Cylindrospermopsin toxicity in mice following a 90-d oral exposure
Cylindrospermopsin toxicity in mice following a 90-d oral exposure
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DOI：
10.1080/15287394.2018.1460787
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发表时间：
2018-01-01
影响因子：
2.6
通讯作者：
Wood, C. R.
中科院分区：
文献类型：
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作者：
Chernoff, N.;Hilla, D. J.;Wood, C. R.
Cylindrospermopsin (CYN) 是一种与世界各地多种淡水蓝藻相关的毒素。据推测，这种病毒通过处理后的饮用水在澳大利亚引发了严重疾病，并对接触农场池塘水的牲畜造成了致命影响。毒性包括表明肝和肾功能障碍的影响。在人类中，症状从最初的肝肿大、呕吐和不适发展为酸中毒和低钾血症、血性腹泻和粘膜充血。实验动物研究主要涉及腹膜内（i.p.）给药途径，并证实了这种毒性模式，肝酶活性和组织病理学的变化与肝损伤和不良肾脏影响一致。本研究的目的旨在评估小鼠亚慢性口服暴露（90天）纯化CYN（75至300μg/kg/天）。在给药期结束时，对动物的检查发现：（1）所有剂量水平下肝脏和肾脏的器官与体重比升高，（2）与治疗相关的血清丙氨酸转氨酶（ALT）活性增加，（3）雄性的血尿素氮（BUN）和胆固醇浓度降低，以及（4）两性的单核细胞计数升高。组织病理学改变包括肝细胞肥大和肝索破坏，以及肾细胞肥大、肾小管扩张和皮质小管病变，这些在男性中更为突出。一系列差异表达的基因包括Bax（细胞凋亡）、Rpl6（组织再生）、Fabp4（脂肪酸代谢）和Proc（凝血）。男性对许多提示毒性的肾脏终点更为敏感。暴露结束时，所有剂量水平均出现毒性，75 μg/kg 组对肝脏和肾脏/体重比、BUN 降低、血清单核细胞增加以及多种组织病理学迹象均表现出显着影响，表明任何剂量水平都无法确定未观察到的不良反应水平。
Cylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is postulated to have caused an episode of serious illnesses in Australia through treated drinking water, as well as lethal effects in livestock exposed to water from farm ponds. Toxicity included effects indicative of both hepatic and renal dysfunction. In humans, symptoms progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies predominantly involved the intraperitoneal (i.p.) route of administration and confirmed this pattern of toxicity with changes in liver enzyme activities and histopathology consistent with hepatic injury and adverse renal effects. The aim of this study was designed to assess subchronic oral exposure (90d) of purified CYN from 75 to 300 mu g/kg/d in mouse. At the end of the dosing period, examinations of animals noted (1) elevated organ to body weight ratios of liver and kidney at all dose levels, (2) treatment-related increases in serum alanine aminotransferase (ALT) activity, (3) decreased blood urea nitrogen (BUN) and cholesterol concentrations in males, and (4) elevated monocyte counts in both genders. Histopathological alterations included hepatocellular hypertrophy and cord disruption in the liver, as well as renal cellular hypertrophy, tubule dilation, and cortical tubule lesions that were more prominent in males. A series of genes were differentially expressed including Bax (apoptosis), Rpl6 (tissue regeneration), Fabp4 (fatty acid metabolism), and Proc (blood coagulation). Males were more sensitive to many renal end points suggestive of toxicity. At the end of exposure, toxicity was noted at all dose levels, and the 75 mu g/kg group exhibited significant effects in liver and kidney/body weight ratios, reduced BUN, increased serum monocytes, and multiple signs of histopathology indicating that a no-observed-adverse-effect level could not be determined for any dose level.