Multidimensional Profiling Platforms Reveal Metabolic Dysregulation Caused by Organophosphorus Pesticides

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.