Determining the Role of Atrazine and Atrazine-Induced Estrogen in Increasing CD4+

确定莠去津和莠去津诱导的雌激素在增加 CD4 中的作用

• 批准号: 8429920
• 负责人: SCOTT Allen WETZEL
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429920
• 关键词: Address; Adoptive Transfer; Affect; Agonist; Agriculture; American; Antibodies; Antigens; Aromatase; Atrazine; Autoimmune Process; Binding; CD4 Positive T Lymphocytes; CYP19A1 gene; Cell Count; Cell Maturation; Cells; Communicable Diseases; Cytokine Activation; Cytolysis; Dendritic Cells; Endocrine Disruptors; Environmental Pollution; Estrogen Antagonists; Estrogens; Experimental Autoimmune Encephalomyelitis; Exposure to; Frequencies; Generations; Health; Helper-Inducer T-Lymphocyte; Herbicides; Immune; Immune response; Immune system; Immunosuppression; In Vitro; Individual; Infection; Inflammatory; Lead; Link; Male Infertility; Malignant Neoplasms; Mediating; Mitogens; Modeling; Mus; Nature; Phenotype; Predisposition; Production; Regulatory T-Lymphocyte; Reporting; Reproduction; Research; Risk; Role; Seasons; Self Tolerance; Severity of illness; Shapes; Signal Transduction; System; T-Cell Activation; T-Lymphocyte; Testing; Transgenic Mice; Transgenic Organisms; United States; Water; Work; antibody inhibitor; antigen challenge; cytokine; drinking water; fighting; ground water; immune function; in vivo; interest; male; microbial; neurotoxicity; pathogen; public health relevance; receptor; reproductive; research study

DESCRIPTION (provided by applicant): Atrazine is one of the most widely used herbicide in the United States. As a result of agricultural runoff after crop applications, it is the most commo ground water contaminant in the US (://water.usgs.gov/nawqa/). Atrazine is classified as an Endocrine-Disrupting Compound due its induction of CYP19 (aromatase), whose catalytic activity leads to increased estrogen production. While a significant amount of research has been done looking into the potential health risks associated with atrazine exposure, most have focused on reproduction abnormalities related to elevated estrogen. A small number of studies have examined the effect of atrazine on the mammalian immune system, but the effects on the immune system remain largely unknown. None of the previous studies have focused on the activation and functions of a critical subset of immune cells, the CD4+ T helper cells. These cells help shape the protective immune response to pathogens and cancer as well as maintaining tolerance of self. Perturbations of CD4+ T cell numbers or effector activity can have dire consequences for the health of the individual. For example, an increase in regulatory T cells (Treg), can lead to immune suppression and resulting in increased susceptibility to infection or cancer. In preliminary in vitro studies, it was observed that atrazine exposure significantly inhibits the proliferation, activation and cytokine production by conventional T cells. Further, there is a significant increase in the frequency of Foxp3+ Treg in atrazine-exposed cells. In this proposal we will examine the mechanism of atrazine-mediated inhibition of CD4+ T cells. The hypothesis of this proposal is that atrazine increases estrogen levels which suppresses CD4+ T cell activation by both directly inhibiting these cells and by inducing a significant increase of Treg cells. It will be tested using 2 specific aims: In the first aim, the mechanism of atrazine-induced Treg frequency will be examined in vitro and in vivo. Using TCR transgenic T cells from Foxp3gfp+ OT-II mice, we will determine whether atrazine is inducing expansion of nTreg or conversion of conventional T cells to induced Treg (iTreg) cells. We will also examine the direct effects of atrazine exposure on the phenotype of conventional T cells in the absence of Treg. In the second aim, using a combination of pharmacological inhibitors and antibody blockade, the role of atrazine-mediated estrogen production on the Treg increase will be examined.

描述（由申请人提供）：Atrazine是美国使用最广泛的除草剂之一。由于农作物施用后的农业径流，它是美国最混乱的地下水污染物（：//water.usgs.gov/nawqa/）。阿特嗪因其诱导CYP19（芳香化酶）而被归类为内分泌干扰化合物，其催化活性导致雌激素产生增加。尽管已经进行了大量研究，研究了与阿atrazine暴露有关的潜在健康风险，但大多数侧重于与雌激素升高有关的繁殖异常。少数研究检查了阿特拉津对哺乳动物免疫系统的影响，但对免疫系统的影响仍然很大程度上未知。先前的研究都没有集中于免疫细胞CD4+ T辅助细胞的临界子集的激活和功能。这些细胞有助于塑造对病原体和癌症的保护性免疫反应，并维持对自我的耐受性。 CD4+ T细胞数量或效应子活性的扰动可能会对个人的健康产生可怕的后果。例如，调节性T细胞（TREG）的增加会导致免疫抑制，并导致对感染或癌症的敏感性增加。在初步的体外研究中，观察到芳津暴露会显着抑制常规T细胞的增殖，激活和细胞因子的产生。此外，在暴露于阿特拉津暴露的细胞中，Foxp3+ Treg的频率显着增加。在此提案中，我们将检查阿atrazine介导的CD4+ T细胞抑制的机理。该提议的假设是，阿特拉津通过直接抑制这些细胞并诱导Treg细胞的显着增加来抑制CD4+ T细胞激活的雌激素水平。它将使用2个特定目的对其进行测试：在第一个目标中，将在体外和体内检查阿特拉津诱导的Treg频率的机制。使用来自FOXP3GFP+ OT-II小鼠的TCR转基因T细胞，我们将确定阿特拉津是诱导NTREG的膨胀或常规T细胞转化为诱导Treg（ITREG）细胞的膨胀。我们还将在没有TREG的情况下检查阿雷津暴露对常规T细胞表型的直接影响。在第二个目的中，将研究伴有药理学抑制剂和抗体阻断的组合，将检查阿atrazine介导的雌激素产生在Treg增加中的作用。