PCB IMMUNOTOXICITY

PCB免疫毒性

• 批准号: 3250131
• 负责人: JAY B SILKWORTH
• 金额: $ 6.01万
• 依托单位: NYSDOH/HEALTH RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-05-01 至 1988-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250131
• 关键词: carbopolycyclic compound; cellular immunity; environmental toxicology; enzyme induction /repression; halobiphenyl /halotriphenyl compound; humoral immunity; immune response genes; immunologic assay /test; immunopathology; immunosuppression; immunotoxicity; isozymes; lymphatic tissue; lymphocyte; monoclonal antibody; radiation detector; radiation immunosuppression; radiotracer; spleen transplantation; tissue /cell culture; toxin metabolism

The primary function of the immune system is the recognition and elimination of cellular and noncellular entities which are non-self (bacteria, viruses, protozoa) or altered self (transformed malignant cells) which would otherwise compromise health. It has been established that some environmental contaminants, including the halogenated aromatic hydrocarbons, polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause immune dysfunction, however, the mechanisms are unresolved. Recent progress in this area has demonstrated that the immunotoxicity of TCDD and of certain PCB congeners is mediated through a cytoplasmic/nuclear receptor protein (the aromatic hydrocarbon (Ah) receptor) which binds certain halogenated aromatic hydrocarbons with high affinity. The formation of this ligand-Ah receptor complex leads to the activation of the Ah gene complex and results in the synthesis of a number of proteins, many of which are enzymes such as aryl hydrocarbon hydroxylase (AHH), and several toxic effects including cleft-palate formation, thymic atrophy, and immune dysfunction, but the mechanisms by which activation of this complex results in these effects remains unclear. Since it has been established that the Ah receptor protein is expressed in lymphoid tissue and that Ah receptor ligands can induce lymphoid AHH activity, it is proposed that: 1) lymphoid tissue possesses all the necessary cellular apparatus to be functionally impaired by activation of its Ah gene complex, 2) only specific subpopulations of T and B lymphocytes are sensitive to Ah gene activation, 3) only lymphocytes at certain stages of differentiation are sensitive to Ah gene activation, and 4) that activation of this complex in lymphoid tissue leads to the synthesis of products which directly or indirectly result in impairment of immune function. These hypotheses will be tested using in vivo and in vitro methods of toxicology and immunology to evaluate several parameters of humoral and cellular immunity in mice which are either Ah responsive or nonresponsive and whose lymphoid tissues have been experimentally exchanged or forced to cooperate with those of the opposite Ah genotype. These studies will further elucidate the mechanisms by which halogenated aromatic hydrocarbons interact with mammalian systems and will aid in the human health risk assessments of these pollutants.

免疫系统的主要功能是识别和 消除非自我的细胞和非细胞实体 （细菌，病毒，原生动物）或改变自我（转化的恶性细胞） 否则会危害健康。 据了解，一些 环境污染物，包括卤代芳族化合物 碳氢化合物、多氯联苯和 2，3，7，8-四氯二苯并-对-二恶英（TCDD），引起免疫功能障碍， 然而，机制尚未解决。 最近在这一领域取得的进展 表明TCDD和某些PCB同系物的免疫毒性 是通过细胞质/核受体蛋白（芳香 碳氢化合物（Ah）受体）结合某些卤代芳香族 具有高亲和力的烃。 这种配体-Ah受体的形成 复合物导致Ah基因复合物的激活，并导致 许多蛋白质的合成，其中许多是酶，如芳基 碳氢化合物羟化酶（AHH）和几种毒性作用，包括 腭裂形成，胸腺萎缩和免疫功能障碍，但 激活这种复合物导致这些效应的机制 仍不清楚 由于已经确定Ah受体 蛋白质在淋巴组织中表达，并且Ah受体配体可以 诱导淋巴AHH活性，提出：1）淋巴组织 拥有所有必要的细胞器官， 通过激活其Ah基因复合物，2）仅T细胞的特定亚群 而B淋巴细胞对Ah基因激活敏感; 3）只有淋巴细胞 在某些分化阶段对Ah基因激活敏感， 和4）这种复合物在淋巴组织中的激活导致 直接或间接导致资产减值的产品的综合 免疫功能 这些假设将使用体内和体内 毒理学和免疫学的体外方法，以评价几个参数 的体液和细胞免疫的小鼠，这是Ah反应或 无反应且淋巴组织已被实验性交换 或者被迫与相反的Ah基因型的人合作。 这些 研究将进一步阐明卤代芳族化合物 碳氢化合物与哺乳动物系统相互作用， 这些污染物的健康风险评估。