Effect of Diesel Exhaust Particles on DNA Deletions

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DESCRIPTION (provided by applicant): Exposure to diesel exhaust particles (DEP) has become a serious environmental and occupational health issue since early 1980s and there is ample evidence of carcinogenic activity. In fact, it is estimated that more than 70 percent of the carcinogenic effects of Particulate Matter in Southern California is derived from DEP. The California Air Resources Board estimates a DEP cancer risk of 300 excess cancers per million people per mu/g m-3 for 70 year exposure. However, the mechanism for the association between DEP exposure and cancer is currently unknown. Genetic instability, in particular DMA deletions are involved in the etiology of cancer. We show in preliminary results that gavage exposure of mice during pregnancy to DEP caused an increased frequency of DMA deletions in the offspring using an in vivo pigmentation assay. We have also previously shown that inhalation exposure to cigarette smoke for only four hours producing a blood nicotine level that is similar to what a smoker experiences after smoking a cigarette induces DNA deletions in the offspring indicating that the mouse assay is useful for inhalation studies. This assay is based on the quantification of black spots on fur and eyes resulting from reversion of the pun mutation. This reversion occurs by deletion of 70 kb of an internal duplication within the p gene. We propose to determine in Aim 1 whether offspring mice exposed in utero via inhalation of the pregnant dams to DEP will develop an elevated level of DNA deletions and possibly DNA adducts and/or oxidative DNA damage. The findings could shed mechanistic light on the potential association between DEP exposure and cancer. In addition, it has been shown that ionizing radiation and more recently air pollution show delayed reproductive effects and effects in the next generation after mating of previously exposed mice to unexposed mice, so called transgenerational effects. With our mouse model for DNA deletions we, as well as others, have shown that exposure of male mice to ionizing radiation causes effects in the offspring after mating with unexposed female mice. We propose to determine in the second aim whether exposure of male mice via inhalation to DEP and subsequent mating to unexposed female mice may result in an increased level of DNA deletions in the offspring. The results obtained in this project could establish the in vivo DNA deletion assay as suitable assay for subsequent studies and provide needed preliminary results for grant applications for other funding mechanisms on the comparison between combustion products of different types of diesel fuels for their in vivo potency to induce DNA deletions and of effects in transgenic mice deficient in oxidative DNA damage repair as well as for chemoprevention studies possibly counteracting any DEP caused elevated frequency of DNA deletions as gene-environment-nutritional interactions.