Fetal Endocrine Disruption by Triclosan

说明(申请人提供)：在某种意义上，雌激素是胎儿的一种组织原则，促进分娩准备和新生儿存活。胎盘提供了几乎所有在胎儿血液中循环的雌激素，通过雌激素和相关雌激素的硫酸盐结合物的形式分泌。这些硫酸盐结合物是在胎盘中由雌激素磺基转移酶(SULT1E1)形成的，该酶在胎盘中高度表达。分泌的雌激素硫酸盐结合物在靶组织中通过另一种酶--硫酸酶的作用转化为游离雌二醇和相关雌激素。三氯生是一种抗菌剂，人们通过使用含有三氯生的肥皂、牙膏和其他个人护理产品来接触三氯生，是一种非常有效的SULT1E1抑制剂。尽管许多人同意抑制SULT1E1可能会扰乱雌激素的生物合成或代谢，但到目前为止，还没有人研究过抑制SULT1E1在胎儿中的体内意义。这项建议将使用胎儿在子宫内发育的绵羊模型来检查抑制胎盘SULT1E1的后果。提出了一个具体目标。我们将测试这样一种假设：由于三氯生对SULT1E1的抑制作用，胚胎绵羊暴露于三氯生将降低循环中的雌激素浓度，并具有与降低胎儿雌激素作用一致的基因组作用。方法学将包括对慢性插管胎羊的体内研究，对实验动物对三氯生反应的分子分析，以及对三氯生对血浆和组织分析物浓度影响的体外生化评估。该项目是首次对怀孕动物体内抑制SULT1E1的后果进行研究，使用的动物模型的雌激素生物合成远比啮齿动物物种更接近人类。因此，它将为了解三氯生对妊娠结局和胎儿发育的影响提供一个机制基础，并将为未来的实验提供基础。 公共卫生相关性：这个项目研究了接触三氯生的可能性，三氯生是一种添加到许多个人护理产品中的抗菌剂，它减少了胎儿的雌激素供应，并产生了通过减少雌激素作用而产生的不良影响。

DESCRIPTION (provided by applicant): Estrogen is, in a sense, an organizing principle for the fetus, promoting readiness for birth and neonatal survival. The placenta provides nearly all of the estrogen that circulates in fetal blood, through secretion in the form of sulfate conjugates of estradiol and related estrogens. These sulfate conjugates are formed in the placenta by the enzyme estrogen sulfotransferase (SULT1E1), which is highly expressed in the placenta. The secreted estrogen sulfate conjugates are converted to free estradiol and related estrogens in target tissues through the action of another enzyme, sulfatase. Triclosan, an antibacterial agent to which people are exposed through use of soaps, toothpaste and other personal care products containing Triclosan, is a very potent inhibitor of SULT1E1. Although many agree that inhibiting SULT1E1 is likely to disrupt estrogen biosynthesis or metabolism, to date, no one has examined the in vivo significance of SULT1E1 inhibition in the fetus. This proposal will use the fetal sheep model of in utero fetal development to examine the consequences of inhibiting placental SULT1E1. One specific aim is proposed. We will test the hypothesis that exposure of fetal sheep to Triclosan will, because of its inhibition of SULT1E1, reduce circulating estrogen concentrations and have genomic actions that are consistent with decreased estrogen action in the fetus. Methodology will include studies in vivo in chronically-catheterized fetal sheep, molecular analysis of the responses to Triclosan in the experimental animals, and in vitro biochemical assessment of the effect of Triclosan on plasma and tissue analyte concentrations. This project is the first in vivo study of the consequences of inhibiting SULT1E1 in the pregnant animal, using an animal model whose estrogen biosynthesis is far closer to the human being than rodent species. As such, it will provide a mechanistic basis for understanding disturbances in pregnancy outcome and fetal development after exposure to Triclosan and will provide a foundation for future experiments. PUBLIC HEALTH RELEVANCE: This project examines the possibility that exposure to triclosan, an antibacterial agent added to numerous personal care products, reduces the supply of estrogen to the fetus and has adverse effects that are mediated by reduced estrogen action.