Description: Heat and air pollution pose serious threats to the health of humans and other animals in Southern California. The long term goal of this project is to identify drugs or compounds that could increase organismal resistance to environmental stress. The laboratory fruitfly Drosophila melanogaster will be used a model to allow for rapid screening of potentially protective compounds. In the well-characterized (and evolutionarily conserved) phenomenon called “acquired stress resistance”, or “hormesis”, a mild pre-stress can protect an organism from a subsequent stress that would otherwise be toxic or lethal. Such data demonstrate that expression of one of more stress response genes can be protective. It should be possible to identify small molecules that can activate the expression of such protective genes. Previous studies implicate heat shock proteins (hsps) and the heat shock transcription factor HSF in mediating cellular and organismal resistance to heat and other stresses. In Drosophila hsp70 is preferentially induced in response to heat, while hsp22 is preferentially induced in response to oxidative stress via unknown mechanisms. We propose to:

1. Determine which stress response genes are induced in adult Drosophila in response to ozone and other relevant smog components.
2. Screen compounds for their ability to induce expression of potentially protective genes in adult Drosophila, using hsp22 and hsp70 vital transgenic reporters.
3. Screen the most promising compounds for ability to increase organismal stress resistance.

The pilot project is designed to provide sufficient preliminary data for a subsequent RO1 application to the NIEHS.

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Heterocyclic amines, genetic variation, and colorectal cancer risk: a pathway-based approach

Description: Heterocyclic aromatic amines (HCAs) constitute naturally occurring carcinogens that can be found in foods cooked under ordinary conditions. The epidemiological data on the role of HCAs as colorectal cancer risk factors is inconclusive. HCAs can be formed by pyrolisis of amino acids and proteins or can be generated by heating mixtures of creatine, sugars and amino acids. Tobacco leaves, meats and fish can be sources of HCA when heated. HCAs found in cooked meats (e.g. IQ, MeIQx, MeIQ and PhIP) are some of the most potent mutagens as determined by the Ames test, and are carcinogenic in rodents. HCAs can induce bulky adducts, base frameshifts, double strand breaks and oxidative DNA damage (e.g. base damages) in exposed cells in the colon lumen which is the main extra-hepatic site for HCA induced-adduct formation and carcinogenesis. In rodents, linear-dose responses were observed for MeIQx- and PhIP-DNA adduct formation after exposure to each HCA at exposure levels comparable to those found among humans. Individuals vary in their abilities to metabolize xenobiotics and repair DNA damage. We hypothesize that single nucleotide polymorphisms (SNPs) in key genes that participate in the mechanism of action of HCAs may modify the effect of HCAs in colorectal cancer. We propose to test our hypothesis by using a sequential approach where we will combine conventional logistic regression models to estimate the individual effect of each SNP, followed by hierarchical and Bayes modeling, which will allow us to analyze in a more comprehension fashion the combined contribution of several SNPs per gene in combination with HCA exposure, as well as multiple genes across this pathway. We will focus on key genes that participate in the activation and/or detoxification of HCAs, and in key genes that repair HCA-induced DNA damage. We will conduct this study within the USC component of the Colorectal Family Registry (CFR), an international consortium funded by the National Cancer Institute and formed by six research centers in the US, Australia, and Canada. This registry is the largest in its kind (7,000 patients) and consists of colorectal cancer patients and their families, who provide demographic and nutritional data, biological specimens, and family history of cancer information. The USC component of this registry has enrolled 657 cases who donated biological samples for DNA analyses. Unaffected siblings and/or cousins are available as controls. Our long term goal is to test our hypotheses using the entire CFR, in collaboration with investigators in the other centers. The results we will obtain with this proposed pilot project will be instrumental in providing preliminary evidence to seek NIH RO1 external funding to carry out a CFR-wide project. This pilot project proposes to use the Biostatistics and the Molecular Biology cores of the SCEHSC.

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Description: Numerous studies have linked outdoor air pollution to asthma exacerbations in children, but few have focused specifically on low-income or minority children and the potential interaction of neighborhood stressors, air pollution exposures, and asthma occurrence or exacerbation. The extensive data on individual, neighborhood and health characteristics of Los Angeles residents collected during the first wave of The Los Angeles Family and Neighborhood Survery (L.A. FANS) of approximately 3,000 families provide a unique resource with which to evaluate associations between outdoor air pollution and asthma prevalence and symptoms in children, especially those living in more impoverished areas of the country. The survery includes a detailed assessment of neighborhood characteristics (including those related to health utilization) and perceptions of neighborhood environments, yielding a qualitative apprraisal of neighborhood quality and resultant stressors. These data can be used to examine whether children living in more impoverished areas (real and/or percieved) are more susceptible to the adverse impacts of air pollution and identify what factors may be most important when assessing neighborhood influences. The specific aims of this proposed pilot study are:

1. to estimate the effect of air pollution on asthma exacerbations in Los Angeles children ages 0-17 years during 2001-2002 using Wave One L.A. FANS data; and
2. to use the L.A. FANS data to create measures of individual and neighborhood SES and identify which of these are risk factors for asthma that are also associated with air pollution;
3. to develop multilevel models that account for:
1. confounding of the above effects by individual and neighborhood SES, and
2. clustering of the observations by area and family.

The survey data will be combined with year 2000 US Decennial Census data to characterize each neighborhood's SES also at the level of census tract or block. The L.A. FANS cohort survey has recently been refunded, and at the end of 2005 new information (including more extensive information on asthmatic symptoms and lung function testing) will be collected during a second follow-up of this cohort. The information gathered from this pilot study will be used as preliminary data for a future NIH grant application. In this future proposal we plan to suggest linking L.A. FANS Wave 2 data to air pollution measures obtained during the field period of L.A. FANS Wave 2 (a CARB review group has recently recommended to fund our proposal to sample and model traffic related air pollution in the L.A. FANS neighborhoods) and explore the SES interaction on asthma incidence and lung function in this cohort of approximately 3,000 families and children. Pilot funding from the SCEHSC will help us to establish meaningful measures and analytic models based on the existing L.A. FANS Wave One cross sectional data and provide important preliminary data for an application that builds onto the L.A. FANS Wave 2 cohort data.

Description: Recent epidemiologic results have linked a number of respiratory health outcomes among California school children with increased ambient exposures to a highly inter-correlated package of pollutants associated with vehicle emissions. Additional analyses have suggested associations with some metric of proximity to traffic. To assess the importance of volatile organic compounds (VOCs) in these observations, we propose to measure the intra-community variability of VOCs in three California communities participating in a multi-year health study. Commercial passive samplers will be deployed for two-week sampling periods in both summer and winter in the three study communities. Samplers will be placed at discrete distances from major traffic arteries, at the community monitoring station, at local schools, and outside homes of students participating in the longitudinal health investigation. Sampling will be performed in conjunction with a larger field deployment of passive ozone (O3) and oxides of nitrogen (NOx) samplers to allow for the direct comparision of the concurrently-collected data and to leverage personnel and logistic commitments. Analyses will assess the relative intra-community variability of VOCs, their correlation with O3 and NOx measurements, and whether the central community monitoring site adequately describes exposure for the surrounding community. This should provide credible pilot data for subsequent larger-scale investigations of pollutant spatial variability within study communities.

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Description: The underlying hypothesis in this application is that exposure to PM results in an adaptation process involving the induction of key cellular proteins that protect the cell against additional insults from PM sources. The insults could arise from the particles themselves or from reactive chemical associated with the particles. We propose to test the hypothesis by determining the changes in three key proteins, quinone reductase, glutathione turnover and multidrug resistant proteins that may affect the toxicity of reactive chemical species found in PM. Our studies will utilize two chemicals whose reactivity is known to cause cellular events analogous to those found after PM exposure, benzoquinone and phenanthroquinone. Using these chemicals, we will establish protocols for assessment of the potential for PM samples to initiate the same changes and expose the test cells, human epthelial cell line (NCI-H727) and macrophages (THP-1) to ambient particle samples collected with a mobile particle concentrator by the Exposure and Assessment and GIS Facility at UCLA. The concentrator will collect PM of coarse, fine and ultrafine fractions for study. As the chemical constituents of the three particles differ quantitatively, their actions on the cells could differ, depending on the requirements by the cell for protective protein induction.

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