Validation of Human Vaginal Tissue Assay for Endocrine Disruptors

描述（由申请人提供）：环境或职业暴露于多种化学物质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方法来鉴定ED是一个非常重要的领域。本研究项目将验证一个外阴组织模型，用于一级筛选具有内分泌干扰潜力的化学物质。I期研究将验证MatTek的器官型阴道-外宫颈（EpiVaginalTM）组织模型用于识别ED。将从修订后的ICCVAM推荐物质清单中选择75种已知ED活性的模型化合物。组织模型产生的雌酮以及组织形态和基因表达的变化将作为ED的生物标志物进行监测。ED的预测模型将最终确定，测试方法将在多中心GLP研究中进行正式验证。此外，将研究测定方法的可重复性和该方法对高通量筛选格式的适应性。如果成功，所提出的方法将对环境化学品安全计划产生重大影响，并最终减少这些化学品对人类健康的影响。

DESCRIPTION (provided by applicant): Environmental or occupational 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 validate an organotypic EpiVaginal tissue model for Tier 1 screening of chemicals with endocrine disrupting potential. Phase I research will validate MatTek's organotypic vaginal-ectocervical (EpiVaginalTM) tissue model for use in identifying ED. A battery of 75 model compounds with known ED activity will be selected from the revised ICCVAM list of recommended substances. The production of estrone by the tissue model and changes to tissue morphology and gene expression will be monitored as biomarkers of ED. A prediction model for ED with be finalized and the test method will undergo formal validation in a multi-center, GLP study. In addition, reproducibility of the assay method and adaptation of the method to a high throughput screen format will be investigated. If successful, the proposed method will have high impact in environmental chemical safety programs and ultimately will reduce the effect of these chemicals on human health. PUBLIC HEALTH RELEVANCE: Validation an in vitro organotypic tissue based assay to screen for endocrine disrupting potential is important to minimize hazards to humans and wildlife exposed to chemicals that interfere with normal hormonal regulation. The assay method will be adapted to a high throughput format to allow rapid and low- cost screening of chemicals. The organotypic tissue based in vitro screening method will have enormous environmental and public health significance.