Abstract：
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.
摘要：
六价铬[Cr（VI）]是一种公认的人肺致癌物，但是对致癌机理了解甚少。染色体不稳定,肺癌的标志,被认为是Cr(VI)诱导的肺癌的主要驱动因素。未修复的DNA双链断裂是根本原因，同源重组修复是防止Cr（VI）诱导的DNA断裂引起染色体不稳定的主要机制。细胞培养研究表明，急性Cr（VI）暴露会导致DNA双链断裂并增加同源重组修复活性。然而,Cr（VI）诱导的DNA断裂和修复影响的能力仅在细胞培养研究中报道。因此,我们研究了急性Cr（VI）暴露是否可以诱导大鼠肺的断裂和同源重组修复。雄性和雌性Wistar大鼠通过口咽抽吸急性暴露于盐溶液中的铬酸锌颗粒或单独的盐水中。这种暴露途径导致每个肺叶中的Cr水平增加。我们发现Cr（VI）以浓度依赖的方式诱导DNA双链断裂，女性比男性更容易受到影响，并在两种性别中以相似的水平诱导同源重组修复。因此，这些数据表明，在细胞培养中发现的这种驱动机制确实在体内转化为肺组织。
