New tools may help identify both intended and unintended effects of chemicals in the body, according to Daniel Nomura, Ph.D., from the University of California (UC), Berkeley. Nomura spoke to a packed audience at NIEHS Feb. 29 about “Mapping Toxicological Mechanisms Using Chemoproteomic and Metabolomic Platforms.” His talk was part of the Keystone Science Lecture Seminar Series.
The search for off-target effects
Nomura, who is affiliated with the UC Berkeley Superfund Research Center said that tools toxicologists use to explore chemical toxicity may miss unexpected off-target effects. For example, common organophosphate insecticides are designed to kill insects by inhibiting an enzyme called acetylcholinesterase. Inhibition of that enzyme has a negative effect on both insect and human nervous systems. However, he said that people chronically exposed to these insecticides may experience adverse health effects that are not fully explained by inhibition of acetylcholinesterase alone, so the insecticides may be affecting additional functions, or off-targets, within the body.
According to Nomura, emerging technologies allow toxicologists to map the full range of targets a chemical may have, and possibly, to modify chemicals to make them safer. “These are the same technologies used to discover new drug targets in pharmaceutical research,” Nomura said. “When you apply them to environmental chemicals, you can start identifying off-targets of these chemicals and then, hopefully, optimizing those chemical structures so they don’t have those off-targets.”
“Nomura’s new approach can provide a rapid, comprehensive, and unbiased assessment of the ways a chemical may affect the human body,” explained Michelle Heacock, Ph.D., health scientist administrator with the NIEHS Superfund Research Program and host of the talk. “These clues to a chemical’s toxicity can otherwise take much longer, even years, to uncover.”
Mapping protein reactivity to test toxic effects
Nomura’s lab is developing a technique called reactivity-based protein-profiling that broadly assesses how chemicals interact with protein targets in the body, and how these interactions may produce chemical toxicity. Their approach, published October 2015, focuses on the ways that environmental electrophiles — a group of chemicals that includes organophosphate pesticides, as well as widely used fungicides and herbicides — directly interact with protein targets and affect their activity (see sidebar).
Nomura theorizes that analyzing direct chemical interactions with protein targets is the best way to understand mechanisms of chemical toxicity, especially with respect to off-targets. “Under normal toxicological testing paradigms, you’d never look for a lot of these targets and whether or not they’re inhibited,” he explained.
The promise of a new toxicological tool
Many of the NIEHS scientists attending the seminar said they were impressed by the methods Nomura shared. “Toxicologists have been trained to focus on a single mechanism of action, or a single target. This provides a novel and much needed approach to toxicity testing,” said Linda Birnbaum, Ph.D., director of NIEHS and the National Toxicology Program.
“Nomura is combining creativity with his expertise in both analytical chemistry and toxicology to ask questions that have been very difficult to answer using traditional methods,” remarked Jason Williams, Ph.D., co-director of the NIEHS Mass Spectrometry Research and Support Group. “His approach is extremely sensitive and broadly assesses toxicity, simultaneously illuminating which specific enzymes and pathways are sensitive to the compounds tested. This knowledge about the mechanisms of toxicity has often been an Achilles heel for the field of toxicology.”
Several scientists acknowledged the potential of reactivity-based protein-profiling. “Many environmental chemicals are having off-target effects, doing things they are not intended to do once they are out in the environment,” said Jerry Heindel, Ph.D., health scientist administrator in the NIEHS Population Health Branch. “That’s why we need methods like those presented today.”
Citation: Medina-Cleghorn D, Bateman LA, Ford B, Heslin A, Fisher KJ, Dalvie ED, Nomura DK. 2015. Mapping proteome-wide targets of environmental chemicals using reactivity-based chemoproteomic platforms. Chem Biol 22(10):1394-1405.