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Circulating levels of miR-122 increase post-mortem, particularly following lethal dosing with pentobarbital sodium: implications for pre-clinical liver injury studies.
Toxicology Research ( IF 2.1 ) Pub Date : 2017-04-11 , DOI: 10.1039/c6tx00442c
Joanna I Clarke 1 , Shiva Seyed Forootan 1 , Jonathan D Lea 1 , Lawrence S Howell 1 , Josep Monne Rodriguez 2 , Anja Kipar 2 , Christopher E Goldring 1 , B Kevin Park 1 , Ian M Copple 1 , Daniel J Antoine 1
Affiliation  

microRNA-122 (miR-122) is increasingly being measured in pre-clinical and clinical settings due to greater sensitivity and hepatic specificity compared to the gold standard liver injury biomarker alanine aminotransferase (ALT). In pre-clinical studies, various culling methods can be employed prior to collection of blood samples, including lethal injection with pentobarbital sodium (Pentoject). However, little is known about whether such an approach could alter the circulating levels of miR-122 and compromise the interpretation of data. We therefore exposed C57BL/6J mice to saline or the model hepatotoxin paracetamol and collected blood samples pre-cull (via tail bleed) and post-cull (via cardiac puncture following exposure to a rising concentration of CO2 or intraperitoneal injection of Pentoject). Compared to pre-cull levels there was a significant increase in serum miR-122 level in mice culled with CO2 and, to a much greater extent, in mice culled with Pentoject. As a result, whilst the serum level of miR-122 increased in Pentoject-culled animals exposed to paracetamol, the higher level in saline-treated mice rendered this difference statistically non-significant, in contrast to findings in animals culled with CO2. ALT levels were unaffected by sacrifice method. Consistent with the in vivo findings, exposure of primary mouse hepatocytes to Pentoject provoked a rapid and concentration-dependent release of miR-122 into the culture media. Thus, for optimal design and interpretation of data from pre-clinical liver injury studies in which miR-122 is to be used as a biomarker, we recommend that blood samples are collected pre-cull whenever possible, and that lethal injection with Pentoject is avoided.

中文翻译:

miR-122的循环水平在验尸后增加,尤其是在使用戊巴比妥钠进行致死剂量给药后:对临床前肝损伤研究的意义。

由于与金标准肝损伤生物标志物丙氨酸氨基转移酶(ALT)相比具有更高的敏感性和肝特异性,因此在临床前和临床环境中越来越多地检测到microRNA-122(miR-122)。在临床前研究中,可以在收集血液样本之前采用各种剔除方法,包括使用戊巴比妥钠进行致命注射(Pentoject)。但是,对于这种方法是否会改变miR-122的循环水平并危及数据解释知之甚少。因此,我们将C57BL / 6J小鼠暴露于生理盐水或肝毒素对乙酰氨基酚模型中,并在剔除前(通过尾部出血)和剔除后(通过暴露于浓度不断升高的CO2或经腹膜内注射Pentoject的心脏穿刺)收集血样。与剔除前的水平相比,用CO2剔除的小鼠血清miR-122水平显着提高,而用Pentoject剔除的小鼠血清miR-122水平则更高。结果,虽然在暴露于扑热息痛的Pentoject剔除动物中miR-122的血清水平升高,但与用CO2剔除动物相比,盐水处理的小鼠中较高的水平使这一差异在统计学上不显着。ALT水平不受牺牲方法的影响。与体内发现一致,将原代小鼠肝细胞暴露于Pentoject会引起miR-122快速且浓度依赖性地释放到培养基中。因此,为了优化设计和解释临床前肝损伤研究的数据,其中miR-122用作生物标记,
更新日期:2017-04-11
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