Islam Zahidul, Harkema Jack R, Pestka James J
Center for Integrative Toxicology, Department of Microbiology and Molecular Genetics, and Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, USA.
Environ Health Perspect. 2006 Jul;114(7):1099-107. doi: 10.1289/ehp.8854.
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 microg/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 microg/kg bw) indicated that maximum atrophy of the olfactory epithelium occurred at 3 days PI. Exposure to lower doses (100 microg/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-alpha, 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.
葡萄穗霉毒素G（SG）是由链格孢菌产生的一种大环单端孢霉烯族霉菌毒素，这种“黑霉菌”被认为在病因上与水浸建筑相关疾病有关。通过在小鼠中使用滴鼻给药模型，我们发现急性SG暴露特异性地诱导了嗅觉上皮中嗅觉感觉神经元（OSN）的凋亡。剂量反应分析显示，滴鼻后24小时（PI）的无效应和最低效应水平分别为5和25微克/千克体重（bw）的SG，且严重程度随剂量增加。使用免疫组织化学检测半胱天冬酶-3表达、电子显微镜观察超微结构细胞形态以及实时聚合酶链反应检测促凋亡基因Fas、FasL、p75NGFR、p53、Bax、半胱天冬酶-3和CAD的表达升高来鉴定OSN的凋亡。单次滴鼻SG（500微克/千克bw）的时间进程研究表明，嗅觉上皮的最大萎缩在滴鼻后3天出现。连续5天暴露于较低剂量（100微克/千克bw）导致类似的萎缩和凋亡，表明在短期内，这些效应是累积的。SG还早在滴鼻后24小时就诱导了急性嗜中性鼻炎。在滴鼻后24小时，在鼻气道的筛鼻甲和相邻的脑嗅球中均检测到促炎细胞因子肿瘤坏死因子-α、白细胞介素-6（IL-6）和IL-1以及趋化因子巨噬细胞炎性蛋白-2（MIP-2）的mRNA表达升高。到滴鼻后7天，还可检测到嗅神经和嗅球的肾小球层明显萎缩以及轻度嗜中性脑炎。这些发现表明，鼻子和大脑内的神经毒性和炎症是暴露于水浸建筑室内空气中的葡萄穗霉毒素和链格孢菌的潜在不良健康影响。
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