Abstract
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-N4-monoxide (M4) and 3-methyl-2-(1-hydroxyethyl) quinoxaline-N1-monoxide (M8), were detected in the serum of mice, which directly confirms the relationship between the N→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 in vivo.
Highlights
Mequindox (3-methyl-2-acetyl-N-1,4-dioxyquinoxaline, C11H10N2O3; MEQ) (Figure 1) is structurally similar to QdNOs, a group of chemicals consisting of one or two acyclic chain moieties combined with a quinoxaline ring
To verify the hypothesis that MEQ may pass through the blood-testis barrier (BTB) into the testes to cause reproductive toxicity, we identified MEQ and its metabolites in serum and testis by LC/MS-IT-TOF analysis according to the retention times and fragment ions
The results demonstrated that the metabolites of MEQ, oxidative stress, mitochondrion dysfunction and spermatogenesis deficiency are involved in the reproductive toxicity in mice after the chronic administration of MEQ for up to 18 months
Summary
Mequindox (3-methyl-2-acetyl-N-1,4-dioxyquinoxaline, C11H10N2O3; MEQ) (Figure 1) is structurally similar to QdNOs, a group of chemicals consisting of one or two acyclic chain moieties combined with a quinoxaline ring. QdNOs are synthetic agents with a wide range of biological properties including antibacterial, anti-candida, anti-tubercular, anti-cancer, anti-protozoal and Abbreviations: 8-OHdG, 8-hydroxydeoxyguanosine; BTB, blood-testis barrier; CBX, carbadox; ESs, ectoplasmic specializations; GJs, gap junctions; LC/MS-IT-TOF, high-performance liquid chromatography-mass spectrometry-ion trap-time-of-flight; M4, 3-methyl-2-(1-hydroxyethyl) quinoxaline-N4-monoxide; M4-R, M4 radical; M8, 3-methyl-2-(1hydroxyethyl) quinoxaline-N1-monoxide; M8-R, M8 radical; MDA, malondialdehyde; MEQ, mequindox; N1-MEQ, N1desoxymequindox; OLA, olaquindox; QCT, quinocetone; QdNOs, quinoxaline-di-N-oxides; ROS, reactive oxygen species; TEM, Transmission electron microscope; TJs, tight junctions. Mequindox’s Toxic Metabolites in Mice growth-promoting activities (Wu et al, 2007; Vicente et al, 2009; Wang et al, 2011a, 2015, 2016d; Cheng et al, 2015; Liu Q. et al, 2016). Four QdNO derivatives, CBX, OLA, QCT and cyadox (CYA), have been developed for use in livestock and poultry farming, contributing to their significant antibacterial abilities and growth-promotion properties (Wang et al, 2015; Zhang et al, 2015). MEQ is a relatively new synthetic antibacterial agent that was widely applied in China in pigs and chickens owing to its strong inhibitory effect against both gram-positive and negative bacteria (Ihsan et al, 2010, 2011, 2013; Huang et al, 2015)
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