Environmental Health Perspectives Volume 114

[Guest guest]

Environmental Health Perspectives Volume 114, Number 7, July 2006

http://www.ehponline.com/members/2006/8854/8854.html

Research

- Abstract (HTML)

- Full (PDF)

- Related EHP Articles

- PubMed:Related Articles

- PubMed:Citation

- PubMed:References

- Cited in PMC

- Purchase This Issue

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 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

•Introduction

•Materials and Methods

•Results

•Discussion

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@...

We thank L. Bramble, M. , A. Porter, R. Rosebury, K. , 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.

Introduction

Numerous adverse human health effects have been attributed to damp indoor air

environments generated by aberrant water exposure due to excessive condensation

and failure of water-use devices, as well as building envelope breach during

heavy rains or flooding, as occurred during Hurricanes Katrina and Rita on the

Gulf Coast of the United States. An Institute of Medicine (IOM) expert panel

concluded that an association exists between damp buildings and upper

respiratory tract symptoms, wheeze, cough, and exacerbation of chronic lung

diseases such as asthma, whereas supportive data for other reported outcomes

such as neurocognitive dysfunction, mucous membrane irritation, fatigue, fever,

and immune disorders are lacking (IOM 2004). Building-related illnesses are

often linked to dampness-promoted growth of fungi (Fog Nielsen 2003) and, most

notably, Stachybotrys chartarum, a saprophytic " black mold " that grows on

cellulosic materials, including wallboard, ceiling tiles, and cardboard (Hossain

et al. 2004). Incidences of indoor S. chartarum contamination often generate

costly litigation and remediation, are extensively reported by the media, and

have evoked intense public and scientific controversy (Hardin et al. 2003). The

IOM panel suggested that although in vitro and in vivo research on S. chartarum

and its mycotoxins suggests that adverse effects in humans are indeed

" biologically plausible, " their association with building-related illnesses

requires rigorous validation from the perspectives of mechanisms, dose response,

and exposure assessment (IOM 2004).

The satratoxins, macrocyclic trichothecenes produced by S. chartarum, are potent

inhibitors of protein translation that initiate both inflammatory gene

expression and apoptosis in vitro after upstream activation of mitogen-activated

protein kinases (MAPKs) (Chung et al. 2003; Yang et al. 2000). Satratoxin

equivalent airborne concentrations ranging from 2 to 34 ng/m3 (Yike et al. 1999)

and from 54 to 330 ng/m3 (Vesper et al. 2000) have been previously estimated, by

a translational bioassay, to occur in rooms of water-damaged homes heavily

contaminated with Stachybotrys. These water-soluble mycotoxins occur in the

outer plasmalemma surface and the inner wall layers of conidiospores ( et

al. 2004) as well as in nonviable airborne particulates (Brasel et al. 2005),

which could facilitate entry and release into respiratory

[Guest guest]

Thanks, KC and Hi!

>

> Environmental Health Perspectives Volume 114, Number 7, July 2006

>

>

> http://www.ehponline.com/members/2006/8854/8854.html

>

>

>

> Research

>