Topal Tuana Rana, Karan Mehmet, Çavuşoğlu Kültiğin, Yalçın Emine
Department of Biology, Institute of Science, Giresun University, Giresun, Turkey.
Department of Biology, Faculty of Science and Art, Giresun University, 28200, Giresun, Turkey.
Sci Rep. 2025 Jul 18;15(1):26187. doi: 10.1038/s41598-025-12230-0.
In this study, toxic effects of metronidazole (Mtz) on albino mice, a non-target organism, were investigated using organ weight, genotoxicity assays, serum markers, liver and kidney histopathology. Mice were administered three different doses of Mtz (125-500 mg/kg, 250 mg/kg and 500 mg/kg) by oral gavage. The mice in each group were sacrificed at the end of the 14th day, blood and tissue samples were collected. Liver weight increased with Mtz treatment, the highest organ weight was 2.29 ± 0.22 g in the group treated with 500 mg/kg Mtz and increased by 57.9% compared to the control group. Similary, in the 500 mg/kg Mtz treated group, kidney organ weight was 0.59 ± 0.36 g and 37.3% increase was found compared to the control group. Mtz exposure caused statistically significant increases in the micronucleus (MN) frequency and chromosomal abnormalities (CAs), as well as a decrease in cell proliferation. Compared to the control group, mitotic index (MI) decreased by 6.8% in the 125 mg/kg b.w Mtz group, 16.5% in the 250 mg/kg Mtz group and 25.6% in the 500 mg/kg Mtz group. Comet assay revealed that Mtz exposure caused significant DNA fragmentation at all three treatment doses. Compared to the control group, the percentage of head DNA decreased by approximately 32% in the 500 mg/kg b.w Mtz treated group, while the percentage of tail DNA increased by 727%. MI, MN, CAs and Comet test results support each other and confirm the genotoxic effect of Mtz. Changes in serum marker enzymes indicate liver and kidney damage, which is also supported by histopathological examinations. Blood urea nitrogen levels increased by 16.7% and 25.8% in the 250 mg/kg and 500 mg/kg Mtz groups, respectively. The increase in creatinine levels ranged from 13 to 19.2%. In the 500 mg/kg Mtz-treated group, alanine aminotransferase and aspartate aminotransferase levels were also increased and these increases were 41% and 21.3%, respectively, compared to control. These abnormalities in liver and kidney markers were confirmed by histopathological examinations. Inflammation, glomerular hypertrophy, hyaline casts, crystal deposition, necrosis and tubular dilatation were found in the kidney. In the liver, inflammation, fibrosis, congestion, giant cells, apoptosis, necrosis, binuclear cells and hepatocyte hypertrophy were found. In conclusion, Mtz, which is used in the treatment of bacterial infections, may be toxic to albino mice, which are classified as mammals, such as humans. Consequently, a re-evaluation of the doses and administration times of Mtz, a pharmaceutical agent employed in the treatment of various infections, should be a priority for human health.
在本研究中，使用器官重量、遗传毒性检测、血清标志物、肝脏和肾脏组织病理学方法，研究了甲硝唑（Mtz）对非靶标生物白化小鼠的毒性作用。通过口服灌胃给小鼠施用三种不同剂量的Mtz（125 - 500毫克/千克、250毫克/千克和500毫克/千克）。每组小鼠在第14天结束时处死，采集血液和组织样本。Mtz处理后肝脏重量增加，在500毫克/千克Mtz处理组中最高器官重量为2.29±0.22克，与对照组相比增加了57.9%。同样，在500毫克/千克Mtz处理组中，肾脏器官重量为0.59±0.36克，与对照组相比增加了37.3%。Mtz暴露导致微核（MN）频率和染色体异常（CA）在统计学上显著增加，以及细胞增殖减少。与对照组相比，125毫克/千克体重Mtz组的有丝分裂指数（MI）下降了6.8%，250毫克/千克Mtz组下降了16.5%，500毫克/千克Mtz组下降了25.6%。彗星试验表明，在所有三个处理剂量下，Mtz暴露均导致显著的DNA片段化。与对照组相比，500毫克/千克体重Mtz处理组的头部DNA百分比下降了约32%，而尾部DNA百分比增加了727%。MI、MN、CA和彗星试验结果相互支持，证实了Mtz的遗传毒性作用。血清标志物酶的变化表明肝脏和肾脏损伤，组织病理学检查也支持这一点。250毫克/千克和500毫克/千克Mtz组的血尿素氮水平分别增加了16.7%和25.8%。肌酐水平的增加范围为13%至19.2%。在500毫克/千克Mtz处理组中，丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平也升高，与对照组相比，这些升高分别为41%和21.3%。肝脏和肾脏标志物的这些异常通过组织病理学检查得到证实。在肾脏中发现了炎症、肾小球肥大、透明管型、晶体沉积、坏死和肾小管扩张。在肝脏中发现了炎症、纤维化、充血、巨细胞、凋亡、坏死、双核细胞和肝细胞肥大。总之，用于治疗细菌感染的Mtz可能对诸如人类等被归类为哺乳动物的白化小鼠有毒。因此，重新评估用于治疗各种感染的药物制剂Mtz的剂量和给药时间，应成为人类健康的优先事项。
