Exploration of the endocrine disrupting effects of triclocarban

描述（由申请人提供）：最近发现三氯卡班（TCC）具有新的内分泌干扰物（ED）特性，这提高了每天接触含有TCC的个人护理产品可能对人类健康产生或可能已经产生不良影响的可能性。体外研究和体内初步研究表明，TCC可以增强循环睾酮的生物学效应，改变雄性大鼠副性器官（包括前列腺）的形态。在大鼠体内发现的不利影响表明了对人类健康产生特定不利影响的可能性，并为未来进行基于人群的研究和可能的临床研究提供了令人信服的论据。然而，在进行此类研究之前，还需要进行额外的体内和体外研究来提供基本信息。目前的提案将解决两个特定的目标，每个目标都有体外和/或体内研究的假设驱动。TCC的潜在作用机制将在人类细胞系中进行研究，而其致瘤潜力将在定义明确的细胞系和免疫缺陷小鼠动物模型中进行评估。利用人前列腺细胞系进行的体外研究将更好地确定TCC在细胞内水平的作用机制。第一个具体目的是研究TCC如何刺激前列腺上皮细胞的细胞增殖和前列腺特异性蛋白的分泌。第二个具体目标将描述雄激素受体（AR）的表达、稳定性和易位的变化，并将研究关键的AR共激活物。从这些拟议的研究中获得的预期结果将为未来的研究人员提供调查TCC的基本信息和方法，并为暴露于TCC及其相关化合物对前列腺疾病的潜在健康风险提供见解。这些研究将首次提供关于TCC对人类前列腺功能和发育的影响和作用方式的深入数据。

DESCRIPTION (provided by applicant): The recent finding that triclocarban (TCC) has novel endocrine disruptor (ED) properties raises the possibility that daily exposures to personal care products containing TCC could have, or may have already had, adverse health effects in humans. In vitro studies as well as preliminary in vivo studies demonstrate that TCC can act to augment the biological effect of circulating testosterone and change the morphology of accessory sex organs in male rats including the prostate gland. The probability of specific adverse human health effects are indicated by the finding of in vivo adverse effects in rats and provide a compelling argument for future population-based and possibly clinical studies to be conducted. Prior to such studies, however, additional in vivo and in vitro studies are needed to provide basic information. The present proposal will address two specific aims, each with hypothesis driven in vitro and/or in vivo studies. TCC's potential mechanism(s) of action is pursued with human cell lines while its tumorigenic potential will be evaluated using well-defined cell lines and an immunodeficient mouse animal model. In vitro studies using human prostate cell lines will better define the mechanism(s) of action of TCC at the intracellular level. The first specific aim will investigate how TCC stimulates cell proliferation and the secretion of prostate specific protein in prostate epithelial cells. The second specific aim will characterize the change in expression, stability and translocation of the androgen receptor (AR) and will investigate key AR co-activators. The expected results obtained from these proposed studies will provide future investigators with both the basic information and methodologies to investigate TCC and provide insight into the potential health risks from exposures to TCC and related compounds on prostate disease. These studies will provide the first in depth data regarding the effect and mode of action of TCC on human prostate function and development. PUBLIC HEALTH RELEVANCE: The recent finding that triclocarban (TCC) has novel endocrine disruptor (ED) properties raises the possibility that daily exposures to personal care products containing TCC could have, or may have already had, a wide range of adverse health effects in humans. Animal studies indicate the prostate gland is enlarged by TCC's toxic effects and suggests a similar adverse effect on the human prostate. The proposed studies will provide information and guide future population-based or clinical studies to investigate the health risks from exposures to TCC and related compounds in both household products and the environment.