title: Mapping Proteome-wide Targets of Glyphosate in Mice.
abstract: Glyphosate, the active ingredient in the herbicide Roundup, is one of the most widely used pesticides in agriculture and home garden use. Whether glyphosate causes any mammalian toxicity remains highly controversial. While many studies have associated glyphosate with numerous adverse health effects, the mechanisms underlying glyphosate toxicity in mammals remain poorly understood. Here, we used activity-based protein profiling to map glyphosate targets in mice. We show that glyphosate at high doses can be metabolized in vivo to reactive metabolites such as glyoxylate and react with cysteines across many proteins in mouse liver. We show that glyoxylate inhibits liver fatty acid oxidation enzymes and glyphosate treatment in mice increases the levels of triglycerides and cholesteryl esters, likely resulting from diversion of fatty acids away from oxidation and toward other lipid pathways. Our study highlights the utility of using chemoproteomics to identify novel toxicological mechanisms of environmental chemicals such as glyphosate.
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA.
authors.forename: Breanna
authors.initials: B
authors.lastname: Ford
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bateman
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA.
authors.forename: Leilani
authors.initials: L
authors.lastname: Gutierrez-Palominos
authors.affiliation: Integrated Proteomics Applications, Inc., 12707 High Bluff Drive Suite 200, San Diego, CA 92130, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Park
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA. Electronic address: dnomura@berkeley.edu.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006540:Herbicides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D040081:Protein Array Analysis; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics; D013329:Structure-Activity Relationship; D000097797:Glyphosate
chemical_list: D005227:Fatty Acids; D005998:Glycine; D006540:Herbicides; D011506:Proteins; D000097797:Glyphosate
keywords: activity-based protein profiling; chemoproteomics; fatty acid oxidation; glyphosate; lipid metabolism; pesticide toxicology