The nematode, Caenorhabditis elegans, as a model for mammalian cholinergic neurotoxicity
Melstrom, Paul Cory
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Assessing the toxicity of compounds acting on the nervous system has proved to be difficult, as measurable endpoints are often subjective and fraught with confounding variables. This dissertation examines the potential of Caenorhabditis elegans to serve as a toxicological model for mammalian neurotoxicity. The intent is to focus on one component of C. elegans’ nervous system, the cholinergic nervous system, and determine how its responses to well-characterized agonists and antagonists compare to the responses of mammals. The literature pertaining to the acetylcholinesterase enzymes and the acetylcholinergic receptors of C. elegans is reviewed, as well as the literature pertaining to toxicological studies using C. elegans. In the first experiment, C. elegans was exposed to the reversible AChE-inhibitor carbamate class of pesticides in order to determine whether the endpoint, movement, could be used with reversible compounds by predicting their relative potencies in mammals. Given the functional redundancy of C. elegans’ AChE enzymes, movement was measured to assess whether there was a difference in the contributions of either of the two main classes of AChE enzymes, and whether this difference influences the sensitivity of measuring movement in the second experiment. Next, agonists and antagonists that are well-characterized in ACh-activated receptors of vertebrates and some nematode species were exposed to C. elegans, and measuring movement was used to determine whether their actions would be the same in C. elegans. Finally, some preliminary work on a new method to recover C. elegans from soil for toxicity testing is discussed.