Synergistic Immunosuppression by PAHs and Arsenite

PAH 和亚砷酸盐的协同免疫抑制

• 批准号: 8301069
• 负责人: Scott W Burchiel
• 金额: $ 33.7万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-17 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301069
• 关键词: Age; Air; Animal Model; Antibody Formation; Aromatic Polycyclic Hydrocarbons; Arsenic; Arsenites; Base Excision Repairs; Benzo(a)pyrene; Binding; Biochemical; Biological Models; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Suppression; Bos taurus PARP protein; Breathing; C57BL/6 Mouse; Cells; DNA; DNA Adduction; DNA Adducts; DNA Repair; DNA Repair Inhibition; DNA Repair Pathway; Data; Dependence; Diet; Dose; Eating; Ethnic Origin; Exposure to; Female; Food; Health; Human; Humoral Immunities; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Individual; Individual Differences; Infection; Intervention; Knockout Mice; Lead; Lesion; Lymphoid Cell; Lymphoid Tissue; Malignant Neoplasms; Measures; Mental Depression; Mus; Nucleotide Excision Repair; Oral; Oxidative Stress; Pathway interactions; Peripheral Blood Mononuclear Cell; Population; Property; Protein Inhibition; Proteins; Pyrenes; Role; Signal Transduction; Sodium; Spleen; Stem cells; Supplementation; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Time; XPA gene; Zinc Fingers; adduct; base; drinking water; environmental agent; exposed human population; fighting; genotoxicity; granulocyte; human data; human male; immunosuppressed; immunotoxicity; in vivo; in vivo Model; monocyte; mouse model; sodium arsenite; theories; xeroderma pigmentosum group A complementing protein

DESCRIPTION (provided by applicant): The purpose of these studies is to evaluate the mechanisms of immunosuppression in mice and humans associated with combined exposures to polycyclic aromatic hydrocarbons (PAHs) and sodium arsenite (As+3). Suppression of the immune system is known to be associated with a decreased ability to fight infections and cancer. Preliminary data is presented that mice demonstrate synergistic immunosuppression when exposed to As+3 and PAHs in vivo through their food and drinking water. We also present preliminary data demonstrating that human peripheral blood mononuclear cells (HPBMC) are immunosuppressed at environmentally relevant levels of sodium As+3 found in drinking water. PAHs were found to increase the amount of As+3 induced immune suppression as well. Therefore, it is important to understand the mechanism(s) of immunosuppression produced by these agents when exposures occur alone or in combination. The central hypothesis to be tested in this application is that PAHs and As+3 produce synergistic immunosuppression through DNA- damaging and repair pathways. It is important to develop animal models to study synergistic immunosuppression and to pursue mechanistic studies of relevance to human exposures. These studies will determine whether co-exposures from As+3 in drinking water and PAHs in the diet (which are present in the air we breathe and the food we eat) in mouse models result in greater suppression than has previously been found for either class of agents on their own. We will determine the biochemical mechanisms potentially responsible for these interactions, and we will determine whether Zn+2 present in drinking water can protect mice from As+3 exposures. Finally, because we found that human blood T lymphocytes are extremely sensitive to low concentrations of As+3 that are present in drinking water in many populations in the U.S. and elsewhere in the world, we will determine the sensitivities of various humans (males and females of different ages and ethnicities) to these exposures. We will obtain peripheral blood cells from these individuals to determine whether their immune response are suppressed by As+3 and PAH given in vitro alone or in combination. The results of these studies will make an important contribution to understanding environmental agents that modulate the human immune system and perhaps provide an approach to intervention for As+3 drinking water exposures. PUBLIC HEALTH RELEVANCE: The purpose of these studies is to evaluate the mechanisms of immunosuppression in mice and humans associated with combined exposures to polycyclic aromatic hydrocarbons (PAHs) and sodium arsenite (As+3). Suppression of the immune system is known to be associated with a decreased ability to fight infections and cancer. Preliminary data is presented that mice demonstrate synergistic immunosuppression when exposed to As+3 and PAHs in vivo. We also present preliminary data demonstrating that human peripheral blood mononuclear cells (HPBMC) are extremely sensitive to T cell immunosuppression by environmentally relevant levels of exposure to sodium As+3 and that PAHs interact significantly with As+3 as well. Therefore, it is important to understand the mechanism(s) of immunosuppression produced by these agents when exposures occur alone or in combination. The central hypothesis to be tested in this application is that PAHs and As+3 produce synergistic immunosuppression through genotoxic pathways resulting from DNA adduct formation and inhibition of DNA repair. It is important to develop in vivo models to study synergistic immunosuppression and to pursue mechanistic studies of relevance to human exposures. In SA1 we will utilize our established mouse model for studies of the combined effects of PAHs, on the T-dependent antibody response (TDAR) in murine spleen and pre-B and granulocyte/monocyte (GM) progenitor cell activity of bone marrow (BM) cells. We provide exciting new in vitro data demonstrating that Zn+2 can overcome the immunosuppression (spleen TDAR) produced by exposures to As+3, perhaps based on the zinc finger protein theory discussed below. We know that genotoxicity and p53 signaling are important mechanisms of immunosuppression produced by PAHs, and perhaps for As+3 in mice. Therefore, we will examine the p53- dependence of spleen and BM suppression using p53 null mice. In SA2 we will determine whether the mechanism of synergy is due to inhibition of DNA repair. Our preliminary data show that As+3 inhibits DNA repair and that co-exposures to PAHs and As+3 may lead to an increase in PAH bulky and oxidative stress adducts resulting in increased p53 signaling. In our previous studies we showed that As+3 binds to the zinc finger proteins, PARP-1 and XPA, leading to inhibition of DNA repair in both Nucleotide Excision Repair (NER) and Base Excision Repair (BER) pathways. We will test the hypothesis that Zn+2 supplementation can reverse the effects of As+3 in vivo in mice. In SA3, we will build on our preliminary data that human T cells are inhibited by low nanomolar (nM) concentrations of As+3 exposures in vitro. We will also examine the ability of Zn+2 to reverse this immunosuppression in HPBMC in vitro. Because we have found that there are significant inter-individual differences, we will perform initial characterization of As+3 and PAH exposure in 150 different individuals. Completion of these studies will yield critical new data relating to our central hypothesis and will determine th potential sensitivities of the human immune system to binary exposures of PAHs and As+3.

描述（由申请方提供）：这些研究的目的是评价与多环芳烃（PAH）和亚砷酸钠（As+3）联合暴露相关的小鼠和人类免疫抑制机制。已知免疫系统的抑制与抵抗感染和癌症的能力下降有关。初步数据显示，小鼠表现出协同免疫抑制时，暴露于As+3和多环芳烃在体内通过他们的食物和饮用水。我们还提出了初步的数据表明，人外周血单核细胞（HPBMC）的免疫抑制在环境相关的水平的钠As+3在饮用水中发现。多环芳烃也能增加As+3诱导的免疫抑制作用。因此，重要的是要了解这些药物单独或联合暴露时产生的免疫抑制机制。在本申请中待检验的中心假设是多环芳烃和As+3通过DNA损伤和修复途径产生协同免疫抑制。重要的是开发动物模型来研究协同免疫抑制，并进行与人类接触相关的机制研究。这些研究将确定在小鼠模型中，饮用水中的As+3和饮食中的PAH（存在于我们呼吸的空气和我们吃的食物中）的共同暴露是否会导致比以前发现的任何一类药物本身更大的抑制。我们将确定可能负责这些相互作用的生化机制，我们将确定是否Zn+2存在于饮用水中可以保护小鼠免受As+3暴露。最后，由于我们发现人类血液T淋巴细胞对美国和世界其他地方许多人群饮用水中存在的低浓度As+3非常敏感，我们将确定不同人群（不同年龄和种族的男性和女性）对这些暴露的敏感性。我们将从这些人获得外周血细胞，以确定他们的免疫反应是否受到抑制的As+3和PAH在体外单独或组合。这些研究的结果将作出重要贡献，了解环境代理人，调节人体免疫系统，并可能提供一种方法来干预As+3饮用水暴露。 公共卫生相关性：这些研究的目的是评估与多环芳烃（PAHs）和亚砷酸钠（As+3）联合暴露相关的小鼠和人类免疫抑制机制。已知免疫系统的抑制与抵抗感染和癌症的能力下降有关。初步数据显示，小鼠表现出协同免疫抑制时，暴露于As+3和多环芳烃在体内。我们还提出了初步的数据表明，人外周血单核细胞（HPBMC）是非常敏感的T细胞免疫抑制环境相关水平的暴露于钠As+3和多环芳烃相互作用显着As+3以及。因此，重要的是要了解这些药物单独或联合暴露时产生的免疫抑制机制。在本申请中要测试的中心假设是多环芳烃和As+3通过DNA加合物形成和DNA修复抑制引起的遗传毒性途径产生协同免疫抑制。重要的是开发体内模型来研究协同免疫抑制和进行与人体暴露相关的机制研究。在SA 1中，我们将利用我们建立的小鼠模型研究多环芳烃对小鼠脾脏中T依赖性抗体反应（TDAR）和骨髓（BM）细胞的前B和粒细胞/单核细胞（GM）祖细胞活性的综合影响。我们提供了令人兴奋的新的体外数据表明，Zn+2可以克服暴露于As+3产生的免疫抑制（脾TDAR），也许是基于下面讨论的锌指蛋白理论。我们知道，遗传毒性和p53信号是由多环芳烃产生的免疫抑制的重要机制，并可能为As+3在小鼠。因此，我们将使用p53敲除小鼠检查脾脏和BM抑制的p53依赖性。在SA 2中，我们将确定协同作用的机制是否是由于DNA修复的抑制。我们的初步数据表明，As+3抑制DNA修复，并共同暴露于多环芳烃和As+3可能会导致增加PAH庞大的和氧化应激加合物，从而增加p53信号。在我们以前的研究中，我们表明As+3与锌指蛋白PARP-1和XPA结合，导致核苷酸切除修复（NER）和碱基切除修复（BER）途径中的DNA修复抑制。我们将测试的假设，Zn+2补充剂可以逆转As+3在小鼠体内的影响。在SA 3中，我们将在初步数据的基础上， 体外低纳摩尔（nM）浓度的As+3暴露抑制人T细胞。我们还将在体外研究Zn+2逆转HPBMC中这种免疫抑制的能力。由于我们发现个体间存在显著差异，因此我们将在150名不同个体中对As+3和PAH暴露进行初步表征。这些研究的完成将产生与我们的中心假设相关的关键新数据，并将确定人类免疫系统对多环芳烃和As+3二元暴露的潜在敏感性。