Satratoxin G from the Black Mold Stachybotrys chartarum Evokes Olfactory Sensory Neuron Loss and Inflammation in the Murine Noseand Brain

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-α, 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.

Neurotoxic, Inflammatory, and Mucosecretory Responses in the Nasal Airways of Mice Repeatedly Exposed to the Macrocyclic Trichothecene Mycotoxin Roridin A

“…The DM might have been spared from the effects of a single intranasal instillation of SG because of distinct populations of odorant receptors found in the nose (Islam, Harkema, and Pestka 2006). Ressler, Sullivan, and CORPS ET AL.…”

Satratoxin-G from the Black Mold Stachybotrys chartarum Induces Rhinitis and Apoptosis of Olfactory Sensory Neurons in the Nasal Airways of Rhesus Monkeys

“…Our observations demonstrate that the nasal airways of rhesus macaques, an animal model whose upper airways are structurally and functionally similar to those of humans, are vulnerable to injury induced by SG, and raise new questions about the potential hazards associated with exposure to S. chartarum in water-damaged environments. Olfactory mucosal injury has been previously described in the nasal airways of laboratory mice following intranasal exposure to low doses of SG, as well as other macrocyclic trichothecene mycotoxins (Corps et al 2010;Islam et al 2007Islam et al , 2006. In the present study, we used a comparable, low dose of SG (1 mg per nasal passage) to determine whether the olfactory mucosa of rhesus monkeys, a model for the nasal airways of people, exhibits similar vulnerability.…”

Accelerated Shedding of Prions following Damage to the Olfactory Epithelium

“…It is conceivable that apoptosis of prion-infected ORNs could release prion infectivity into nasal fluids, especially since there is evidence for PrP Sc deposition in terminal dendrites of ORNs that project into the mucus layer. ORNs are also the most environmentally exposed subset of neurons, and there are many types of environmental factors that can cause stress to ORNs and induce apoptosis (3,16,22,24,25,34,43,57,61). An increase in ORN apoptosis can also disrupt the mucosal integrity of the OSE and cause a sloughing off of cells into the nasal airway.…”

“…However, many environment-borne pathogens, toxins, and chemicals can induce apoptosis of ORNs, leading to hyposmia or anosmia. Those insults that can induce apoptosis in ORNs include viruses, bacteria, fungi, bacterial cell wall components, mycotoxins, allergies, man-made chemicals dispersed in the environment, and tobacco smoke (3,16,22,24,25,34,43,57,61). Since encounters with these biological and environmental nasotoxic insults can occur often and multiple times, we investigated whether an increase in apoptosis of ORNs or damage to the OSE in a prion-infected host could increase the amount of prion infectivity released into nasal fluids.…”