Project 3: PCBs and Cytosolic Phenol and Steroid Sulfotransferases

项目摘要 多氯联苯（PCB）继续存在于我们的环境中，并与多种威胁有关， 人体健康最近最令人关注的是，在室外和室外环境中， 由于它们存在于较旧的建筑物中而导致的室内空气（例如，公立学校），在遗留污染附近的地点 与多氯联苯，并由于目前无意中工业生产这些代理。低含量的多氯联苯 氯原子更易挥发，也更容易代谢。这种代谢可能导致 解毒或产生毒性更大的代谢物。项目3的重点是羟基化的 哺乳动物细胞溶质磺基转移酶（SULT）从多氯联苯衍生的代谢物。羟基化多氯联苯（OH- 多氯联苯（PCBs）可作为SULT催化的硫酸化作用的底物或生理活性的抑制剂。 这些酶催化的硫酸化反应。项目3的长期目标是了解 人类SULT与对空气中低氯化多氯联苯的毒性反应之间的关系。一 即将到来的项目期间的中心假设是，SULT催化羟基化的硫酸化， 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， 生物学效应，包括通过血清蛋白转运至相关组织和甲状腺功能改变， 激素浓度和/或类固醇激素硫酸化。我们已经确定低氯化PCB 硫酸盐是甲状腺素运载蛋白上甲状腺素结合位点的高亲和性配体。先前的研究还表明， OH-PCB可以抑制或作为hSULT2A1和hSULT1E1的底物， 通过硫酸化作用释放类固醇激素。在即将到来的项目期间，我们将：1）确定 催化生理甾体硫酸化的关键酶的相互作用的特异性 用OH-PCB和PCB硫酸盐代谢物对空气样品中最常检测到的PCB进行测定，2） PCB硫酸盐与血清甲状腺激素转运蛋白的结合亲和力，评估 甲状腺激素浓度的改变，并确定多氯联苯硫酸盐在相关组织中的分布， 和3）评估人体内多氯联苯硫酸盐代谢产生的酶促潜力，并将其与 人类血清和尿液样本中硫酸化多氯联苯代谢物的浓度。我们相信建议的 研究是高度创新的，因为事实上，多氯联苯的硫酸化代谢物一直被忽视， 这些环境污染物的代谢物的类别。此外，这些PCB中的一些的高亲和力 血清蛋白上甲状腺素结合位点的硫酸盐可能有助于运输到组织， 毒理学效应本项目拟开展的研究具有多项目、多核心的高度互动性 爱荷华州超级基金研究计划，即将到来的结果将产生新的见解， 重要的是实现与评估和优先考虑与以下方面有关的风险有关的全中心目标： 空气中的PCB

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.