Abstract
Mequindox (MEQ) is a relatively new synthetic antibacterial agent widely applied in China since the 1980s. However, its reproductive toxicity has not been adequately performed. In the present study, four groups of male Kunming mice (10 mice/group) were fed diets containing MEQ (0, 25, 55 and 110 mg/kg in the diet) for up to 18 months. The results show that M4 could pass through the blood-testis barrier (BTB), and demonstrate that Sertoli cells (SCs) are the main toxic target for MEQ to induce spermatogenesis deficiency. Furthermore, adrenal toxicity, adverse effects on the hypothalamic-pituitary-testicular axis (HPTA) and Leydig cells, as well as the expression of genes related to steroid biosynthesis and cholesterol transport, were responsible for the alterations in sex hormones in the serum of male mice after exposure to MEQ. Additionally, the changed levels of Y chromosome microdeletion related genes, such as DDX3Y, HSF2, Sly and Ssty2 in the testis might be a mechanism for the inhibition of spermatogenesis induced by MEQ. The present study illustrates for the first time the toxic metabolites of MEQ in testis of mice, and suggests that SCs, sex hormones and Y chromosome microdeletion genes are involved in reproductive toxicity mediated by MEQ in vivo.
Highlights
IntroductionSerious health hazard effects have been noted when QdNOs was used as an animal feed additive or antimicrobial agent [2]
Mequindox (3-methyl-2-acetyl-N-1,4-dioxyquinoxaline, C11H10N2O3; MEQ) (Figure 1), structurally similar to other classical members of the quinoxaline-di-N-oxides (QdNOs) [1], is a relatively new synthetic antibacterial agent that was developed by the Lanzhou Institute of Animal Husbandry and Veterinary Drugs at the Chinese Academy of Agricultural Sciences [2]
Regarding the reproductive toxicity induced by MEQ, we recently found that MEQ causes adverse effects on spermatogenesis and the integrity of the blood-testis barrier (BTB) with tight junctions (TJs) as the macromolecular target
Summary
Serious health hazard effects have been noted when QdNOs was used as an animal feed additive or antimicrobial agent [2]. Previous studies revealed that teratogenic effects and significant decreases in fetal and maternal body weights were observed in rats after exposure to CBX at doses as low as 25 mg/. OLA was reported to be responsible for toxic effects in the testes of rats after administration at a dose of 5 mg/kg b.w./day [8]. MEQ and its primary metabolites, N1-desoxymequindox (N1-MEQ) and bidesoxy-mequindox (B-MEQ), exhibited adrenal toxicity in H295R cells that originated from a human adrenocortical carcinoma [11], and showed genotoxicity in short-term in vitro and in vivo tests [5, 12]. The underlying mechanisms of the reproductive toxicity of MEQ in vivo still remain unclear
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