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

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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.