Precocious immune senescence induced by pre- & postnatal atrazine exposure

描述(由申请人提供)：NIEHS有一项研究任务，即了解环境在成人疾病的胎儿基础上的作用。我们认为，除了我们的初步数据(3)之外，还有许多事实使对阿特拉津的发育免疫毒性的研究具有说服力。其一，阿特拉津是目前美国农业中使用最多的单一除草剂，也是美国地下水中检测到的最常见的除草剂污染物(http://water.usgs.gov/nawqa).因此，儿童在孕期发育期间或在新生儿时期因母亲在怀孕期间摄入阿特拉津污染的水或在怀孕期间在受阿特拉津污染的水中洗澡而暴露于风险很大。第二，使用阿特拉津的发育免疫毒理学研究发表的很少。第三，阿特拉津此前已被证明会影响人类的产前发育(5，6)。最后，例如，这项研究可能会为母亲通过改变水源来改善对胎儿的损害开辟道路。这也将为其他人解决职业健康干预有效性研究奠定基础。关于阿特拉津对发育中的免疫系统的影响的研究很少。我们的初步数据显示，孕期/哺乳期暴露于阿特拉津的3月龄雄性Balb/C小鼠的B细胞反应、混合淋巴细胞反应和细胞毒性T淋巴细胞反应显著增加(P/L)，其中DAM通过时间释放颗粒接受环境相关剂量的阿特拉津。P/L阿特拉津男性免疫功能的增强可能会使他们患上自身免疫性疾病的风险更高，例如系统性红斑狼疮，与女性相似。基于我们对P/L阿特拉津暴露的初步研究，我们假设BALB/C小鼠在产前、新生儿或发育的综合时期暴露于阿特拉津会导致其T细胞的长期功能变化。我们计划通过以下具体目标来解决这一假设。具体目标1：建立P/L阿特拉津暴露对子代免疫系统的纵向影响。这一特定目的的假设是，P/L阿特拉津暴露导致早熟免疫衰老。特异性目标2：明确P/L阿特拉津暴露后3个月和6个月免疫功能改变的机制。 与公众健康相关1阿特拉津是美国使用最广泛的除草剂之一，在生长季节约有8000万磅用于作物。阿特拉津及其代谢物是美国最常见的水污染物。已经有许多成人研究来确定这种化合物是否有明显的毒性作用。然而，很少有研究这种化合物对发育中的胎儿的影响，尽管众所周知，胎儿和新生儿对有毒化合物非常敏感，而且通常会出现一系列不同的症状，使成年人暴露在危险之中。我们的初步数据表明，产前和哺乳期暴露于阿特拉津的影响会对免疫系统产生性别和年龄依赖性的影响。我们的长期目标是了解这些影响的机制，并确定这些动物在一年的时间里是否继续表现出免疫反应的恶化；我们将这种现象称为“早熟免疫衰老”。

DESCRIPTION (provided by applicant): NIEHS has a research mandate to understand the role of the environment on the fetal basis of adult disease. We believe that there are a number of facts, in addition to our preliminary data (3); that make a study of the developmental immunotoxicity of atrazine compelling. One, atrazine is both the most heavily used single herbicide employed in USA agriculture at this time and, the most common herbicide contaminant detected in ground water in the USA (http://water.usgs.gov/nawqa). Thus, there is ample risk that the children will be exposed during gestational development or neonatally via the mother's ingestation or bathing in atrazine-contaminated water during pregnancy. Two, there are few published developmental immunotoxicological studies using atrazine. Three, atrazine has been previously shown to affect prenatal development in humans (5, 6). Finally, this research could open the way for mothers' to ameliorate the damage to their fetus by changing water sources, for example. This would also set the stage for others to address intervention effectiveness research in occupational health. Few studies have been performed on the effect of atrazine on the developing immune system. Our preliminary data demonstrated a significant increase in the B cell response, mixed lymphocyte response and cytotoxic T-lymphocyte response of 3 month old male Balb/C mice that were exposed prenatally/lactationally (P/L) to atrazine in an experimental paradigm where the dam received environmentally relevant doses of atrazine via a time-release pellet. The increases in immune function in P/L atrazine males may put them at higher risk to developing autoimmune diseases, e.g., systemic lupus erythematosus, similar to that seen in females. Based on our preliminary P/L atrazine exposure studies, we hypothesize that exposure of Balb/C mice to atrazine during the prenatal, neonatal or a combination period of development induces long term functional changes in their T-cells. We plan to address this hypothesis via the following specific aims. Specific Aim 1: Establish the longitudinal effects of P/L atrazine exposure on the immune system of the offspring. The hypothesis for this specific aim is that P/L atrazine exposure causes precocious immune senescence. Specific Aim 2: Identify the mechanism of the altered immune function at 3 and 6 moa caused by P/L atrazine exposure. PUBLIC HEALTH RELEVANCE 1Atrazine is one of the most heavily used herbicides in the United States of America (USA) with approximately 80 million pounds applied to crops during a growing season. Atrazine and its metabolites are the most common water contaminant in the USA. There have been numerous adult studies done to determine any overt toxic effects of this compound. However, there have been very few studies that study the effects of this compound on the developing fetus even though it is well recognized that fetuses and neonates are exquisitely sensitive to toxic compounds and often have a different array of symptoms that exposed adults. Our preliminary data indicates that the effect of prenatal and lactational exposure to atrazine causes both sex and age-dependent effects on the immune system. Our long range goal is to understand the mechanism of these effects and determine if these animals continue to show a deterioration of their immune response over a 1 year period; a phenomenon that we have termed `precocious immune senescence'.