Date of Award

1-1-2011

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Environmental Health Sciences

Content Description

1 online resource (xiii, 127 pages) : illustrations (some color)

Dissertation/Thesis Chair

Xinxin Ding

Committee Members

Laurence Kaminsky, Kurunthachalam Kannan, Jun Gu, David Lawrence

Keywords

Herbicides, Mice as laboratory animals

Subject Categories

Toxicology

Abstract

The overall goal of this study is to investigate mechanisms of the potent nasal specific toxicity of the herbicide 2,6-dichlorobenzonitrile (DCBN) in rodents, and to determine whether DCBN could induce similar nasal toxicity in humans. The central hypotheses are 1) that the nasal specific toxicity of DCBN in rodents is mediated by its electrophilic intermediates that are formed through metabolic activation catalyzed by target tissue cytochrome P450 enzymes (P450) and can interfere with stem cell regeneration and differentiation in the olfactory epithelium (OE); and 2) that human nasal tissues are also capable of catalyzing bioactivation of DCBN. The specific aims are 1) to identify the mouse P450 enzyme(s) responsible for DCBN metabolic activation in vivo, and to determine whether hepatic P450-generated DCBN metabolites play a significant role in DCBN toxicity in the olfactory mucosa (OM); 2) to examine the capability of human nasal tissues to activate DCBN, and to identify potential biomarkers for monitoring DCBN exposure and nasal toxicity; and 3) to determine the role of inflammatory cytokines in the permanent loss of olfactory receptor neurons (ORNs) induced by DCBN in mice.

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