Effect of Particulate Matter on DNA Deletions in Mice

描述(申请人提供)：墨西哥城是北美呼吸污染最严重空气的1800多万人的家园。空气污染中包含的颗粒物(PM)由数量惊人的已知致癌物质组成，有一些流行病学迹象表明，暴露在PM中会导致人类癌症。我们已经在初步结果中表明，暴露在柴油废气颗粒物中显著增加了小鼠DNA缺失的频率。遗传不稳定，特别是DNA缺失，与癌症的病因学有关。此外，许多其他致癌物会导致这种缺失，其中几种是通过氧化机制实现的。第一个目的是确定墨西哥城不同地区的PM是否增加了小鼠DNA缺失的频率。这些发现可能会从机制上阐明PM暴露与癌症之间的潜在联系，这一点目前尚不清楚。由于氧化应激似乎与PM的不利生物活性有关，并且我们的缺失分析对促氧化剂非常敏感，目标2是确定抗氧化剂暴露是否可能降低PM对缺失频率的潜在影响。这个项目的结果可能会强化PM通过产生氧化应激而起作用的概念，并有可能在人类中进行类似的研究后，导致职业PM暴露的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家癌症研究所与Alvaro R.Osornio Vargas和Claudia Garcia Cuella合作进行，作为NIH#R01 ES09519补助金的延伸。

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.