Project 3: PCBs and Cytosolic Phenol and Steroid Sulfotransferases

项目总结 多氯联苯继续存在于我们的环境中，并与多种威胁有关 人类健康。最近最令人关注的是户外和室内挥发性多氯联苯持续污染 由于它们存在于较老的建筑(如公立学校)、靠近遗留污染的地点而产生的室内空气 多氯联苯，并由于目前这些试剂的不经意的工业生产。数量较少的多氯联苯 氯原子更易挥发，也更容易代谢。这种新陈代谢可能会导致 解毒解毒或产生更有毒的代谢物项目3的重点是羟基的相互作用。 来自含有哺乳动物胞浆磺基转移酶的多氯联苯的代谢物。羟基多氯联苯(OH- 多氯联苯)可用作硫酸盐催化的硫化反应的底物或生理活性物质的抑制剂 这些酶催化的硫酸盐化反应。项目3的长期目标是了解 人体硫磺与空气中较低氯化多氯联苯毒性反应之间的关系。一个 即将到来的项目期的中心假设是，硫磺能催化羟基化的硫化反应。 在空气样本中发现的主要低氯化多氯联苯的代谢物，以及由此产生的多氯联苯硫酸盐具有 生物效应，包括通过血清蛋白转运到相关组织和甲状腺的改变 激素浓度和/或类固醇激素硫酸盐化。我们已经确定较低的氯化多氯联苯 硫酸盐是甲状腺激素结合部位的高亲和力配体。之前的研究也表明 羟基多氯联苯可以抑制或作为hSULT2A1和hSULT1E1的底物，这两种酶起作用 通过硫酸盐化使类固醇激素失活。在即将到来的项目期间，我们将：1)确定 生理类固醇硫酸盐化关键酶的特异性及其相互作用 用空气样品中最常检测到的多氯联苯的羟基-多氯联苯和多氯联苯硫酸盐代谢物，2)确定 多氯联苯硫酸盐与血清甲状腺激素转运蛋白的结合亲和力，评估 改变甲状腺激素浓度，并确定多氯联苯硫酸盐在相关组织中的分布， 以及3)评估在人类中代谢产生多氯联苯硫酸盐的酶的潜力，并将其与 人血清和尿样中硫化多氯联苯代谢物的浓度。我们相信，拟议的 研究具有很高的创新性，因为多氯联苯的硫酸盐代谢物一直被忽视 这些环境污染物的代谢物。此外，其中一些印刷电路板的高亲和力 血清蛋白上甲状腺激素结合部位的硫酸盐可能有助于转运到组织中，随后 毒理作用。该项目的拟议研究与多个项目和核心具有高度的互动性 爱荷华州超级基金研究计划，即将公布的结果将产生新的见解， 在实现与评估和确定风险优先顺序有关的全中心目标方面很重要 空气中的多氯联苯。

PROJECT SUMMARY Polychlorinated biphenyls (PCBs) continue to persist in our environment and are linked to multiple threats to human health. Of most recent concern is the ongoing contamination by volatile PCBs in both outdoor and indoor air as a result of their presence in older buildings (e.g., public schools), at sites near legacy pollution with PCBs, and due to current inadvertent industrial production of these agents. PCBs with lower numbers of chlorine atoms are more volatile and are also more readily metabolized. Such metabolism may result in either detoxication or creation of more toxic metabolites. Project 3 is focused on the interactions of hydroxylated metabolites derived from PCBs with mammalian cytosolic sulfotransferases (SULTs). Hydroxylated PCBs (OH- PCBs) may serve as either substrates for sulfation catalyzed by SULTs or inhibitors of the physiological sulfation reactions that these enzymes catalyze. The long term goal of Project 3 is to understand the relationships between human SULTs and toxic responses to the lower chlorinated PCBs present in air. A central hypothesis for the upcoming project period is that SULTs catalyze the sulfation of hydroxylated metabolites of the major lower chlorinated PCBs found in air samples, and that the resulting PCB sulfates have biological effects that include transport to relevant tissues via serum proteins and alterations in thyroid hormone concentrations and/or steroid hormone sulfation. We have determined that lower chlorinated PCB sulfates are high affinity ligands for the thyroxine-binding site on transthyretin. Previous studies also indicate that OH-PCBs can either inhibit or serve as substrates for hSULT2A1 and hSULT1E1, enzymes that function to inactivate steroid hormones via sulfation. During the upcoming project period we will: 1) identify the specificities of key enzymes catalyzing the sulfation of physiological steroids with respect to their interactions with OH-PCB and PCB sulfate metabolites of the most frequently detected PCBs in air samples, 2) determine the binding affinities of PCB sulfates with serum thyroid hormone transport proteins, evaluate the potential for alteration of thyroid hormone concentrations, and determine the distribution of PCB sulfates to relevant tissues, and 3) evaluate the enzymatic potential for metabolic generation of PCB sulfates in humans and relate this to concentrations of sulfated PCB metabolites in human serum and urine samples. We believe that the proposed studies are highly innovative due to the fact that the sulfated metabolites of PCBs have been an overlooked class of metabolites of these environmental contaminants. Moreover, high affinity of some of these PCB sulfates for thyroxine-binding sites on serum proteins may facilitate transport to tissues with subsequent toxicological effects. The proposed research in this project is highly interactive with multiple projects and cores of the Iowa Superfund Research Program, and the results to be forthcoming will yield new insights that will be important in achieving the center-wide goals relating to evaluation and prioritization of risks associated with airborne PCBs.