Synergistic Immunosuppression by PAHs and Arsenite

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。本申请中要测试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。

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.