Grantee Research Project Results
Glufosinate Neurotoxicity TargetsEPA Grant Number: FP917139
Title: Glufosinate Neurotoxicity Targets
Investigators: Lantz, Stephen R
Institution: University of California - Berkeley
EPA Project Officer: Cobbs-Green, Gladys M.
Project Period: September 1, 2010 through August 31, 2013
Project Amount: $111,000
RFA: STAR Graduate Fellowships (2010)
Research Category: Fellowship - Pesticides and Toxic Substances , Academic Fellowships
This research will determine if the neurotoxicity of the major organophosphorus herbicide glufosinate is primarily due to glutamate subtype N-methyl-D-aspartate (NMDA) receptor activation, glutamine synthetase inhibition or another high affinity glufosinate binding site interaction using radioligand binding and enzyme assays coupled with structure activity and molecular biology approaches.
Genetically-modified (GM) plants, as well as herbicides used in conjunction with them, are often the tools of choice to increase crop yields and feed an expanding population. Weed resistance developed to the safest and most used herbicide (glyphosate) is requiring the deployment of less safe alternatives. This research defines the neurotoxicity of the main herbicidal alternative for GM crops, glufosinate. The results are necessary for informed human and environmental safety decisions.Approach:
Radiolabeled [3H]glufosinate will be synthesized at 30-60 Ci/mmol and used in kinetic and competition binding assays of mouse brain membrane and cytosol fractions to characterize the binding site. Comparative assays with known NMDA or glutamate receptor radioligands will be carried out to further characterize the interaction of glufosinate with known molecular sites. Glutamine synthetase inhibition will be analyzed by colorimetric assay for glutamine formation. Interactions of glufosinate with glutamate receptors (binding assays) and glutamine synthetase (colorimetric assays) will be compared in sensitivity, localization and toxicological relevance.Expected Results:
Binding assays will define a high affinity glufosinate binding site in brain that is glycine concentration dependent, and inhibited by known NMDA receptor antagonists or agonists. I also expect to find that the characterized binding site is more important to neurotoxicity than glutamine synthetase inhibition. Conversion to the N-acetyl derivative of glufosinate by plants is the mechanism for resistance in GMO plants. N-Acetyl glufosinate is also more likely than glufosinate to cross the blood brain barrier. The interaction of glufosinate and the N-acetyl derivative with glutamate receptors and glutamine synthetase will be compared. These results will constitute a much better understanding of the relevant site(s) for glufosinate neurotoxicity than currently exists.
Potential to Further Environmental/Human Health Protection:
Increasing worldwide population and decreasing farmlands are leading to demands for increased crop yields. GM crops are being developed and utilized in response to this demand. Glufosinate-resistant and related GM crops are one of the leading solutions to date. The potential for human exposure to glufosinate crop applications and residues is high. The knowledge base on the glufosinate neurotoxic phenotype is incomplete. The projected increase in demand for GM crops, and thereby glufosinate, signals an increasing need to fully characterize the neurotoxic phenotype. In line with this need, this study aims to achieve a better understanding of glufosinate through characterization of the binding site and analysis of multiple target site relevance. With more complete knowledge about the neurotoxic effect, more educated use decisions can be made to protect humans and the environment.Supplemental Keywords:
glufosinate, glutamate receptor, neurotoxicity, radioligand, binding site,