Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene mycotoxin roridin a: kinetics and potentiation by bacterial lipopolysaccharide coexposure.

Abstract

Macrocyclic trichothecene mycotoxins produced by indoor air molds potentially contribute to symptoms associated with damp building illnesses. The purpose of this investigation was to determine (1) the kinetics of nasal inflammation and neurotoxicity after a single intranasal instillation of roridin A (RA), a representative macrocyclic trichothecene; and (2) the capacity of lipopolysaccharide (LPS) to modulate RA's effects. C57Bl/6 female mice were intranasally instilled once with 50 mul of RA (500 mug/kg body weight [bw]) in saline or saline only and then nose and brain tissues were collected over 72 h and processed for histopathologic and messenger RNA (mRNA) analysis. RA-induced apoptosis specifically in olfactory sensory neurons (OSNs) after 24 h postinstillation (PI) causing marked atrophy of olfactory epithelium (OE) that was maximal at 72 h PI. Concurrently, there was marked bilateral atrophy of olfactory nerve layer of the olfactory bulbs (OBs) of the brain. In the ethmoid turbinates, upregulated messenger RNA (mRNA) expression of the proapoptotic gene FAS and the proinflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-6, IL-1, and macrophage inhibitory protein-2 was observed from 6 to 24 h PI, whereas expression of several other proapoptotic genes (PKR, p53, Bax, and caspase-activated DNAse) was detectable only at 24 h PI. Simultaneous exposure to LPS (500 ng/kg bw) and a lower dose of RA (250 mug/kg bw) magnified RA-induced proinflammatory gene expression, apoptosis, and inflammation in the nasal tract. Taken together, the results suggest that RA markedly induced FAS and proinflammatory cytokine expression prior to evoking OSN apoptosis and OE atrophy and that RA's effects were augmented by LPS.

• Authors: Zahidul Islam, Chidozie J Amuzie, Jack R Harkema, James J Pestka
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 98 Issue 2 Pg. 526-41 (Aug 2007) ISSN: 1096-6080 [Print] United States
• PMID: 17483119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Lipopolysaccharides
• Mycotoxins
• RNA, Messenger
• Trichothecenes
• fas Receptor
• roridin A

Topics

• Animals
• Apoptosis
• Cytokines (genetics)
• Drug Synergism
• Female
• Gene Expression Regulation (drug effects)
• Kinetics
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred C57BL
• Mycotoxins (toxicity)
• Nasal Mucosa (drug effects, immunology, pathology)
• Neurons, Afferent (drug effects, pathology)
• Neurotoxicity Syndromes (etiology, immunology, pathology)
• Neutrophils (drug effects, immunology)
• Olfactory Bulb (drug effects, immunology)
• RNA, Messenger (metabolism)
• Rhinitis (chemically induced, immunology, pathology)
• Trichothecenes (toxicity)
• fas Receptor (genetics)