EVALUATION OF SUPERFUND CHEMICALS AS EPIGENETIC TOXICANTS

化学物质可以引起毒性的机制，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，(表观发生)。由于许多重要的环境问题 毒物没有致突变性(遗传毒性)，重要的是检测 开发并表征了可以检测这类毒物的仪器。 到目前为止，已经设计了几种啮齿动物和人类体外试验来 检测调节细胞间缝隙连接的化学物质 通信(GJIC)。 这些阻止GJIC的化学物质已经在体内被证明存在于许多 包括人类在内的生物体是致畸物质、肿瘤促进剂、 生殖和神经毒物。这个项目的目标是 综合三个学科：生物化学、分子/细胞生物学和 环境工程学确定修复是否有几个等级 环境毒物(多氯联苯、六六六、多环芳烃)混合物的减少 母体混合物的毒性或实际上增强了 毒物。为了实现这一目标，提出了几个主要目标： 也就是说，为了确定超级基金毒物是否激活了蛋白激酶 C可以被预测为潜在的肿瘤促进剂；评估 各种类型的修复/生物修复技术以去除或 提高混合毒物的毒性，通过它们的 能够调节GJIC；并理解混合物的机制 这些化学物质可能以不同的方式激活PKC第二信使 系统，并在不同的细胞株中影响GJIC。 这个子项目是在几个人类发展的基础上发展起来的 和啮齿动物的体外模型，以检测阻断GJIC等的化学物质 分子/生化机制的研究进展 哪些化学物质调制了GJIC，以至于它将直接测试 来自各种补救项目的化学品。它的主要目标将是 向Masten博士的补救研究提供直接反馈，以便 可以改进对补救条件的修改。这个 第二个目标是开始研究混合物的作用机制 在补救措施前后，毒物可能会相互作用。 相加的、协同的或对抗的。

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.