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The Effects of Propanil and its Metabolites on Calcium Homeostasis and T Cell Function

EPA Grant Number: F07D90211
Title: The Effects of Propanil and its Metabolites on Calcium Homeostasis and T Cell Function
Investigators: Lewis, Tricia L.
Institution: West Virginia University
EPA Project Officer: Willett, Stephanie H.
Project Period: September 1, 2007 through September 1, 2009
RFA: GRO Graduate Fellowships (2007)
Research Category: Fellowship - Immunotoxicology , Health Effects , Academic Fellowships

Description:

Objective:

Propanil (also known as DCPA) is a widely used, post-emergent herbicide registered for use against several broadleaf and grassy weeds. Annual use of propanil in the United States is estimated to be 7 million pounds per year. Recently propanil has also been proposed for use on turf. Several studies have demonstrated that propanil has immunotoxic effects. The two major metabolites of propanil cause methemoglobinemia in acutely exposed individuals and may be immunotoxic like their parent compound propanil. Since the metabolites are produced in the body it is important to ascertain any potential immunotoxic effects. To date there have been no studies that directly assess the acute and chronic immunotoxic effects of propanil and its metabolites on T cell function. T cells are critical in coordinating the activation of several immune cells and in mounting an effective immune response. Interleukin-2 (IL-2) is an important cytokine secreted by T cells and can be used to assess T cell function. In addition, IL-2 production is regulated by intracellular calcium (Ca2+) which regulates virtually every aspect of T cell activation, differentiation and function. Influx of Ca2+ through Ca2+ release activated Ca2+ (CRAC) channels on the T cell surface is essential for an effective immune response. It has been demonstrated that alterations in calcium homeostasis can result in immunosuppression, autoimmunity and cancer.

The objective of this study is to determine acute and chronic effects of propanil and its major metabolites on T cell function with specific emphasis on calcium homeostasis.

Approach:

Human T cells will be exposed to several concentrations of propanil, or its metabolites and T cell function will be assessed through changes in the level of IL-2 secretion. Further studies will examine the changes in intracellular calcium using single cell Ca2+ imaging techniques that allows visualization of intracellular calcium through its binding to a fluorescent Ca2+ indicator. Patch clamp techniques will also be used to assess the effects of propanil and its metabolites on specific Ca2+ channels. The effects of chronic exposure will be conducted using a mouse model.

Expected Results:

Calcium is an important regulator of T cell activation and disruptions in calcium homeostasis can have a profound impact on the immune response. Exposure of propanil and/or its metabolites is expected to alter the calcium homeostasis of human T cells through leading to immunosuppression. Results from this project will provide further insight into the short and long term effects of propanil and its metabolites. In addition valuable information from this project can be used to make decisions on its continued regulation and use.

Supplemental Keywords:

propanil, DCPA, herbicide, human T cell, immune system, immunosuppression, calcium, CRAC, immunotoxicity, acute exposure, chronic exposure, DCPA metabolites, IL-2,

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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