| Satratoxin G from the Black Mold Stachybotrys chartarum Evokes Olfactory Sensory Neuron Loss and Inflammation in the Murine Nose and Brain Zahidul Islam,1,2,3 Jack R. Harkema,1,4 and James J. Pestka1,2,3 1Center for Integrative Toxicology, 2Department of Microbiology and Molecular Genetics, 3Department of Food Science and Human Nutrition, and 4Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA Abstract
Satratoxin G (SG) is a macrocyclic trichothecene mycotoxin produced by Stachybotrys chartarum, the "black mold" suggested to contribute etiologically to illnesses associated with water-damaged buildings. Using an intranasal instillation model in mice, we found that acute SG exposure specifically induced apoptosis of olfactory sensory neurons (OSNs) in the olfactory epithelium. Dose-response analysis revealed that the no-effect and lowest-effect levels at 24 hr postinstillation (PI) were 5 and 25 µg/kg body weight (bw) SG, respectively, with severity increasing with dose. Apoptosis of OSNs was identified using immunohistochemistry for caspase-3 expression, electron microscopy for ultrastructural cellular morphology, and real-time polymerase chain reaction for elevated expression of the proapoptotic genes Fas, FasL, p75NGFR, p53, Bax, caspase-3, and CAD. Time-course studies with a single instillation of SG (500 µg/kg bw) indicated that maximum atrophy of the olfactory epithelium occurred at 3 days PI. Exposure to lower doses (100 µg/kg bw) for 5 consecutive days resulted in similar atrophy and apoptosis, suggesting that in the short term, these effects are cumulative. SG also induced an acute, neutrophilic rhinitis as early as 24 hr PI. Elevated mRNA expression for the proinflammatory cytokines tumor necrosis factor- , interleukin-6 (IL-6) , and IL-1 and the chemokine macrophage-inflammatory protein-2 (MIP-2) were detected at 24 hr PI in both the ethmoid turbinates of the nasal airways and the adjacent olfactory bulb of the brain. Marked atrophy of the olfactory nerve and glomerular layers of the olfactory bulb was also detectable by 7 days PI along with mild neutrophilic encephalitis. These findings suggest that neurotoxicity and inflammation within the nose and brain are potential adverse health effects of exposure to satratoxins and Stachybotrys in the indoor air of water-damaged buildings. Key words: apoptosis, fungus, inflammation, inhalation, mycotoxin, neurotoxicity, olfactory sensory neuron, rhinitis, trichothecene. Environ Health Perspect 114:1099-1107 (2006) . doi:10.1289/ehp.8854 available via http://dx.doi.org/ [Online 27 February 2006]
Address correspondence to J.J. Pestka, 234 G.M. Trout Building, Michigan State University, East Lansing, MI 48824 USA. Telephone: (517) 353-1709. Fax: (517) 353-8963. E-mail: pestka@msu.edu We thank L. Bramble, M. Perry, A. Porter, R. Rosebury, K. Campbell, R. Common, D. Craft, L. Chen, B. Chamberlin, and A. Thelen for their technical assistance. This research was funded by a Michigan State University Foundation Strategic Partnership Grant, the Michigan State Health and Biomedical Research Initiative I, and U.S. Public Health Service grant ES03358 (J.J.P.) from the National Institute of Environmental Health Sciences. The authors declare they have no competing financial interests. Received 14 November 2005 ; accepted 27 February 2006.
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