Translating particulate hexavalent chromium-induced chromosome instability from human lung cells to experimental animals, human lung tumors and whale cells.

Abstract

Lung cancer is a major human health problem. While smoking is the most well-known cause of lung cancer, people who never smoked develop the disease. Understanding how non-tobacco environmental carcinogens cause lung cancer is key to combating this disease. Hexavalent chromium [Cr(VI)] is a well-established human lung carcinogen, but its carcinogenic mechanism is uncertain. Chromosome instability (CIN) is a hallmark of lung cancer and a major factor in Cr(VI)-induced lung cancer. Studies in human lung cells show Cr(VI) induces DNA double strand breaks and suppresses homologous recombination (HR) repair by targeting RAD51, resulting in CIN. We translated these outcomes to rats, as this species develops Cr(VI)-induced lung tumors. We exposed 12-week-old Wistar rats to a single dose of zinc chromate for 24 hours or a weekly dose for 90 days via oropharyngeal aspiration. DNA double strand breaks and HR repair increased in a concentration-dependent manner in rat lungs after 24-hour Cr(VI) exposure. After 90-day exposure, DNA double strand breaks increased, but HR repair decreased. These effects were distinct in bronchioles but muted in alveoli, consistent with Cr(VI)-induced human lung tumors originating in bronchial epithelium. We translated these outcomes to Cr(VI)-associated human lung tumors. DNA double strand breaks significantly increased but RAD51 expression decreased in lung tumors; demonstrating Cr(VI)-induced DNA double strand breaks and HR inhibition persist in tumors. Long-lived whales can experience long-term exposure to environmental contaminants but have low cancer rates. We measured the ability of Cr(VI) to induce DNA double strand breaks, HR repair, and chromosome damage in bowhead whale lung cells. Cr(VI) induced DNA strand breaks in whale cells, but the HR repair response remained intact. Thus, whale cells are resistant to Cr(VI)-induced loss of HR repair with no apparent CIN. These results indicate significant differences in the response of human and bowhead whale lung cells to Cr(VI) exposure. Overall, our studies translate Cr(VI)-induced DNA double strand breaks and HR repair impacts to rat lung tissue, human lung tumors and whale lung cells. Cr(VI) induces DNA double strand breaks and inhibits HR repair in vivo, but does not cause HR repair failure and CIN in whale lung cells.