At concentrations present in the environment, each of three dissimilar toxic agents can seize control of a signaling pathway that regulates developing cells in the brain and spinal cord, researchers report. They suggest that scientists might use the pathway to predict the toxicology of a diverse range of chemicals.
Mark Noble of the University of Rochester Medical Center in New York and his colleagues focused on a pathway that controls the development of cells destined to become oligodendrocytes. Those mature cells produce the material that insulates nerve fibers.
Despite vast differences in structure, many toxic agents in the environment can oxidize cells, notes Noble. In normal development, subtle changes in the oxidative state of the oligodendrocyte precursors determine whether they continue to divide or proceed to their final form. To study how oxidizing chemicals would affect this development, the group exposed cultures of the progenitor cells from newborn rats to methylmercury, lead, and the herbicide paraquat. The researchers applied the chemicals in amounts that people or animals encounter in the environment.
Each chemical slightly shifted the oxidative state of the progenitor cells, in effect telling the cells to mature. That action halted division in 25 percent of the cells. This decrease, Noble says, when carried through many cellular generations, “has an enormous effect on the number of cells that you have.”
The researchers also investigated the effect of one of the chemicals in animals. They provided pregnant mice with drinking water that contained environmentally relevant concentrations of methylmercury. The brains of the pups from those mothers had 20 percent fewer oligodendrocyte progenitor cells than did brains from pups of untreated mothers, the team reports in the February PLoS Biology.
Noble’s group plans longer studies to determine the consequences of a decreased pool of oligodendrocyte progenitor cells.
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By identifying a pathway that might be vulnerable to different environmental chemicals, the research “provides a framework for predictive toxicology,” comments David A. Schwartz, director of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., which partially funded the study. Because exposure to lead gave a similar biological fingerprint as the exposure to methylmercury did, he says “perhaps it predicts what the fingerprint might be for an exposure to arsenic,” which also oxidizes cells.
“It’s a little too early to tell how generalizable [the finding] will be,” Schwartz continues, but if it proves to hold true for other toxic agents, it could affect “not only how we measure the effects of toxicants, but how we predict risk of disease.”
Joel G. Pounds, a toxicologist at the Pacific Northwest National Laboratory in Richland, Wash., agrees. If the pathway is a target for many toxic agents, he says, then by finding ways to measure the pathway’s activity, “we can begin to use those probes to understand the relationship between exposure to the toxicant and the role of the toxicant in chemically induced disease.”