Effects of Endocrine Disrupting Chemicals on Thyroid Hormone Binding

一些外源性内分泌干扰化学物质，如多氯联苯、二苯并对二恶英及其羟基化化合物，可以影响哺乳动物的甲状腺系统。然而，与其他脊椎动物相比，这些化学物质与甲状腺转甲素结合的影响在大型动物中要小一些，因为甲状腺激素结合蛋白——甲状腺转甲素对上述化学物质有很高的亲和力，是啮齿动物、鸟类、两栖动物和鱼类血浆中甲状腺激素结合活性的主要原因。在本研究中，我们研究了几种化学物质与两栖动物和鸟类甲状腺转运蛋白和甲状腺受体的相互作用。纯化的转甲状腺素与[^<125>I]-3,3,5'-三碘甲状腺原氨酸（T_3）在工业、医疗或农业化学品存在下孵育。为了阐明化学物质与甲状腺素相互作用的模式，用Scatchard图确定了表观解离常数和最大结合能力。[^<125>I]还研究了在不同浓度的某些化学物质存在下红细胞对T_3的摄取。合成雌激素己烯雌酚（diethylstilbestrol）取代甲状腺转甲状腺素（transthyretin）中的T_3的效力是T_3的2-50倍。农用化学品ioxynil和五氯酚也是[^<125 bb0 I]T3与甲状腺素结合的显著抑制剂。Scatchatd分析表明，这些化学物质的结合模式是竞争性的。有趣的是，在10^<-9>到10^<-6> m时，杀鼠剂三敌醇激活了[^<125>I]T_3与牛蛙转甲状腺素结合的2倍，[^<125>I]T_3与鸡转甲状腺素的结合受到大多数化学物质的深刻影响，而牛蛙转甲状腺素是T_3的强载体。然而，甲状腺受体对这些化学物质的亲和力非常弱或很少。总之，促甲状腺素以一种特定的方式识别几种内分泌干扰化学物质。一些雌激素化学物质与转甲状腺素的结合不仅可以调节它们进入细胞的途径，还可以改变细胞外T_3 Less的自由浓度

It is well established that some exogenous endocrine disrupting chemicals, polyhalogenated aromatic hydrocarbons such as polychlorinated biphenyls, dibenzo-p-dioxins and their hydroxylated compounds, can affect a mammalian thyroid system. However, the impact of the chemicals' binding to transthyretin is lower in large eutherians than in other vertebrates, because a thyroid-hormone-binding protein, tranthyretin, which has an high affinity for the above chemicals, is responsible for major thyroid hormone-binding activity in plasma of rodents, birds, amphibians and fish. In the present study, we have investigated the interactions of several classes of chemicals with amphibian and avian transthyretins and thyroid receptors. Purified transthyretins were incubated with [^<125>I]-3,3,5'-triiodothyronine (T_3) in the presence of either an industrial, a medical or an agricultural chemical. To clarify the mode of interaction of the chemicals with transthyretins, apparent dissociation constants a … More nd maximum binding capacities were determined by Scatchard plots. [^<125>I]T_3 uptake into red blood cells was also investigated in the presence of various concentrations of some chemicals. A synthetic estrogen, diethylstilbestrol, was 2-50 times more potent than T_3 to displace [^<125>I]T_3 from transthyretin. Agricultural chemicals, ioxynil and pentachlorophenol, were also significant inhibitors on [^<125>I]T3 binding to transthyretins. Scatchatd analyzes indicated that the binding mode of these chemicals was competitive. Interestingly, a miticide dicofol activated [^<125>I]T_3 binding to bullfrog transthyretin up to 2-fold at 10^<-9> to 10^<-6> M. [^<125>I]T_3 binding to chicken transthyretin was profoundly affected by most chemicals investigated here, compared with bullfrog transthyretin which is strong T_3 carrier. However, thyroid receptors showed very weakly or little affinity forthese chemicals. In conclusion, transthyretins recognized several endocrine disrupting chemicals in a species-specific manner. The binding of some estrogenic chemicals to transthyretin may modulate not only their access to the cells but also change the free concentration of extracellular T_3 Less