Herbert E. Lowndes - US grants

Peripheral sensory nerve terminals appear more susceptible than their motor counterparts to the neurotoxic effects of certain agents. A lesion in the spinal cord termination of these nerves, corresponding to that in the peripheral terminals, would result in incorrect integration of proprioceptive information at spinal synapses and thus compound the peripheral defect. Primary afferent terminal function will be investigated in cats with neuropathies included by acrylamide or doxorubicin. Specifically, synapses subserving segmental reflexes and the cells of origin of the dorsal spinocerebellar tracts will be electrophysiologically evaluated. These data will be correlated with those with morphological studies in an attempt to ascertain the contribution of spinal cord defects make to the clinical signs of the peripheral neuropathies.

fluorescence microscopy; biomedical equipment resource;

biomedical equipment purchase;

This application, prepared in response to RFA ES-91-02, will address the need for additional studies on neurological and behavioral aspects of chemicals commonly found in Superfund dumpsites. Research focus within the eight multidisciplinary projects of the program will be achieved by addressing specifically the neurotoxicity of selected solvents (trichloroethylene, monochloroacetic acid, related halogenated hydrocarbons) and metals (lead). Projects have been designed to examine: 1. the hydrogeology of solvents. 2. the neurotoxicity of solvents at the biochemical/cellular levels. 3. the neurotoxicity of lead on developing and adult neuronal systems. 4. the ecological and human neurobehavioral responses to lead and solvents. 5. engineering approaches to the biological treatment of Superfund contaminants. These studies will be conducted by members of the Environmental and Occupational Health Sciences Institute, a research institute comprising investigators from Rutgers, The State University of New Jersey and R.W. Johnson Medical School, The University of Medicine and Dentistry of New Jersey.

environmental toxicology; neurotoxins; biomedical facility; developmental neurobiology; toxin metabolism; histology; enzyme structure;

The overall goal of this research program is to establish the relationship between expression of xenobiotic metabolizing enzymes, xenobiotic metabolism, and neurotoxicity. The neurotoxicity of many xenobiotics is characterized by remarkably specific involvement of particular cell types (pathoclisis) which may reflect unique differences in xenobiotic metabolism in targeted cells. The hypothesis of the proposed research is that regulation of expression of phase I and phase II enzymes in the nervous system is cell specific and this heterogeneity forms the basis for selective vulnerability of cells to some neurotoxicants. Preliminary data using immunocytochemistry and RT-PCR analysis show that CYP2E1, and class alpha, mu, and pi glutathione S-transferase (GST) expression is cell- specific in neural tissues. The proposed experiments will focus on the cerebellum and dorsal root ganglia (DRG) since certain cell types in these tissues exhibit selective vulnerability to experimental and therapeutic neurotoxicants. Gender and species differences in susceptibility to neurotoxicants will be exploited to determine relative contributions of the metabolic enzymes to neurotoxic outcome. Since little information is presently available regarding distribution of drug metabolizing enzymes in the nervous system, systematic characterization of the distribution of the enzymes and their responses to known inducers is required prior to testing the hypothesis using selected neurotoxic agents. Thus, the specific objectives of this research are addressed by the following questions: 1. Are there cell-specific patterns in the distribution of the xenobiotic metabolizing enzymes in cerebellum and DRG (which predispose discrete cellular populations to neurotoxicity)? 2. Are drug metabolizing enzymes in the brain inducible by xenobiotics and if so, is the induction cell-specific? 3. Does the cellular distribution of xenobiotic metabolizing enzymes determine and influence the cells response to neurotoxic chemicals? The relationships will be examined in two pathoclitic models of neurotoxicity; a. Acrylamide neurotoxicity in cerebellum and DRG. b. Methyl chloride neurotoxicity to cerebellar granule cells. These objectives will be approached using a variety of contemporary methodologies capable of detecting the distribution and expression of phase I and II enzymes in vivo and in vitro. The data resulting from these studies will provide a foundation for future mechanistic studies in which manipulation of enzyme level or activity, alone or in combination with other approaches, may be employed to determine the basis of neurotoxicity.