Molecular Mechanisms of Complex Mixture Toxicity

描述(由申请人提供)：这项研究的长期目标是了解暴露在多环芳烃(PAH)和铬的复杂混合物中对健康造成不利影响和毒性的潜在机制，铬是一种致癌金属，通常被发现为多环芳烃的环境共同污染物。本研究的目的是：(1)阐明铬影响诱导性基因表达的机制，(2)评价典型的多环芳烃苯并[a]芘(B[a]P)和铬的混合物对染色质重塑蛋白翻译后修饰的影响，该修饰与基因表达的表观遗传调控有关。铬暴露可以改变可诱导的基因表达，形成铬-DNA加合物和铬-DNA交联链，并破坏转录激活剂/辅激活剂复合体。在这项资助的前4年中，我们已经证明，铬通过干扰可诱导基因启动子上的生产性转录复合体的组装来阻止基因的表达。我们研究了铬对B[a]P诱导的基因表达的影响，结果表明，铬干扰了依赖于B[a]P的AhR激活诱导的I期和II期解毒基因的转录调控，以及参与多种信号转导途径的50多个不同基因的诱导表达。铬的这些效应是抑制了基因反式激活所必需的关键染色质重塑步骤的结果。鉴于组蛋白在维持染色质结构中的核心作用，在未来5年的拨款申请中，我们建议测试这一假设，即暴露于铬和B[a]P混合物中会导致特定的组蛋白修饰，从而产生转录上不活跃的染色质，并诱导无法从每个混合物组分的单独效应中预测的非加性基因表达效应。这项工作的结果将有助于了解接触化学混合物产生的风险，并开发有效手段来预测其对健康的影响。

DESCRIPTION (provided by applicant): 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 chromium, a carcinogenic metal often found as an environmental co-contaminant with PAHs. The objectives of this research project are, (1) to elucidate the mechanisms by which chromium affects inducible gene expression, and (2), to evaluate the effect of mixtures of benzo[a]pyrene (B[a]P), a prototypical PAH, and chromium on the post-translational modifications of chromatin remodeling proteins associated with epigenetic modulation of gene expression. Chromium exposure has been shown to alter inducible gene expression, to form chromium-DNA adducts and chromium-DNA cross-links, and to disrupt transcriptional activator/coactivator complexes. During the previous 4 years of this grant we have shown that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoters of inducible genes. We studied the effects of chromium on the expression of genes induced by B[a]P and showed that chromium disrupted the transcriptional regulation of phase I and phase II detoxification genes induced by B[a]P-dependent Ah receptor activation and the inducible expression of over 50 different genes involved in a variety of signal transduction pathways. These effects of chromium were the result of the inhibition of critical chromatin remodeling steps necessary for gene transactivation. Given the central role of histones in maintaining chromatin structure, for the next 5 years of this grant application we propose to test the hypothesis that exposure to mixtures of chromium and B[a]P causes specific histone modifications that generate transcriptionally inactive chromatin and induce non-additive gene expression effects that cannot be predicted from the individual effect of each mixture component. Results from this work will help to generate an understanding of the risks arising from exposure to chemical mixtures and to develop effective means to predict their health effects.