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: 6296560
• 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/6296560
• 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.

化学品引起毒性的机制，例如 致畸、致癌、生殖和神经毒性，包括 诱变（基因毒性）、细胞杀伤（细胞毒性）和/或改变 基因表达（表观发生）。 由于许多重要的环境 有毒物质不具有致突变性（基因毒性），因此重要的是进行检测 开发并表征了可以检测此类毒物的方法。 迄今为止，已经设计了几种啮齿动物和人类体外试验 检测调节细胞间隙连接的化学物质 通信（GJIC）。 这些阻断 GJIC 的化学物质已在体内的许多实验中得到证实。 生物体，包括人类，成为致畸剂、肿瘤促进剂， 生殖毒物和神经毒物。 该项目的目标是 整合三个学科：生物化学、分子/细胞生物学和 环境工程确定是否修复几类 环境毒物混合物（PCB、HAH、PAH）减少 母体混合物的毒性或实际上增强了 毒性。 为了实现这一目标，提出了几个主要目标： 即确定 Superfund 是否存在激活蛋白激酶的毒物 C可预测为潜在的肿瘤促进剂；评估能力 各种类型的修复/生物修复技术来去除或 增强有毒物质混合物的毒性（通过其测量） 调节 GJIC 的能力；并了解混合物的机制 这些化学物质可能会差异性地激活 PKC 第二信使 系统并影响不同细胞株中的 GJIC。 这个子项目是在几个人类的发展的基础上发展起来的 和啮齿动物体外模型，检测阻断 GJIC 的化学物质并 对机制的分子/生化理解的进展 哪些化学物质会调节 GJIC，以达到直接测试的程度 来自各种修复项目的化学品。 其主要目标是 向 Masten 博士的补救研究提供直接反馈，以便 修改修复条件可以得到改善。 这 第二个目标是开始研究混合物的机制 补救措施之前和之后的有毒物质可能会相互作用 加和地、协同地或拮抗地。