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.

Ochratoxin A induces apoptosis in neuronal cells

“…In accordance to our OTA data, fumonisin B 1 (FB 1 ) [31] as well as trichothecene mycotoxins [15] have been demonstrated to induce apoptosis in cultured neurons.…”

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

“…In contrast, the OE lining the dorsal medial meatus of the mouse nasal cavity had no microscopic evidence of SG-induced injury (Islam et al 2006). This same distribution of injury was also observed in mice following exposure to another macrocyclic trichothecene mycotoxin, roridin-A (Islam et al 2007). One possible explanation for this interspecies variation is the difference in airflow patterns through the nasal airways of rodents and nonhuman primates.…”

“…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.…”

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

“…We previously reported that single, intranasal instillations of RA cause OE atrophy, loss of OSNs, and OB atrophy (Islam et al 2007). Single instillations of RA also resulted in neutrophil infiltration in the affected OE and associated lamina propria.…”

“…We have demonstrated that mice instilled once intranasally with a relatively low amount (250 ng) of the macrocyclic trichothecene satratoxin G (SG) develop rapid and dramatic loss of olfactory sensory neurons (OSNs), through apoptosis, in both the nose and brain (Islam, Harkema, and Pestka 2006). In a subsequent study, it was found that roridin A (RA), a macrocyclic trichothecene with a similar chemical structure, similarly induced rapid apoptosis and marked loss of OSNs in the nasal airways and the olfactory bulb (OB) of mice after a single intranasal instillation (Islam et al 2007).…”