Airborne PCBs and their Metabolites: Risk Factors for Adverse Neurodevelopmental Outcomes in Adolescence

项目总结：项目1 -神经毒性 爱荷华州超级基金研究计划的研究表明，吸入室内空气，特别是在美国， 多氯联苯（PCBs）污染的学校，代表了美国目前的公共卫生问题。 青少年。虽然青少年的大脑容易受到多氯联苯及其代谢物的毒性， 关于空气中多氯联苯的人体代谢物的神经毒性-这些代谢物与空气中形成的代谢物明显不同， 啮齿类动物-目前没有。因此，迫切需要：（1）建立机制， PCB的人类代谢物影响神经化学（即，毒性神经递质代谢物）和随后的 行为结果; 2）确定空气中多氯联苯及其代谢物在大脑中的代谢方式 是暴露于多氯联苯的青少年中多氯联苯介导的神经毒性的关键事件。的目的 该项目是通过定义存在于环境中的神经毒性PCB代谢物之间的联系，为未来的风险评估提供信息。 青春期接触后的大脑和神经毒性结果。我们的核心假设是， 除了母体空气中的多氯联苯外，人体内形成的代谢物也存在于大脑中， 在青春期改变神经发育的因素。我们建议，多氯联苯，特别是其 代谢物，不利地影响神经递质稳态。这一假设是基于初步研究 表明空气中的多氯联苯代谢物：a）存在于啮齿动物的大脑中; B）在体外引起氧化应激 c）改变培养的多巴胺能神经元中的神经递质稳态，产生ROS和毒性 儿茶酚醛;和d）在脑中进一步代谢成潜在的毒性代谢物。指导 根据这些初步数据，新的假设将通过以下方式进行检验：1）识别蜂窝站点和空中目标 多氯联苯代谢物与体外神经毒性的母体化合物; 2）表征区域- 多氯联苯和多氯联苯代谢物在体外模型和青少年大鼠脑中的特异性生物转化 体内; 3）测定空气中PCBs的人体代谢产物对PCBs生化标志物的影响 大鼠在整个青春期体内暴露的神经毒性和行为结果。拟议研究 是创新性的，因为它确定了PCB代谢物对多巴胺平衡的破坏如何干扰 多巴胺水平和/或产生有毒的多巴胺代谢物，对青春期的大脑有害， 脆弱性;并研究大脑中的局部代谢，从而挑战科学范式， 多氯联苯要么耐代谢，要么只在肝脏中代谢。拟议研究的结果将 阐明空气中的多氯联苯及其代谢物对环境的贡献及其作用机制， 神经毒性反应因此，这项研究的成功完成将通过提供 迫切需要基本的、机械的见解，以推进对接触多氯联苯的人类风险评估， 其最终目标是防止或减轻接触此类超级基金后的不良后果 化学品

PROJECT SUMMARY: Project 1 – Neurotoxicity Studies by the Iowa Superfund Research Program demonstrate that inhalation of indoor air, especially in U.S. schools contaminated with polychlorinated biphenyls (PCBs), represents a current public health concern for U.S. adolescents. Although the adolescent brain is vulnerable to the toxicity of PCBs and their metabolites, information regarding the neurotoxicity of human metabolites of airborne PCBs—which differ significantly from those formed in rodents—is currently not available. There is, therefore, a critical need to: 1) establish mechanisms by which human metabolites of PCBs affect neurochemistry (i.e., toxic neurotransmitter metabolites) and subsequent behavioral outcomes; and 2) determine how metabolism of airborne PCBs and their metabolites in the brain represents a key event in PCB-mediated neurotoxicity in adolescents exposed to PCBs. The objective of this project is to inform future risk assessment by defining the link between neurotoxic PCB metabolites present in the brain and neurotoxic outcomes following exposure during adolescence. Our central hypothesis is that, in addition to the parent airborne PCBs, metabolites formed in humans are present in the brain and serve as risk factors for altered neurodevelopment during adolescence. We propose that PCBs, and especially their metabolites, adversely affect neurotransmitter homeostasis. This hypothesis is based on preliminary studies showing that metabolites of airborne PCBs: a) are present in the rodent brain; b) cause oxidative stress in vitro and in vivo; c) alter neurotransmitter homeostasis in dopaminergic neurons in culture, producing ROS and toxic catecholaldehydes; and d) undergo further metabolism to potentially toxic metabolites in the brain. Guided by these preliminary data, the novel hypothesis will be tested by 1) identifying cellular sites and targets of airborne PCB metabolites vs. parent compounds responsible for neurotoxicity in vitro; 2) characterizing the region- specific biotransformation of PCBs and PCB metabolites with in vitro models and in the adolescent rat brain in vivo; and 3) determining the effects of human metabolites of airborne PCBs on biochemical markers of PCB neurotoxicity and behavioral outcomes in rats exposed throughout adolescence in vivo. The proposed research is innovative because it determines how the disruption of dopamine balance by PCB metabolites disturbs dopamine levels and/or produces toxic dopamine metabolites detrimental to the brain in adolescence, a period of vulnerability; and studies localized metabolism in the brain, thus challenging the scientific paradigm that PCBs are either resistant to metabolism or metabolized only in the liver. Outcomes of the proposed studies will elucidate the contributions of airborne PCBs and their metabolites to, and their mechanisms of action in, neurotoxic responses. Thus, the successful completion of this research will impact public health by providing fundamental, mechanistic insights urgently needed to advance the human risk assessment of exposure to PCBs, with the ultimate goal of preventing or mitigating adverse outcomes following exposure to this class of Superfund chemicals.