MOLECULAR MECHANISMS OF COMPLEX MIXTURE TOXICITY

这项研究的长期目标是了解 有害健康影响和毒性的潜在机制 暴露于多环芳烃（PAH）和 致癌金属砷和铬，通常作为共污染物存在于 环境本研究项目的目标是：（1）阐明 砷和铬影响诱导型基因表达的机制，以及 (2)为了评价苯并[α]芘（B[α]P）的混合物的效果， PAK和铬、砷对I相和II相表达的影响 解毒精灵环境政策的制定依赖于风险 关于个人接触的化学品的信息。虽然 有机制来测试个别化学品对健康的影响， 关于复杂环境混合物毒性的数据很少。在没有 特定数据，进行风险评估时必须使用默认假设 对于混合物。例如，在没有证据的情况下。相反，两个 具有类似毒性作用的化学品被认为是以累加方式起作用的。 这种方法对于许多复杂的混合物是不令人满意的，其中广泛的 存在着一系列相互作用，从抑制效应到协同作用。由于大多数 人类暴露于环境污染物、方法 评估这些风险的方法。 大多数（如果不是全部）PAH暴露的毒性作用是由芳香族化合物介导的。 碳氢化合物（Ah）受体，一种配体激活的转录因子， 与Ah受体核转运蛋白（ARNT）结合， I期解毒基因的转录激活，例如编码 细胞色素P450单加氧酶CYP 1A 1、CYP 1B 1和CYPIA 2，以及 II期解毒基因，例如编码醌氧化还原酶的基因 （NQO 1）、谷胱甘肽-S-转移酶（GSTP）和UDP-葡萄糖醛酸转移酶 （UGTIA6）。抗氧化剂和亲电子试剂也可以诱导II相基因 通过Ah受体独立机制。我们的初步工作 实验室已经表明，将培养的哺乳动物细胞暴露于铬酸盐或 亚砷酸盐破坏了二恶英对I期和II期基因的协同诱导， 原型卤代芳烃Ah受体配体。 铬酸 抑制II期基因的诱导的程度大于I期基因的诱导 基因，而亚砷酸盐抑制I期基因诱导和elevia剂量依赖性 超诱导亲电反应元件（EpRE）的氧化应激反应- 介导的II期基因转录。这些观察将我们引向我 假设联合暴露于混合物B[alpha]P和铬酸盐或亚砷酸盐，（1） 会破坏控制从B[alpha]P- 诱导型基因启动子，和（2）将引起I相和II相的解偶联 基因表达和伴随的B[alpha]P代谢失衡。 结果 这项工作将有助于开发一种方法来预测健康风险所产生的 接触化学混合物。

The long-range goal of this research is to develop an understanding of the mechanisms underlying the adverse health effects and toxicity resulting from exposure to complex mixtures of polycyclic aromatic hydrocarbons (PAH) and the carcinogenic metals arsenic and chromium, often found as co-contaminants in the environment. The objectives of this research project are, (1) to elucidate the mechanisms by which arsenic and chromium affect inducible gene expression, and (2), to evaluate the effect of mixtures of benzo[alpha]pyrene (B[alpha]P), a prototypical PAK and chromium and arsenic on the expression of phase I and phase II detoxification genies. 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, exist. Since most humane 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 (ARNT) causes the transcriptional activation of phase I detoxification genes, such as those coding for the cytochromes P450 monooxygenases CYP1Al, CYP1B1 and CYPIA2, and of phase II detoxification genes, such as those coding for quinone oxidoreductase (NQO1), glutathione-S-transferase (GSTP) and UDP-glucuronosyl transferase (UGTIA6). Phase II genes can also be induced by antioxidants and electrophiles through Ah receptor-independent mechanisms. 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 dioxin, the protype halogenated aromatic hydrocarbon Ah receptor ligand. Chromate inhibits induction of phase II genes to a greater extent than induction of phase I genes, whereas arsenite inhibits phase I gene induction and elicits a dose-dependent oxidative stress response that superinduces electrophile response element (EpRE)- mediated transcription of phase II genes. These observations lead us to me hypothesis that combined exposure to a mixture B[alpha]P and chromate or arsenite, (1) Will disrupt the regulatory mechanisms that control transcription from B[alpha]P- inducible gene promoters, and (2) will cause an uncoupling of phase I and phase II gene expression and concomitant imbalance in B[alpha]P metabolism. Results from this work will help develop a means to predict the health risks arising from exposure to chemical mixtures.