Liu Qianying, Lei Zhixin, Huang Anxiong, Lu Qirong, Wang Xu, Ahmed Saeed, Awais Ihsan, Yuan Zonghui
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, China.
MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, China.
Front Pharmacol. 2017 Sep 26;8:679. doi: 10.3389/fphar.2017.00679. eCollection 2017.
Mequindox (MEQ) is a synthetic antimicrobial agent widely used in China since the 1980s. Although the toxicity of MEQ is well recognized, its testis toxicity has not been adequately investigated. In the present study, we provide evidence that MEQ triggers oxidative stress, mitochondrion dysfunction and spermatogenesis deficiency in mice after exposure to MEQ (0, 25, 55, and 110 mg/kg in the diet) for up to 18 months. The genotoxicity and adrenal toxicity may contribute to sperm abnormalities caused by MEQ. Moreover, using LC/MS-IT-TOF analysis, two metabolites, 3-methyl-2-(1-hydroxyethyl) quinoxaline-4-monoxide (M4) and 3-methyl-2-(1-hydroxyethyl) quinoxaline-1-monoxide (M8), were detected in the serum of mice, which directly confirms the relationship between the →O group reduction metabolism of MEQ and oxidative stress. Interestingly, only M4 was detected in the testes, suggesting that the higher reproductive toxicity of M4 than M8 might be due to the increased stability of M4-radical (M4-R) compared to M8-radical (M8-R). Furthermore, the expression of the blood-testis barrier (BTB)-associated junctions such as tight junctions, gap junctions and basal ectoplasmic specializations were also examined. The present study demonstrated for the first time the role of the M4 in testis toxicity, and illustrated that the oxidative stress, mitochondrion dysfunction and interference in spermatogenesis, as well as the altered expression of BTB related junctions, were involved in the reproductive toxicity mediated by MEQ .
喹乙醇（MEQ）是一种合成抗菌剂，自20世纪80年代以来在中国广泛使用。尽管MEQ的毒性已得到充分认识，但其对睾丸的毒性尚未得到充分研究。在本研究中，我们提供证据表明，小鼠在摄入MEQ（饲料中含量为0、25、55和110mg/kg）长达18个月后，MEQ会引发氧化应激、线粒体功能障碍和精子发生缺陷。遗传毒性和肾上腺毒性可能是MEQ导致精子异常的原因。此外，通过液相色谱/质谱-离子阱-飞行时间分析，在小鼠血清中检测到两种代谢产物，3-甲基-2-(1-羟乙基)喹喔啉-4-一氧化物（M4）和3-甲基-2-(1-羟乙基)喹喔啉-1-一氧化物（M8），这直接证实了MEQ的→O基团还原代谢与氧化应激之间的关系。有趣的是，在睾丸中仅检测到M4，这表明M4比M8具有更高的生殖毒性可能是由于M4自由基（M4-R）比M8自由基（M8-R）具有更高的稳定性。此外，还检测了血睾屏障（BTB）相关连接蛋白如紧密连接、缝隙连接和基底外质特化的表达。本研究首次证明了M4在睾丸毒性中的作用，并表明氧化应激、线粒体功能障碍和对精子发生的干扰，以及BTB相关连接蛋白表达的改变，均参与了MEQ介导的生殖毒性。
