Synergistic Immunosuppression by PAHs and Arsenite

描述(申请人提供)：这些研究的目的是评估多环芳烃(PAHs)和亚砷酸钠(As+3)联合暴露对小鼠和人类的免疫抑制机制。众所周知，免疫系统的抑制与抗击感染和癌症的能力下降有关。初步数据显示，当小鼠通过食物和饮用水暴露于As+3和PAHs体内时，表现出协同免疫抑制作用。我们还提供了初步数据，表明在饮用水中发现的与环境相关的钠As+3水平下，人外周血单个核细胞(HPBMC)受到免疫抑制。PAHs还能增加As+3诱导的免疫抑制量。因此，重要的是要了解当暴露单独或联合发生时，这些制剂产生免疫抑制的机制(S)。在这一应用中需要检验的中心假设是，PAHs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，并进行与人类暴露相关的机制研究。这些研究将确定，在小鼠模型中，饮用水中的As+3和饮食中的多环芳烃(存在于我们呼吸的空气和食物中)的共同暴露是否会比之前发现的任何一类制剂单独作用时产生更大的抑制。我们将确定可能导致这些相互作用的生化机制，并确定饮用水中存在的锌+2是否可以保护小鼠免受As+3暴露。最后，由于我们发现，在美国和世界其他地方的许多人群中，人类血液T淋巴细胞对饮用水中存在的低浓度As+3极其敏感，因此我们将确定不同人类(不同年龄和种族的男性和女性)对这些暴露的敏感性。我们将从这些人身上获取外周血细胞，以确定他们的免疫反应是否受到体外单独或联合给予AS+3和PAH的抑制。这些研究的结果将对理解调节人类免疫系统的环境因素做出重要贡献，并可能为AS+3饮用水暴露的干预提供一种方法。

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.