Mechanisms of the Testis Toxicity Induced by Chronic Exposure to Mequindox

Liu, Qianying; Lei, Zhixin; Huang, Anxiong; Lu, Qirong; Wang, Xu; Ahmed, Saeed; Ihsan, Awais; Zhang, Yuan

doi:10.3389/fphar.2017.00679

Cited by 15 publications

(19 citation statements)

References 67 publications

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“…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 ).…”

Section: Discussionmentioning

confidence: 99%

“…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 ).…”

Section: Introductionmentioning

confidence: 88%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Mequindox Induced Genotoxicity and Carcinogenicity in Mice

Liu

Lei

et al. 2018

Front. Pharmacol.

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Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Mequindox Induced Genotoxicity and Carcinogenicity in Mice

Liu

Lei

et al. 2018

Front. Pharmacol.

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“…Chronic studies of MEQ on rats induced adrenal toxicity ( Huang et al, 2009 ), invoked oxidative stress in liver and kidney ( Huang et al, 2010b ), and caused hepatic histological changes ( Ihsan et al, 2010 ). Recent studies revealed that toxicity of liver, kidney, and testis in mice was induced by MEQ at a dose level of 25, 55, and 110 mg/kg diet ( Liu et al, 2017b , c , d , 2018a ). In genotoxicity tests, MEQ exhibited a strong genotoxic potential to bacteria, mammalian cells in vitro and in vivo and its mutagenicity is slightly higher than CBX ( Ihsan et al, 2013a ; Liu et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

The Reproductive Toxicity of Mequindox in a Two-Generation Study in Wistar Rats

Liu

Lei

et al. 2018

Front. Pharmacol.

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Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), has been extensively used as a synthetic antibacterial agent. To evaluate the reproductive toxicity of MEQ, different concentrations of MEQ were administered to Wistar rats by feeding diets containing 0, 25, 55, 110, and 275 mg/kg, respectively. Each group consisting of 25 males and 25 females (F0) was treated with different concentrations of MEQ for 12-week period time, prior to mating and during mating, gestation, parturition and lactation. At weaning, 25 males and 25 females of F1 generation weanlings per group were randomly selected as parents for the F2 generation. Selected F1 weanlings were exposed to the same diet and treatment as their parents. The number of live litter and indexes of mating and fertility were significantly decreased in the F1 and F2 generation at 110 and 275 mg/kg groups. Significant decrease in pup vitality during lactation was observed in F1 litter at 275 mg/kg group, in F2 litter at 55, 110, and 275 mg/kg groups. A downward trend in the body weights was observed in F1 pups at 55, 110, and 275 mg/kg MEQ groups, and in F2 pups at 110 and 275 mg/kg MEQ groups. The changed levels of ALT, AST, CREA, BUN, UA, Na, and K were noted in the serum of rats. The histopathologic examination showed that MEQ induced toxicity in the liver, kidney, adrenal, uterus and testis. The no-observed-adverse-effect level (NOAEL) for reproduction toxicity of MEQ was 25 mg/kg diet. The malformations and severe maternal toxicity of MEQ caused adverse effects on the conceptus and embryo, which result in fetal malformations and fetal deaths. In summary, the present study showed that MEQ induced maternal, embryo and reproductive toxicities as well as teratogenicity in rats.

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“…Recent studies revealed that the toxicity to liver ( Liu et al, 2017 ) and testis ( Liu et al, 2017a , b ) were caused by MEQ in Kunming mice, while the kidney toxicity of MEQ in Kunming mice remains poor understood. Thus, the Kunming mice were chosen in this study.…”

Section: Methodsmentioning

confidence: 99%

Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse

et al. 2018

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Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo.

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Mechanisms of the Testis Toxicity Induced by Chronic Exposure to Mequindox

Cited by 15 publications

References 67 publications

Mequindox Induced Genotoxicity and Carcinogenicity in Mice

Mequindox Induced Genotoxicity and Carcinogenicity in Mice

The Reproductive Toxicity of Mequindox in a Two-Generation Study in Wistar Rats

Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse

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