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

比较毒理学基因组学和对皮肤 PAH 反应的个体差异

• 批准号: 7067251
• 负责人: LEENA A NYLANDER-FRENCH
• 金额: $ 27.07万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067251
• 关键词: adduct; carbopolycyclic compound; clinical research; cytochrome P450; dosage; environmental exposure; environmental toxicology; gene environment interaction; gene expression profiling; genetic susceptibility; human data; human tissue; keratin; keratinocyte; toxicant screening; toxin metabolism

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.

关于异生物质暴露、吸收和皮肤代谢的个体差异以及暴露对个体健康影响评估的潜在价值的知识有限。这降低了我们调查影响皮肤接触的各个因素之间的相关性的能力，并限制了皮肤接触评估的使用及其与其他途径全身接触的关系，损害了总体接触评估。我们提出了几个假设：（1）活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）代谢为亲电体，细胞色素P450加氧酶加合分化和成熟过程中表达的角蛋白的亲核残基，（2）PAH暴露于表皮导致基因表达的个体模式， 其相应的蛋白质;（3）PAH诱导的表皮基因表达的变化与暴露水平相关，因此可以预测PAH暴露剂量反应的个体差异。我们将确定和表征重建的人表皮和人皮肤细胞对PAH暴露的反应。具体来说，我们将确定细胞，表达阶段1和阶段2的酶，代谢多环芳烃，和环境响应基因，可能会改变个人对多环芳烃暴露的反应。其次，我们将确定暴露于已知水平PAH的重建表皮中PAH-亲电体加合角蛋白的浓度是否与剂量响应的PAH暴露相关。 角蛋白加合物是否可用作皮肤的定量生物标志物 暴露于PAH。第三，我们将确定的基因和蛋白质的表达模式，在表皮中，是至关重要的多环芳烃暴露的反应和定量差异，在响应相关的暴露水平，并因此，预测个体差异。最后，如果观察到统计学显著的个体差异，我们将对可能导致这些数量差异的环境响应基因中的等位基因差异的候选基因进行基因分型。个体代谢和表皮中基因表达对PAH暴露和大分子内收和/或损伤（可能存在于人群中）的反应存在潜在显著差异，需要进行表征和纳入 暴露和风险评估模型。这些拟议的研究所获得的结果将增加我们对皮肤接触的作用以及皮肤和内部组织所接受的内部剂量的了解。