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，这增加了每天接触含有TCC的个人护理产品可能对人类产生或已经产生不良健康影响的可能性。体外研究和体内初步研究表明，TCC可增强雄性大鼠血中睾酮的生物学效应，改变包括前列腺在内的附性器官的形态。对大鼠体内不良影响的发现表明了对人类健康特定不利影响的可能性，并为未来基于人群的、可能进行的临床研究提供了令人信服的论据。然而，在这类研究之前，还需要更多的体内和体外研究来提供基本信息。本提案将解决两个具体目标，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(S)在人类细胞系中进行探索，而其致瘤潜力将使用定义明确的细胞系和免疫缺陷的小鼠动物模型进行评估。使用人前列腺细胞系进行的体外研究将在细胞内水平更好地确定TCC的作用机制(S)。第一个具体目标是研究TCC如何刺激前列腺上皮细胞的增殖和前列腺特异性蛋白的分泌。第二个特定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共激活因子。从这些拟议研究中获得的预期结果将为未来的研究人员提供研究TCC的基本信息和方法，并提供对TCC和与前列腺疾病相关的化合物暴露的潜在健康风险的洞察。这些研究将提供有关TCC对人类前列腺功能和发育的影响和作用方式的第一个深入数据。 公共卫生相关性：最近发现三氯卡班(TCC)具有新的内分泌干扰物(ED)特性，这增加了这样一种可能性，即日常接触含有TCC的个人护理产品可能会或已经对人类产生广泛的不良健康影响。动物研究表明，TCC的毒性作用会使前列腺增大，对人类前列腺也有类似的不良影响。拟议的研究将提供信息，并指导今后的以人口为基础的或临床研究，以调查暴露在家用产品和环境中的三氯甲烷和相关化合物的健康风险。

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.