pronounced in bronchioles than alveoli. We also considered these effects in Cr(VI)-associated human lung tumors and observed increased DNA double-strand breaks and reduced RAD51 levels in lung tumor tissue compared with adjacent normal lung tissue. Thus, Cr(VI)-induced induction of DNA double-strand breaks, and inhibition of homologous recombination repair translates from cultured cells to experimental animals, normal lung tissue adjacent to the tumor, and Cr(VI)-associated human lung tumors.

Keywords: Chromosome instability; Cr(VI)-Associated human lung tumor; DNA double-strand breaks; Hexavalent chromium; Homologous recombination repair; Rat lung.