Neurotoxic, Inflammatory, and Mucosecretory Responses in the Nasal Airways of Mice Repeatedly Exposed to the Macrocyclic Trichothecene Mycotoxin Roridin A: Dose-Response and Persistence of Injury

摘要

Macrocyclic trichothecene mycotoxins encountered in water-damaged buildings have been suggested to contribute to illnesses of the upper respiratory tract. Here, the authors characterized the adverse effects of repeated exposures to roridin A (RA), a representative macrocyclic trichothecene, on the nasal airways of mice and assessed the persistence of these effects. Young, adult, female C57BL/6 mice were exposed to single daily, intranasal, instillations of RA (0.4,2, 10, or 50 ng/kg body weight [bw]) in saline (50 ul) or saline alone (controls) over 3 weeks or 250 |xg/kg RA over2 weeks. Histopathologic, immunohistochemical, and morphometric analyses of nasal airways conducted 24 hr after the last instillation revealed that the lowest-effect level was 10 ug/kg bw. RA exposure induced a dose-dependent, neutrophilic rhinitis with mucus hypersecretion, atrophy and exfoliation of nasal transitional and respiratory epithelium, olfactory epithelial atrophy and loss of olfactory sensory neurons (OSNs). In a second study, the persistence of lesions in mice instilled with 250 ug/kg bw RA was assessed. Nasal inflammation and excess luminal mucus were resolved after3 weeks, but OSN loss was still evident in olfactory epithelium (OE). These results suggest that nasal inflammation, mucus hypersecretion, and olfactory neurotoxicity could be important adverse health effects associated with short-term, repeated, airborne exposures to macrocyclic trichothecenes.