Toxic metabolites, Sertoli cells and Y chromosome related genes are potentially linked to the reproductive toxicity induced by mequindox

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.

Mequindox Induced Genotoxicity and Carcinogenicity in Mice

“…Mequindox, a relative new compound in QdNOs, is widely applied in livestock owing to its strong inhibitory activities against microbes in China ( Liu et al, 2012 ; Wu et al, 2012 ; Li et al, 2014 ; Wang et al, 2016b ). Early findings have demonstrated that adrenal toxicity ( Huang et al, 2009 ), testicular toxicity ( Ihsan et al, 2011 ; Liu et al, 2017c , b ), kidney and liver toxicity ( Huang et al, 2010a ; Liu et al, 2017d ) induced by MEQ in vivo . CBX ( World Health Organization [WHO], 1991a ) and OLA ( World Health Organization [WHO], 1991b ), structural analogs of MEQ, were prohibited in food-producing animals due to its potential mutagenic and carcinogenic effects ( Wu et al, 2007 ; Liu et al, 2016 ).…”

“…MEQ induced oxidative stress in liver and kidney in rats after exposure to MEQ (25, 55, 110, and 275 mg/kg) for 180 days ( Huang et al, 2009 , 2010b ). Recently, we also found that MEQ produced toxicity in liver and testis of KM mice at a dose level of 25, 55, and 110 mg/kg diet ( Liu et al, 2017b , c , d ).…”

“…Quinoxaline-di- N -oxides (QdNOs), consisting of one or two acyclic chain moiety combined with quinoxaline ring, are a great family with the wide range of biological properties, including antibacterial, anti-candida, antitubercular, anticancer, antiprotozoal and growth promoting activities ( Carta et al, 2005 ; Cheng et al, 2015 ; Vicente et al, 2009 ; Wang et al, 2011a , 2016b ; Liu et al, 2017a ). Four QdNOs, carbadox (CBX), olaquindox (OLA), quinocetone (QCT), and cyadox (CYA) ( Figure 1 ), are used as growth promoters in livestock and poultry farming because of their strong antimicrobial activities ( Liu et al, 2016 , 2017a , b , d ). Mequindox ([3-methyl-2-acetyl] quinoxaline-1,4-dioxide, C 11 H 10 N 2 O 3 ; MEQ) ( Figure 1 ), a relative new compound in QdNOs, is a synthetic antibacterial agent with strong inhibitory effect against both Gram-positive and negative bacteria ( Ihsan et al, 2010 , 2011 , 2013a ).…”

“…It was widely used in the food-producing animals in China due to its efficacious in the treatment of clinical infections caused by Treponeme, Pasteurella, E. coli, Staphylococcus aureus , and Salmonella sp. ( Ihsan et al, 2011 , 2013a ; Ding et al, 2012 ; Liu et al, 2017c , b ). However, the use of MEQ as animal feed additive or antimicrobial agent has raised serious health hazard effects.…”

Tracing major metabolites of quinoxaline‐1,4‐dioxides in abalone with high‐performance liquid chromatography tandem positive‐mode electrospray ionization mass spectrometry

“…It was reported that 1‐DMEQ, 4‐DMEQ, and 1,4‐BDMEQ were the major metabolites of MEQ in zebra fish . The metabolites of QdNOs could also induce severe toxic effects similar to the precursors . It seems that dietary exposure assessments of QdNOs should focus on their metabolites as well as the precursors.…”