Molecular mechanisms of complex mixture toxicity

描述（摘自应用程序） 本研究项目的目的是：（1）评估 苯并[a]芘（B[a]P）的混合物，一种典型的多环芳烃 碳氢化合物（PAH）和致癌金属铬或砷 I期和II期解毒基因的表达，以及（2）阐明 这些影响的分子机制。发展 环境政策依赖于有关化学品的风险信息， 个人暴露。尽管已经有机制来测试 关于个别化学品的影响， 复杂的环境混合物。在没有具体数据的情况下， 在对混合物进行风险评估时，必须使用假设。为 例如，在没有相反证据的情况下， 假定类似的毒性效应以累加的方式起作用。这种方法 对于许多复杂的混合物来说是不令人满意的，其中广泛的 可以观察到从抑制效应到协同作用的相互作用。以来 大多数人都暴露在复杂的环境混合物中， 污染物，评估这些暴露风险的方法需要 开发大多数（如果不是全部）PAH暴露的毒性作用是由以下物质介导的： 芳香烃（Ah）受体，一种配体激活的转录 该因子与Ah受体核转运蛋白结合， 负责I期解毒的转录激活 基因，如编码细胞色素P450单加氧酶CYP 1A 1的基因， CYP 1B 1和CYP 1A 2，以及II期解毒基因，如编码 醌氧化还原酶（NQO 1）、谷胱甘肽-S-转移酶（GST 1）和UDP-葡萄糖醛酸基 转移酶（UDPGT）。我们实验室的初步工作 显示培养的哺乳动物细胞暴露于铬酸盐或亚砷酸盐 破坏Ah受体对I相和II相基因的协同诱导 配体。铬酸盐在更大程度上抑制II期基因的诱导 而亚砷酸盐对I相基因的影响很小， 基因诱导但超诱导II期基因。这些观察导致 我们的假设是，联合暴露于B[a]P和铬酸盐的混合物， 或亚砷酸盐，（1）破坏控制转录的调节机制 来自B[a] P-诱导型基因启动子;（2）引起I相的解偶联， II期基因表达和伴随的B[a]P代谢失衡;和 (3)产生一种特征性的“基因表达标记”， 接触和混合物对健康影响的分子生物标志物。 这项工作的结果将有助于开发一种预测健康风险的方法 由于暴露于化学混合物。

DESCRIPTION (Taken from application) The objectives of this research project are, (1) to evaluate the effects of mixtures of benzo[a]pyrene (B[a]P), a prototypical polycyclic aromatic hydrocarbon (PAH), and the carcinogenic metals chromium or arsenic on the expression of Phase I and Phase II detoxification genes, and (2) to elucidate the molecular mechanisms responsible for these effects. Development of environmental policy relies on risk information about the chemicals to which individuals are exposed. Although mechanisms are in place to test the health effects of individual chemicals, there is little data on the toxicity of complex environmental mixtures. In the absence of specific data, default assumptions must be used when conducting risk assessment for mixtures. For example, in the absence of evidence to the contrary, two chemicals having similar toxic effects are assumed to act in an additive manner. This approach is not satisfactory for many complex mixtures in which a wide spectrum of interactions, from repression of effects to synergy, may be observed. Since most individuals are exposed to complex mixtures of environmental contaminants, methods for assessing the risk of these exposures need to be developed. Most if not all the toxic effects of PAH exposure are mediated by the aromatic hydrocarbon (Ah) receptor, a ligand-activated transcription factor that, in combination with the Ah receptor nuclear translocator, is responsible for the transcriptional activation of phase I detoxification genes, such as those coding for the cytochromes P450 monooxygenases CYP1A1, CYP1B1 and CYP1A2, and of phase II detoxification genes, such as those coding for quinone oxido-reductase (NQO1), glutathione-S-transferase (GST1) and UDP-glucuronosyl transferase (UDPGT). Preliminary work from our laboratory has shown that exposure of cultured mammalian cells to chromate or arsenite disrupts the coordinate induction of phase I and phase II genes by Ah receptor ligands. Chromate inhibits induction of phase II genes to a greater extent than induction of phase I genes, whereas arsenite has little effect on phase I gene induction but superinduces phase II genes. These observations have lead us to the hypothesis that combined exposure to a mixture of B[a]P and chromate or arsenite, (1) disrupts the regulatory mechanisms that control transcription from B[a]P-inducible gene promoters; (2) causes an uncoupling of phase I and phase II gene expression and a concomitant imbalance in B[a]P metabolism; and (3) produces a characteristic "gene expression signature" that can be used as a molecular biomarker of exposure and of the health effects of the mixture. Results from this work will help develop a means to predict the health risks arising from exposure to chemical mixtures.