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。这样的影响是 环境毒理学，但在很大程度上缺乏机械性的理解。了解这些 鉴于CYP在氧化过程中的核心作用，效应需要明确了解所涉及的CYP 外源生物和许多调节分子的生物转化。目前，尚无动物模型可供选择。 对全套CYP基因的发育表达有概括性的看法。双重奏 这项研究的目标是建立正常和化学影响的细胞周期蛋白的全面图像 基因在发育过程中的表达，并确定选定的CYP在发育毒性中的作用 突出的环境化学物质。主要的努力将涉及斑马鱼(Danio Rerio)脊椎动物 模特。初步研究将通过图谱确定斑马鱼Cyp在基因家族1-4中的身份 隐马尔可夫模型和贝叶斯分析。All CYP的表达及其诱导或抑制作用 开发过程中的化学物质，将通过定量聚合酶链式反应和聚焦CYP基因芯片进行检测。 潜在参与CYP诱导的核受体的表达也将被检测。关键点CYP 在发育过程中诱导的，将通过干扰它们的 在化学处理的胚胎中的表达。细胞色素P450-1家族基因(细胞色素P1a、细胞色素P1B1和新基因)的作用 将利用受体基因敲除和 CYP过度表达。这些CYP对氧化应激的贡献，这可能是一条共同的途径 发育毒性，将进行评估。由孕烷x受体(PXR)调节的CyP也将类似 检查过了。对斑马鱼的研究结果的环境相关性将通过研究选定的 来自被高度污染的超级基金网站的鱼类Fundulus Heterocltus的同源基因 多氯联苯。这些研究将进一步探讨CYP的表达变化是否与毒性有关 有助于在这些鱼类中进化出对多氯联苯毒性的抵抗性。这些研究将提供一种独特的 全面观察CYP在斑马鱼发育中的作用，指出可能类似的同源基因 涉及其他脊椎动物物种。这些研究将提供一个持久的基础，对当前和 未来评估细胞色素P对化学物质发育毒性的贡献。

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.