Comparative Toxico-Genomics and Individual Differences in Response to Dermal PAH

对外源暴露、摄取和皮肤代谢的个体差异以及对个体健康影响的暴露评估的潜在价值的了解有限。这降低了我们调查影响皮肤暴露的个体因素之间相关性的能力，限制了皮肤暴露评估的使用及其与其他途径的全身暴露的关系，损害了整体暴露评估。我们提出验证几个假设：(1)活体细胞表皮的角质形成细胞通过诱导细胞色素P450加氧酶将多环芳烃（PAH）代谢为亲电物质，该酶加合在分化和成熟过程中表达的角蛋白亲核残基；(2)暴露于表皮的多环芳烃会导致基因和基因的个体表达模式

Knowledge of individual differences in xenobiotic exposure, uptake, and metabolism in the skin, and the potential value for exposure assessment of individual health effects is limited. This reduces our ability to investigate the correlation between individual factors that affect dermal exposure and limits the use of dermal exposure assessment and its relationship to systemic exposure from other routes, compromising overall exposure assessment. We propose to test several hypotheses: (1) keratinocytes of the viable epidermis metabolize polycyclic aromatic hydrocarbons (PAH) to electrophiles through the induction of the cytochrome P450 oxygenases that adduct nucleophilic residues of keratin expressed during differentiation and maturation, (2) PAH exposure to the epidermis results in an individual pattern of expression of genes and their corresponding proteins; (3) PAH induced changes in gene expression in the epidermis correlate with exposure level and, thus, can predict individual differences in the dose response to PAH exposure. We will determine and characterize the response in the reconstructed human epidermis and human skin cells to PAH exposure. Specifically, we will identify the cells that express phase 1 and phase 2 enzymes, which metabolize PAH, and the environmentally responsive genes which may modify individual response to the PAH exposure. Secondly, we will determine if the concentration of PAH-electrophile adducted keratin in reconstructed epidermis exposed to known levels of PAH correlates with PAH exposure in a dose-responsive manner and establish if keratin adducts may be used as quantitative biomarkers of dermal exposure to PAH. Third, we will determine the pattern of gene and protein expression in the epidermis that are critical to PAH-exposure response and to quantitative differences in response to exposure levels that correlate, and, thus, predict individual differences. Finally, where statistically significant individual differences are observed, we will genotype candidate genes for allelic differences in environmentally responsive genes that may be responsible for these quantitative differences. The potential significant differences in individual metabolism and gene expression in the epidermis in response to PAH exposure and macromolecule adduction and/or damage, which may exist in the human population, require characterization and inclusion into exposure and risk assessment models. The results obtained by these proposed studies will increase our knowledge of the role of dermal exposure and the internal dose received to both the skin and internal tissues.