The studies proposed herein are designed to look at olfactory mucosal metabolic capabilities and susceptibility to olfactory toxic agents as they vary with age, and to investigate, using a transgenic mouse model, whether damage to the olfactory mucosa causes detectable damage to tracts dependent upon olfactory sensory input in the central nervous system. The studies to characterize alterations in metabolic capabilities across different age groups is a result of observations that there are age- dependent differences in dose-response to two systemically-administered olfactory mucosal toxicants (i.e. beta-beta-iminodipropionitrile and methimazole). Therefore, a major effort will be put into quantitating metabolic activities in olfactory mucosal and cytosolic preparations (e.g. various P450 isozymes, the flavin-containing monooxygenases, epoxide hydrolase, and glutathione S-transferase isozymes) in pre- pubescent, young adult, and aged male Long-Evans rats. The transgenic mouse studies stem from two different lines of thought. First, there is hesitation on the part of some regulators as to whether olfactory mucosal changes are appropriate endpoints for risk assessment calculations, as the olfactory epithelium has extensive regenerative capabilities. There are also suggestions among the published literature that damage to the olfactory system is associated with the development of neurodegenerative diseases. The lacZ-GFAP transgenic mouse model will allow for visualization of reactive astrocytes within the central nervous system in order to infer where neuronal loss has occurred in response to loss of sensory input to the olfactory bulb.
