Validation of Organotypic Vaginal Tissue Based Assay for Endocrine Disruptors

描述(由申请人提供)：环境或故意暴露在多种化学制剂中会改变正常的内分泌功能。这些“内分泌干扰物”(ED)的影响可能会对健康产生严重影响，包括对生殖能力、胎儿发育、免疫系统和致癌的有害影响。目前的动物试验费用昂贵，使用大量动物，而且不一定适用于人类。因此，一种有效的、人类体外鉴定ED的方法是一个非常重要的领域。本研究项目将开发这样一种测试方法。第一阶段研究将预先验证Mattek的器官型阴道-宫颈外(VEC-FT)组织模型用于识别内分泌干扰物(ED)。将使用由25种已知ED活性的模型化合物组成的电池。将监测关键激素受体、酶活性、组织结构、增殖和基因表达的变化。这些数据将被用来开发一个预测模型，该模型将成为ED潜力的一个敏感和特异的预测因子。在第二阶段，该测试方法将在多中心的GLP研究中接受正式验证。为评估化学品/制剂的内分泌干扰潜力而开发的预先验证的体外试验将具有巨大的环境和公共卫生意义。评估内分泌干扰物对于将对人类和野生动物暴露在干扰正常荷尔蒙调节的化学物质中的危害降至最低非常重要。提出的基于人体器官组织的检测方法将提供一种灵敏和特异的检测方法，以降低成本筛选大量的内分泌干扰物。

DESCRIPTION (provided by applicant): Environmental or intentional exposure to a broad variety of chemical agents can alter normal endocrine function. The effects of these "endocrine disruptors" (ED) can have serious health implications including deleterious effects to reproductive capacity, fetal development, the immune system, and carcinogenesis. Current animal tests are expensive, use a large number of animals, and are not necessarily applicable to humans. Thus, a validated, human in vitro method to identify ED is an area of great importance. This research project will develop such a test method. Phase I research will prevalidate MatTek's organotypic vaginal- ectocervical (VEC-FT) tissue model for use in identifying endocrine disruptors (ED). A battery of 25 model compounds with known ED activity will be used. Changes to key hormonal receptors, enzyme activity, tissue structure, proliferation, and gene expression will be monitored. These data will be used to develop a prediction model that will be a sensitive and specific predictor of ED potential. During Phase II, the test method will undergo formal validation in a multi-center, GLP study. The prevalidated in vitro test to be developed for assessing the endocrine disrupting potential of chemicals/ formulations will have enormous environmental and public health significance. Evaluation of endocrine disruptors is important to minimize hazards to humans and wildlife exposed to chemicals that interfere with normal hormonal regulation. The proposed human organotypic tissue based assay will provide a sensitive and specific assay method to screen a large number of endocrine disrupting chemicals at a reduced cost.