Assessment of developmental neurotoxicology-associated alterations in neuronal architecture and function using...

Few of the many chemicals that regulatory agencies are charged with assessing for risk have been carefully tested for developmental neurotoxicity (DNT). To speed up assessment, and to reduce the use of vertebrate animals, great effort is being devoted to alternative laboratory models for DNT. A major DNT mechanism is altered neuronal architecture resulting from chemical exposure during neurodevelopment. Caenorhabditis elegans is a nematode that has been extensively studied by neurobiologists and developmental biologists, and to a lesser extent by neurotoxicologists. The development of the nervous system in C. elegans is easily visualized, entirely invariant, and fully mapped. We hypothesized that C. elegans could be a powerful in vivo model to test chemicals for their potential to alter neuronal architecture during development. We developed a novel C. elegans DNT testing paradigm that includes developmental exposure, examines major neurotransmitter neuronal types for architectural alterations, and tests neuron-specific behaviors. We characterized the effects of exposures to the developmental neurotoxicants lead, cadmium, and benzo(a)pyrene on neuronal architecture and specification. We identified no cases in which the apparent neurotransmitter type of the neurons we examined changed, but many in which neuronal morphology was altered. We found that neuron-specific behaviors were altered during C. elegans mid-adulthood for populations with measured morphological neurodegeneration in earlier stages. The functional changes were consistent with the morphological changes in terms of the type of neuron affected. Finally, we identified changes consistent with those reported in the mammalian DNT literature, strengthening the case for C. elegans as a DNT model.