Effect of Particulate Matter on DNA Deletions in Mice

墨西哥城拥有超过1800万人，他们呼吸着北美污染最严重的空气。空气污染中所含的颗粒物（PM）由数量惊人的已知致癌物质组成，并且有一些流行病学迹象表明，暴露于PM会导致人类癌症。我们已经在初步结果中表明，暴露于柴油机废气颗粒显着增加小鼠DNA缺失的频率。遗传不稳定性，特别是DNA缺失与癌症的病因学有关。此外，许多其他致癌物质也会诱导这种缺失，其中一些是通过氧化机制。目的1是确定来自墨西哥城不同地区的PM是否会增加小鼠DNA缺失的频率。这些发现可能揭示PM暴露与癌症之间的潜在联系，这是目前未知的。由于氧化应激似乎参与了PM的不良生物活性，并且我们的缺失测定对促氧化剂非常敏感，目的2是确定抗氧化剂暴露是否可以降低PM对缺失频率的潜在影响。在这个项目中获得的结果可以加强PM通过产生氧化应激而起作用的概念，并且在对人类进行类似的研究之后，可能会导致职业PM暴露工人服用营养抗氧化剂的建议。这项研究将主要在墨西哥国立自治大学和国立癌症研究所与阿尔瓦罗·R·Osornio Vargas和Claudia Garcia Cuellar作为NIH资助#R01 ES 09519的扩展。

DESCRIPTION (provided by applicant): Mexico City is home to more than 18 million individuals who breathe the most polluted air in North America. Particulate Matter (PM) contained in air pollution consists of a staggering number of known carcinogens and there is some epidemiological indication that exposure to PM causes cancer in people. We have shown in preliminary results that an exposure to diesel exhaust particles significantly increases the frequency of DNA deletions in mice. Genetic instability, in particular DNA deletions are involved in the etiology of cancer. In addition, many other carcinogens induce such deletions, several of them through an oxidative mechanism. Aim 1 is to determine whether PM from different parts of Mexico City increase the frequency of DNA deletions in mice. The findings could shed mechanistic light on the potential association between PM exposure and cancer, which is currently unknown. Since oxidative stress seems to be involved in the adverse biological activity of PM and our deletion assay is very sensitive towards prooxidants, aim 2 is to determine whether antioxidant exposure may reduce the potential effect of PM on the frequency of deletions. The results obtained in this project could reinforce the notion that PM act through generation of oxidative stress and potentially, after similar studies have been carried out in humans, could lead to the recommendation of taking nutritional antioxidants by occupationally PM exposed workers. This research will be done primarily in Mexico at Universidad Nacional Autonoma de Mexico and the Institute Nacional de Cancerologia in collaboration with Alvaro R. Osornio Vargas and Claudia Garcia Cuellar as an extension of NIH grant #R01 ES09519.