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 testing efforts, as well as to reduce the use of vertebrate animals, great effort is being devoted to alternate laboratory models for testing DNT. A major mechanism of DNT 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 developmental trajectory of the nervous system in C. elegans is easily visualized, normally entirely invariant, and fully mapped. Therefore, we hypothesized that C. elegans could be a powerful in vivo model to test chemicals for the potential to alter developmental patterning of neuronal architecture. To test whether this might be true, we developed a novel C. elegans DNT testing paradigm that includes exposure throughout development, examines all major neurotransmitter neuronal types for architectural alterations, and tests behaviors specific to dopaminergic, cholinergic, and glutamatergic functions. We used this paradigm to characterize the effects of early-life exposures to the developmental neurotoxicants lead, cadmium, and benzo(a)pyrene (BaP) on dopaminergic, cholinergic, and glutamatergic architecture. We also assessed whether exposures would alter neuronal specification as assessed by expression of reporter genes diagnostic of specific neurotransmitters. 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 also 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 we observed in terms of type of neuron affected. We identified changes consistent with those reported in the mammalian DNT literature, strengthening the case for C. elegans as a DNT model, and made novel observations that should be followed up in future studies.