National Reference Laboratory of Veterinary Drug Residues and MOA Key Laboratory of Food Safety Evaluation, Huazhong Agricultural University, Wuhan 430070, PR China.
Toxicol Appl Pharmacol. 2011 May 1;252(3):281-8. doi: 10.1016/j.taap.2011.02.020. Epub 2011 Mar 3.
Mequindox (MEQ) is a synthetic antimicrobial chemical of quinoxaline 1, 4-dioxide group. This study was designed to investigate the hypothesis that MEQ exerts testicular toxicity by causing oxidative stress and steroidal gene expression profiles and determine mechanism of MEQ testicular toxicity. In this study, adult male Wistar rats were fed with MEQ for 180days at five different doses as 0, 25, 55, 110 and 275mg/kg, respectively. In comparison to control, superoxide dismutase (SOD), reduced glutathione (GSH) and 8-hydroxydeoxyguanosine (8-OHdG) levels were elevated at 110 and 275mg/kg MEQ, whereas the malondialdehyde (MDA) level was slightly increase at only 275mg/kg. Furthermore, in LC/MS-IT-TOF analysis, one metabolite 2-isoethanol 4-desoxymequindox (M11) was found in the testis. There was significant decrease in body weight, testicular weight and testosterone at 275mg/kg, serum follicular stimulating hormone (FSH) at 110 and 275mg/kg, while lutinizing hormone (LH) levels were elevated at 110mg/kg. Moreover, histopathology of testis exhibited germ cell depletion, contraction of seminiferous tubules and disorganization of the tubular contents of testis. Compared with control, mRNA expression of StAR, P450scc and 17β-HSD in testis was significantly decreased after exposure of 275mg/kg MEQ while AR and 3β-HSD mRNA expression were significantly elevated at the 110mg/kg MEQ group. Taken together, our findings provide the first and direct evidence in vivo for the formation of free radicals during the MEQ metabolism through N→O group reduction, which may have implications to understand the possible mechanism of male infertility related to quinoxaline derivatives.
美喹多司（MEQ）是一种合成的喹喔啉 1,4-二氧化物类抗菌化学物质。本研究旨在通过检测 MEQ 是否会引起氧化应激和甾体基因表达谱变化来验证 MEQ 产生睾丸毒性的假说，并确定 MEQ 睾丸毒性的作用机制。在这项研究中，成年雄性 Wistar 大鼠分别用 0、25、55、110 和 275mg/kg 的 MEQ 连续喂养 180 天。与对照组相比，275mg/kg 的 MEQ 可使超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）和 8-羟基脱氧鸟苷（8-OHdG）水平升高，而丙二醛（MDA）水平仅在 275mg/kg 时略有升高。此外，在 LC/MS-IT-TOF 分析中，在睾丸中发现了一种代谢产物 2-异乙醇 4-去甲美喹多司（M11）。275mg/kg 的体重、睾丸重量和睾丸酮，110 和 275mg/kg 的血清卵泡刺激素（FSH），以及 110mg/kg 的促黄体生成素（LH）水平显著降低。此外，睾丸组织病理学显示生精细胞耗竭、精曲小管收缩和管内内容物紊乱。与对照组相比，暴露于 275mg/kg MEQ 后，StAR、P450scc 和 17β-HSD 的 mRNA 表达在睾丸中显著降低，而 AR 和 3β-HSD 的 mRNA 表达在 110mg/kg MEQ 组中显著升高。综上所述，本研究结果首次直接提供了体内证据，证明 MEQ 通过 N→O 基团还原代谢产生自由基，这可能有助于理解与喹喔啉衍生物相关的男性不育的可能机制。
