title: Multidimensional profiling platforms reveal metabolic dysregulation caused by organophosphorus pesticides.
abstract: We are environmentally exposed to countless synthetic chemicals on a daily basis, with an increasing number of these chemical exposures linked to adverse health effects. However, our understanding of the (patho)physiological effects of these chemicals remains poorly understood, due in part to a general lack of effort to systematically and comprehensively identify the direct interactions of environmental chemicals with biological macromolecules in mammalian systems in vivo. Here, we have used functional chemoproteomic and metabolomic platforms to broadly identify direct enzyme targets that are inhibited by widely used organophosphorus (OP) pesticides in vivo in mice and to determine metabolic alterations that are caused by these chemicals. We find that these pesticides directly inhibit over 20 serine hydrolases in vivo leading to widespread disruptions in lipid metabolism. Through identifying direct biological targets of OP pesticides, we show heretofore unrecognized modes of toxicity that may be associated with these agents and underscore the utility of using multidimensional profiling approaches to obtain a more complete understanding of toxicities associated with environmental chemicals.
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley , 127 Morgan Hall, Berkeley, California 94720, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina-Cleghorn
authors.forename: Ann
authors.initials: A
authors.lastname: Heslin
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morris
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Mulvihill
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
mesh_terms: D000818:Animals; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000633:toxicity; D010575:Pesticides / Q000378:metabolism* / Q000633:toxicity; D020543:Proteome / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040901:Proteomics; D057057:Serine Proteases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000378:metabolism
chemical_list: D009943:Organophosphorus Compounds; D010575:Pesticides; D020543:Proteome; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases