Abstract
Identification of common mechanistic principles that shed light on the action of the many chemically diverse toxicants to which we are exposed is of central importance in understanding how toxicants disrupt normal cellular function and in developing more effective means of protecting against such effects. Of particular importance is identifying mechanisms operative at environmentally relevant toxicant exposure levels. Chemically diverse toxicants exhibit striking convergence, at environmentally relevant exposure levels, on pathway-specific disruption of receptor tyrosine kinase (RTK) signaling required for cell division in central nervous system (CNS) progenitor cells. Relatively small toxicant-induced increases in oxidative status are associated with Fyn kinase activation, leading to secondary activation of the c-Cbl ubiquitin ligase. Fyn/c-Cbl pathway activation by these pro-oxidative changes causes specific reductions, in vitro and in vivo, in levels of the c-Cbl target platelet-derived growth factor receptor-α and other c-Cbl targets, but not of the TrkC RTK (which is not a c-Cbl target). Sequential Fyn and c-Cbl activation, with consequent pathway-specific suppression of RTK signaling, is induced by levels of methylmercury and lead that affect large segments of the population, as well as by paraquat, an organic herbicide. Our results identify a novel regulatory pathway of oxidant-mediated Fyn/c-Cbl activation as a shared mechanism of action of chemically diverse toxicants at environmentally relevant levels, and as a means by which increased oxidative status may disrupt mitogenic signaling. These results provide one of a small number of general mechanistic principles in toxicology, and the only such principle integrating toxicology, precursor cell biology, redox biology, and signaling pathway analysis in a predictive framework of broad potential relevance to the understanding of pro-oxidant–mediated disruption of normal development.
Highlights
Determining whether chemically diverse substances induce similar adverse effects at the cellular and molecular level is one of the central challenges of toxicological research
We have discovered a previously unrecognized regulatory pathway on which chemically diverse toxicants converge, at environmentally relevant exposure levels, to disrupt the function of progenitor cells of the developing central nervous system
We found that the ability of low levels of methylmercury, lead, and paraquat to make progenitor cells more oxidized causes activation of an enzyme called Fyn kinase
Summary
Determining whether chemically diverse substances induce similar adverse effects at the cellular and molecular level is one of the central challenges of toxicological research. The identification of general principles that transcend the specific chemistries of individual substances has the potential of providing broadly relevant insights into the means by which toxicants disrupt normal development. If such principles were found to apply to the analysis of toxicant levels frequently encountered in the environment, this would be of even greater potential importance in providing efficient means of analyzing this diverse array of chemicals. Of all of the effects associated with toxicant exposure, one of the few that appears to be common to multiple chemically diverse substances is the ability of these agents to cause cells to become more oxidized. The ability to cause cells to become more oxidized is shared by many toxicants, regardless of their chemical structure
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