EFFECTS OF PRIOR OR CONCURRENT DIELDRIN EXPOSURE ON TISSUE ATRAZINE METABOLISM

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。阿特拉津是美国广泛使用的除草剂之一，它会对人体各器官系统产生有害影响。然而，为了确定这些研究与人类健康的相关性，需要进行组织剂量学和药代动力学研究。此外，阿特拉津代谢在很大程度上依赖于细胞色素P450 （CYP）单加氧酶的活性。某些现已被禁止，但仍广泛存在于环境中的农药，如杀虫剂狄氏剂，就是已知的CYP诱导剂。狄氏剂的持续使用和阿特拉津的大量使用增加了同时接触这两种农药的可能性。现有的分析生物基质中莠去津的方法存在各种缺陷。我们最近开发了一种LC-MS方法来分析小鼠血浆和尿液中的阿特拉津及其所有主要哺乳动物代谢物。在本项目中，我们将优化该方法用于测定靶组织中阿特拉津及其代谢物，并利用它来确定先前或同时接触狄氏剂对阿特拉津组织配置和药代动力学的影响。我们的长期目标是更好地了解当生物体暴露于农药混合物中时，与环境相关的农药的药代动力学和组织分布是如何变化的。更具体地说，我们将确定先前/持续接触狄氏剂是否会改变阿特拉津的药代动力学。这项研究完成后，不仅可以描述狄氏剂暴露对阿特拉津药代动力学的影响，还可以强调农药相互作用在风险评估中的重要性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Exposure to atrazine, one of the widely used herbicides in the United States, has been associated with deleterious effects on various organ systems. However, in order to establish the human health relevancy of these studies, tissue dosimetry and pharmacokinetics studies are needed. In addition, atrazine metabolism is dependent in large measure upon the activities of cytochrome P450 (CYP) mono-oxygenases. Certain pesticides that are now banned, but still widely present in the environment, such as the insecticide dieldrin, are known CYP inducers. The persistence of dieldrin and the high use of atrazine, increase the likelihood of exposure to these two pesticides in combination. Existing analytical methods to analyze atrazine in biological matrices have various drawbacks. We have recently developed an LC-MS method to analyze atrazine and all of its major mammalian metabolites in mouse plasma and urine. In this project, we will optimize this method for determination of atrazine and its metabolites in target tissues and then use it to determine how atrazine¿s tissue disposition and pharmacokinetics are influenced by prior or concurrent dieldrin exposure. Our long-term goal is to understand better how the pharmacokinetics and tissue distribution of environmentally-relevant pesticides changes when organisms are exposed to pesticide mixtures. More specifically, we will determine whether prior/ongoing exposure to dieldrin will alter atrazine¿s pharmacokinetics. When completed, this research is expected to not only delineate the effects of dieldrin exposure on the pharmacokinetics of atrazine, but to also underscore the importance of pesticide interaction in risk assessment.