Research Project 6: CYP Genes and Developmental Toxicity

这项持续研究的长期目标是了解细胞色素P450酶在 环境化学品的发育毒性。这些影响是最令人关切的问题之一， 环境毒理学，但机制的理解在很大程度上是缺乏的。了解这些 考虑到α-淀粉酶在氧化过程中的核心作用， 外源性物质和许多调节分子的生物转化。目前，还没有动物模型 其中有一个发育的完整的互补基因的表达的概要视图。双 这项研究的目的是建立一个全面的图片正常和化学影响的肿瘤 发育过程中的基因表达，并确定所选择的抑制剂在发育毒性中的作用 重要的环境化学品。主要的努力将涉及斑马鱼（Danio rerio）脊椎动物 模型初步的研究将建立身份的斑马鱼的基因家族1-4的概况 隐马尔可夫模型和贝叶斯分析。所有的表达和诱导或抑制， 将通过定量PCR和聚焦PCR基因微阵列来确定开发过程中的化学物质。 还将检查可能参与β诱导的核受体的表达。关键字 将检查发育期间诱导的干扰对毒性的贡献， 在化学处理的胚胎中表达。CYP 1A 1家族基因（CYP 1A、CYP 1B 1和新的CYP 1B 1）的作用 CYPlCs）对O？t/jo-多氯联苯将通过受体敲低建立， 过度表达。这些激素对氧化应激的贡献，一种可能的共同途径， 将评估发育毒性。受α-羟色胺X受体（PXR）调节的β-羟色胺将类似地 考察斑马鱼研究结果的环境相关性将通过检查选定的 在鱼类物种中的同源基因，异基底，从超级基金网站高度污染， PCB。这些研究将进一步阐明是否改变了与毒性有关的β-内酰胺酶的表达 有助于这些鱼类进化出对多氯联苯毒性的抗性。这些研究将提供一个独特的 全面了解斑马鱼发育过程中的基因突变，指出可能与斑马鱼相似的同源物。 与其他脊椎动物物种有关。这些研究将为当前和未来的发展提供一个必不可少的持久基础。 今后评估氟氯化碳对化学品发育毒性的影响。

The long-term goal of this continuing research is to understand the role of cytochrome P450 enzymes in developmental toxicity of environmental chemicals. Such effects are among the most significant concerns in environmental toxicology, and yet a mechanistic understanding is largely absent. Understanding these effects requires explicit knowledge of the CYP involved, given the central role of CYP in the oxidative biotransformation of xenobiotics and many regulatory molecules. At present, there is no animal model for which there is a synoptic view of developmental expression of the full complement of CYP genes. The dual goals of this research are to establish a comprehensive picture of normal and chemically impacted CYP gene expression during development, and to determine the roles of selected CYP in developmental toxicity of prominent environmental chemicals. The major effort will involve the zebrafish (Danio rerio) vertebrate model. The initial studies will establish the identities of zebrafish CYP in gene families 1-4 by profile Hidden Markov Models and Bayesian analysis. The expression of all CYP and induction or suppression by chemicals during development, will be determined by quantitative PCR and focused CYP gene microarrays. Expression of nuclear receptors potentially involved in CYP induction also will be examined. Key CYP induced during development will be examined for contribution to toxicity by interfering with their expression in chemically treated embryos. The roles of CYP 1 family genes (CYP1A, CYP1B1, and novel CYPlCs) in toxicity of o?t/jo-polychlorinated biphenyls will be established using receptor knockdown and CYP over-expression. The contribution of these CYP to oxidative stress, a possible common pathway to developmental toxicity, will be assessed. CYP regulated by the pregnane x receptor (PXR) will be similarly examined. The environmental relevance of findings in zebrafish will be tested by examining selected homologous genes in the fish species, Fundulus heteroclitus, from a Superfund site highly contaminated by PCBs. These studies will address further whether altered expression of CYP that are implicated in toxicity contributes to the resistance to PCB toxicity evolved in these fish. The studies will provide a uniquely comprehensive view of CYP in developing zebrafish, pointing to homologues that may be similarly involved in other vertebrate species. The studies will provide a lasting foundation essential to current and future assessment of the contribution of CYP to developmental toxicity of chemicals.