Validation of Organotypic Vaginal Tissue Based Assay for Endocrine Disruptors

基于器官型阴道组织的内分泌干扰物测定的验证

• 批准号: 7270190
• 负责人: Seyoum Ayehunie
• 金额: $ 21.18万
• 依托单位: MATTEK CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270190
• 关键词: Adrenocortical carcinoma; Advisory Committees; Affect; Agonist; Agriculture; Androgens; Animal Model; Animal Testing; Animals; Anus; Area; Aromatase; Aromatase Inhibition; Biological Assay; Brain; CYP19A1 gene; Cell Line; Cells; Chemical Agents; Chemicals; Class; Cultured Cells; Data; Development; Dinitrobenzenes; Disruption; Drug Formulations; Drug Industry; Economics; Educational process of instructing; Embryo; End Point; Endocrine; Endocrine Disruptors; Endocrine disruption; Endocrine system; Environmental Health; Environmental Pollution; Epithelial; Epithelial Cell Proliferation; Estrogen Receptors; Estrogens; Ethical Issues; Evaluation; Evolution; Experimental Designs; Experimental Models; Exposure to; Fetal Development; Fluorescence Polarization; Food Processing; Gene Expression; Goals; Growth; Health; Hormonal; Hormone Receptor; Human; Immune system; In Vitro; Industry; Laboratories; Lead; Ligands; MCF7 cell; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Methods; Modeling; Monitor; Numbers; Operative Surgical Procedures; Paper; Pesticides; Phase; Phytoestrogens; Progesterone Receptors; Public Health; Reproducibility; Reproduction; Research; Research Project Grants; Risk Assessment; Rodent; Screening procedure; Sensitivity and Specificity; Signal Transduction; Stratification; Structure; System; Testing; Thick; Thyroid Gland; Tissue Model; Tissues; Toxic effect; Transformed Cell Line; United States Environmental Protection Agency; Uterus; Vagina; Validation; Women' s Health; base; carcinogenesis; cell growth; cost; enzyme activity; estrogenic activity; hazard; hormone regulation; human tissue; in vitro Assay; in vitro Model; in vivo; keratinization; monolayer; neoplastic cell; receptor; receptor binding; receptor expression; reproductive; response; species difference; validation studies

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.

描述（由申请人提供）：环境或故意暴露于各种化学制剂可改变正常的内分泌功能。这些“内分泌干扰物”（艾德）的影响可能对健康产生严重影响，包括对生殖能力、胎儿发育、免疫系统和致癌作用的有害影响。目前的动物试验价格昂贵，使用大量动物，不一定适用于人类。因此，鉴定艾德的经验证的人体外方法是非常重要的领域。本研究项目将开发这样的测试方法。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（艾德）。将使用一组具有已知艾德活性的25种模型化合物。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。这些数据将用于开发预测模型，该模型将是艾德潜力的敏感和特异性预测因子。在第II阶段，将在多中心GLP研究中对试验方法进行正式确认。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测试将具有巨大的环境和公共卫生意义。对内分泌干扰物的评估对于尽量减少暴露于干扰正常激素调节的化学品的人类和野生动物的危害非常重要。提出的基于人体器官型组织的检测方法将提供一种灵敏和特异的检测方法，以较低的成本筛选大量的内分泌干扰物。