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Amino acid mimicry: Insights into glyphosate transport and toxicity to mitochondria

Award Number: R03ES034881
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/10/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Amino acid mimicry: Insights into glyphosate transport and toxicity to mitochondria - Extensive use of glyphosate-based herbicides (GBH) has led to glyphosate entering the food chain, and causing human sera and urine levels to increase over time. This exposure has led to numerous claims that glyphosate causes diseases ranging from multiple types of cancer to affecting human development and reproduction. However, no mechanism of glyphosate import into human cells is known; in yeast, importation occurs through the glutamate/ aspartate (D/E) transporters due to its structural resemblance. Glyphosate is thought not to have acute effects on humans because they lack the shikimate pathway that produces aromatic amino acids (WYF), which is inhibited in the presence of glyphosate, and humans instead acquire aromatic amino acids through diet or the gut microbiome. The differences in commercial preparations of glyphosate have complicated the studies because GBHs have surfactants that increase tissue penetration. Yeast can bypass the inhibition of the shikimate pathway when supplemented with (WYF), which permits the assessment of the role of surfactants or, more likely, discover the unknown glyphosate targets. Our initial studies have found that genes regulating mitochondria, DNA damage, and the cell cycle are differentially regulated in GBH treatments. The long-term goal is to identify the glyphosate transportation mechanisms into cells, the brain, and other tissues that affect mitochondrial metabolism. This application's objective is to determine how mitochondrial metabolism is affected by glyphosate alone and in commercial formulations in the model organism S. cerevisiae. Our central hypothesis is that the transport of glyphosate is due to mimicry of glutamate and aspartate; thus, it will affect other enzymes that utilize glutamate and aspartate, especially within the mitochondria. The rationale of this proposal is that mitochondrial effects of glyphosate have a biochemical basis and will provide a mechanistic understanding of cellular effects in vertebrate species. Specific aims proposed are 1. Measure the import of glyphosate into different compartments in different mutants and how adding D/E rescues growth inhibition from glyphosate 2. Measure changes in specific mitochondrial metabolites (ATP and NADH) in glyphosate treated cells. The proposed research is innovative because the hypothesis proposed is using unbiased experiments, such as genome-wide association, transcriptomics, and In-Lab Evolution experiments to determine the mechanism of extra- and intracellular glyphosate transport using D/E transporters. Glyphosate mimics D/E amino acids in transport, so it likely affects other enzymes that use D/E, particularly in the mitochondria. In plants, fungi, and bacteria, D/E transporters have all been implicated in glyphosate transport and glyphosate affecting mitochondrial functions. While humans do not have the shikimate pathway, they have D/E transporters, and conserved mitochondrial proteins that use D/E, which may be the off-targets of glyphosate leading to the range of diseases claimed to have been caused by glyphosate.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$3,545 )
2025	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Environmental Health	000	2	6/17/2025	NON-COMPETING CONTINUATION	-$3,545
														Subtotal = -$3,545

Issue Date FY: 2024 ( Subtotal = $76,000 )
2024	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Environmental Health	000	2	1/15/2024	NON-COMPETING CONTINUATION	$76,000
														Subtotal = $76,000

Issue Date FY: 2023 ( Subtotal = $76,000 )
2023	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Environmental Health	001	1	6/15/2023	NEW	$0
2023	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Environmental Health	000	1	2/10/2023	NEW	$76,000
														Subtotal = $76,000

Grand Total All Awards = $148,455

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Amino acid mimicry: Insights into glyphosate transport and toxicity to mitochondria

Award Number: R03ES034881

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/10/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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