The olfactory mucosa has recently been found to be a rich source of metabolic enzymes as well as a target tissue for various xenobiotic exposures. Destruction of the olfactory mucosa not only compromises the sense of smell, but also results in persistent gliotic changes in the olfactory bulb. Though the consequences of this CNS lesion are unknown, the olfactory mucosa is capable of partial to complete recovery following destruction by xenobiotics. A wide range of structurally varied compounds have been identified as olfactory toxicants. This proposal deals with elucidating the mechanism of olfactory toxicity of several of these compounds, e.g., the model neurotoxicant beta,beta'- iminodipropionitrile [IDPN], the herbicide 2,6-dichlorobenzonitrile [dichlobenil], its primary environmental metabolite 2,6-dichlorobenzamide [DBA], and the related herbicide 2,6-dichlorothiobenzamide [DTB], as well as testing the latter three compounds to determine whether they cause behavioral changes similar to the """"""""waltzing syndrome,"""""""" memory loss, and hearing deficits caused by IDPN. In addition, a series of unsaturated aliphatic organonitriles will be examined for potential olfactory toxicity; the outcome of these studies will provide important clues into the mechanism of olfactory toxicity of these and other olfactory toxicants, as well as aiding in structure-activity predictions as to what other compounds might have this effect. As there is a real potential for human exposure to dichlobenil and DTB, with their numerous terrestrial and aquatic herbicidal uses, determination of whether ethanol consumption (putatively through the induction of cytochrome P450 2E1) enhances the olfactory toxicity of dichlobenil and/or DB. This phenomenon has been observed in this laboratory in rats whose P450 2E1 activity was induced with acetone prior to IDPN treatment. We will also determine whether dermal exposure to dichlobenil or DTB results in olfactory epithelial damage, and whether skin microsomes can metabolize dichlobenil, as this is the most significant route of human exposure to most pesticides.
| Bain, L J; McLachlan, J B; LeBlanc, G A (1997) Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein. Environ Health Perspect 105:812-8 |
| LeBlanc, G A; Bain, L J; Wilson, V S (1997) Pesticides: multiple mechanisms of demasculinization. Mol Cell Endocrinol 126:1-5 |
