Epigenetic toxicity of polycyclicaromatic hydrocarbons

多环芳烃的表观遗传毒性

• 批准号: 7051836
• 负责人: Brad L. Upham
• 金额: $ 18.23万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051836
• 关键词: DNA damage; apoptosis; biological signal transduction; carbopolycyclic compound; cell differentiation; chromatography; gap junctions; gene environment interaction; gene expression; genetic susceptibility; intercellular connection; mitogen activated protein kinase; proteomics; smoking; tobacco abuse

Considerable toxicological research on polycyclic aromatic hydrocarbons (PAHs), which are prevalent compounds in cigarette smoke that contribute to cancer, has focused on their genotoxic attributes. However, cancer is not solely the consequence of non-reversible mutagenic events but also include reversible, epigenetic events. Thus, there is a need to reassess the toxicity of PAHs at the epigenetic level. Gap junctional intercellular communication (GJIC) centrally modulates signal transduction pathways that epigenetically alters gene expression. There is considerable evidence linking abnormal regulation of GJIC with the nongenotoxic steps of tumor promotion. Mitogen activated protein kinases (MAPKs) also play a central role in cell signaling. We will use a series of tobacco smoke-relevant PAHs and determine structure activity relationships with inter- and intracellular signaling mechanisms in pluripotent mammalian epithelial cell lines. We will specifically test the hypothesis SA#1 that phospholipases are the upstream regulators of GJIC and MAPK in response to PAHs by using specific phospholipase inhibitors and the emerging and powerful technique of silencing genes using small interfering RNA. We will use chromatography and state of the art proteomic techniques to test the hypothesis SA#2 that lipid-derived second messengers are released from the plasma membrane, and activate cell signal proteins. We will also test the hypothesis SA#3 that inhibition of GJIC and activation of MAPK by PAHs will induce mitogenesis, and block apoptosis and differentiation. We would like to note that the use of biologically active vs inactive PAH isomers for all of the aims allows us to systematically identify molecular events that are specific to the regulation of GJIC and MAPK and subtract out non-specific events. Overall, determining the effect of tobacco-relevant PAHs on key signaling events would provide invaluable mechanistically based information on the epigenetic toxicity of these compounds, thereby aiding in the development of preventative and therapeutic strategies for cancer.

多环芳烃（PAHs）是香烟烟雾中常见的致癌化合物，大量的毒理学研究集中在其遗传毒性属性上。然而，癌症不仅仅是不可逆的诱变事件的结果，还包括可逆的表观遗传事件。因此，有必要在表观遗传水平上重新评估多环芳烃的毒性。间隙连接细胞间通讯（GJIC）集中调节信号转导途径，表观遗传学改变基因表达。有相当多的证据表明GJIC的异常调节与肿瘤促进的非遗传毒性步骤有关。丝裂原活化蛋白激酶（MAPK）也发挥作用， 在细胞信号传导中的核心作用。我们将使用一系列的烟草烟雾相关的多环芳烃，并确定结构活性与多能哺乳动物上皮细胞系间和细胞内信号传导机制的关系。我们将通过使用特定的磷脂酶抑制剂和使用小干扰RNA沉默基因的新兴和强大的技术来具体测试假设SA#1，即磷脂酶是响应于多环芳烃的GJIC和MAPK的上游调节剂。我们将使用色谱法和最先进的蛋白质组学技术来测试假设SA#2，即脂质衍生的第二信使从质膜释放，并激活细胞信号蛋白。我们还将检验假设SA#3， 多环芳烃抑制GJIC和激活MAPK可诱导有丝分裂，阻断细胞凋亡和分化。我们想指出的是，使用生物活性与非活性PAH异构体的所有目标，使我们能够系统地确定特定的GJIC和MAPK的调节分子事件，并减去非特异性事件。总的来说，确定烟草相关的多环芳烃对关键信号事件的影响将提供关于这些化合物的表观遗传毒性的宝贵的基于机制的信息，从而有助于开发癌症的预防和治疗策略。

项目成果

Role of integrative signaling through gap junctions in toxicology.

• DOI: 10.1002/0471140856.tx0218s47
• 发表时间: 2011-02
• 期刊: Current protocols in toxicology
• 作者: Upham, Brad L

Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure.

• DOI: 10.1371/journal.pone.0065150
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Osgood RS;Upham BL;Hill T 3rd;Helms KL;Velmurugan K;Babica P;Bauer AK
• 通讯作者: Bauer AK

Bronchoalveolar Lavage Fluid Utilized Ex Vivo to Validate In Vivo Findings: Inhibition of Gap Junction Activity in Lung Tumor Promotion is Toll-Like Receptor 4-Dependent.

使用离体支气管肺泡灌洗液来验证体内研究结果：对肺肿瘤促进过程中间隙连接活性的抑制是 Toll 样受体 4 依赖性的。

• DOI: 10.4172/2155-9929.1000160
• 发表时间: 2013
• 期刊: Journal of molecular biomarkers & diagnosis
• 作者: Hill3rd,Thomas;Osgood,RossS;Velmurugan,Kalpana;Alexander,Carla-Maria;Upham,BradL;Bauer,AlisonK
• 通讯作者: Bauer,AlisonK