EVALUATION OF SUPERFUND CHEMICALS AS EPIGENETIC TOXICANTS

超级基金化学品作为表观遗传毒物的评估

• 批准号: 6217623
• 负责人: JAMES Edward TROSKO
• 金额: $ 15.1万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217623
• 关键词: bioassay; carbopolycyclic compound; cell cell interaction; cytotoxicity; environmental engineering; environmental protection; environmental toxicology; gap junctions; gene expression; halobiphenyl /halotriphenyl compound; method development; protein kinase C; tissue /cell culture; toxicant screening; toxin metabolism; tumor promoters

The mechanisms by which chemicals can induce toxicities, such as teratogenesis, carcinogenesis, reproductive and neuro-toxicities, include mutagenesis (genotoxicity), cell killing (cytotoxicity) and/or altered gene expression, (epigenesis). Since many important environmental toxicants are not mutagenic (genotoxic), it is important that assays be developed and characterized which can detect this class of toxicants. To date, several rodent and human in vitro assays have been designed to detect chemicals which modulate gap junctional intercellular communication (GJIC). These chemicals which block GJIC have been shown in vivo in a number of organisms, including humans, to be teratogens, tumor promoters, reproductive- and neuro-toxicants. The objective of this project is to integrate three disciplines: biochemistry, molecular/cell biology and environmental engineering to determine if remediation of several classes of mixtures of environmental toxicants (PCB's, HAH's, PAH's) decreases the toxicities of the parent mixtures or actually enhances the toxicities. To achieve this goal, several primary aims are proposed: namely, to determine if Superfund toxicants which activate protein kinase C can be predicted to be potential tumor promoters; to assess the ability of various types of remediation/bioremediation techniques to remove or enhance the toxicities of mixtures of toxicants as measured by their ability to modulate GJIC; and to understand how mechanisms of mixtures of these chemicals might differentially activate the PKC second messenger system and affect GJIC in different cell strains. This subproject has evolved, based on the development of several human and rodent in vitro models, to detect chemicals which block GJIC and on advances in the molecular/biochemical understanding of mechanisms by which chemicals modulate GJIC, to the point where it will directly test chemicals from various remediation projects. Its primary aim will be to provide direct feedback to the remediation studies of Dr. Masten so that modification in the conditions for remediation can be improved. The second aim is to start examining the mechanisms by which mixtures of toxicants, before and after remediation efforts, might interact addititively, synergistically or antagonistically.

化学品可能引起毒性的机制，例如 致畸、致癌、生殖和神经毒性，包括 诱变（遗传毒性）、细胞杀伤（细胞毒性）和/或改变 基因表达（表观遗传）。 由于许多重要的环境 毒物不具有致突变性（遗传毒性），重要的是， 开发并表征了可以检测这类毒物的方法。 迄今为止，已经设计了几种啮齿动物和人类体外测定， 检测调节细胞间隙连接的化学物质 通信（GJIC）。 这些阻断GJIC的化学物质已经在体内的许多实验中被证明是有效的。 生物体，包括人类，是致畸剂，肿瘤促进剂， 生殖和神经毒物。 该项目的目标是 整合三门学科：生物化学、分子/细胞生物学和 环境工程，以确定是否修复几个类 环境毒物的混合物（多氯联苯，环烷烃，多环芳烃）减少 母体混合物的毒性或实际上增强了 毒性 为实现这一目标，提出了若干主要目标： 也就是说，为了确定是否超级基金毒物激活蛋白激酶， C可以被预测为潜在的肿瘤促进剂;评估其能力， 各种类型的补救/生物补救技术，以消除或 增强毒物混合物的毒性， 调节GJIC的能力;并了解混合物的机制 这些化学物质的差异可能激活PKC第二信使， 不同细胞株GJIC活性差异。 这个子项目已经发展，基于几个人的发展， 和啮齿动物体外模型，以检测阻断GJIC的化学物质， 在分子/生物化学的机制理解的进展， 哪些化学物质调节GJIC，到了它将直接测试 各种修复项目的化学品。 其主要目标是 为Masten博士的补救研究提供直接反馈， 可以改善补救条件的改变。 的 第二个目标是开始研究混合物的机制， 有毒物质，在补救工作之前和之后， 相加地、协同地或拮抗地。