Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, People's Republic of China.
Laboratory of Veterinary Pharmacology and Toxicology, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, People's Republic of China.
Arch Toxicol. 2018 Mar;92(3):1267-1281. doi: 10.1007/s00204-017-2113-8. Epub 2017 Nov 11.
Maduramicin, an excellent ionophore antibiotic, is extensively used to control coccidiosis in poultry. Numerous maduramicin intoxications have been reported in farm animal and human due to its relatively narrow safety range, with necrosis or degeneration of cardiac and skeletal muscles as hallmark. To date, the mechanisms of maduramicin-induced cardiotoxicity remain unclear in chicken and other animals. Maduramicin (5 µg/mL)-treated primary chicken myocardial cells were used for RNA sequencing (RNA-Seq) and bioinformatics analysis in this study. A total of 1442 differential expressed genes were identified. 810 genes were up-regulated and the rest 632 genes were down-regulated. Transcriptome analysis revealed that the cytokine-cytokine receptor interaction, apoptosis, calcium signal and cytoplasmic vacuolization pathways were significantly affected. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis showed that gene expression patterns were consistent with RNA-Seq analysis. Pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8), apoptosis ratios, cleaved caspase-3, intracellular calcium level and Ca-ATPase activity were elevated after maduramicin (0.05, 0.5 and 5 µg/mL) treatment. Massive vacuole formation was found in the cytoplasm by morphology and transmission electron microscopy observation. Taken together, the results suggested that maduramicin exerted its cardiotoxicity by multiple molecular mechanisms in primary chicken myocardial cells.
麦迪霉素是一种优秀的离子载体抗生素，广泛用于控制家禽的球虫病。由于其安全性范围较窄，已有许多农场动物和人类因麦迪霉素中毒的报道，其特征是心肌和骨骼肌坏死或退化。迄今为止，麦迪霉素引起鸡和其他动物的心脏毒性的机制尚不清楚。本研究中，使用 5 µg/mL 麦迪霉素处理原代鸡心肌细胞进行 RNA 测序（RNA-Seq）和生物信息学分析。共鉴定出 1442 个差异表达基因。810 个基因上调，其余 632 个基因下调。转录组分析表明，细胞因子-细胞因子受体相互作用、细胞凋亡、钙信号和细胞质空泡化途径受到显著影响。实时定量聚合酶链反应（RT-qPCR）分析表明，基因表达模式与 RNA-Seq 分析一致。炎性细胞因子，如肿瘤坏死因子-α（TNF-α）和白细胞介素-8（IL-8），细胞凋亡比例，caspase-3 切割，细胞内钙水平和 Ca-ATP 酶活性在麦迪霉素（0.05、0.5 和 5 µg/mL）处理后升高。形态学和透射电子显微镜观察发现细胞质中形成大量空泡。综上所述，这些结果表明麦迪霉素通过原代鸡心肌细胞中的多种分子机制发挥其心脏毒性作用。
