Abstract
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.
Highlights
As a class of synthetic heterocyclic agents, QdNOs are known as deoxyribonucleic acid (DNA) synthesis inhibitors and are usually used in human and veterinary medicine due to their broad range of biological properties including antibacterial, anti-candida, antitubercular, anticancer, antiprotozoal and growth promoting activities (Carta et al, 2005; Vicente et al, 2009; Wang et al, 2011a, 2016a; Cheng et al, 2015; Liu et al, 2017a)
Together with genotoxic findings of MEQ, two primary metabolites of MEQ were concluded to be genotoxic in a battery of four different short-term tests, including mouse lymphoma assay (MLA), Ames test, chromosomal aberration assay and bone marrow erythrocyte micronucleus assay (Liu et al, 2016, 2017d)
SD, standard deviation; M, mequindox; M25, 25 mg/kg diet; M55, 55 mg/kg diet; M110, 110 mg/kg diet; M275, 275 mg/kg diet. aData presented as mean ± standard deviation of 20 animals per group
Summary
As a class of synthetic heterocyclic agents, QdNOs are known as DNA synthesis inhibitors and are usually used in human and veterinary medicine due to their broad range of biological properties including antibacterial, anti-candida, antitubercular, anticancer, antiprotozoal and growth promoting activities (Carta et al, 2005; Vicente et al, 2009; Wang et al, 2011a, 2016a; Cheng et al, 2015; Liu et al, 2017a). MEQ (3-methyl-2-acetyl-N-1,4-dioxyquinoxaline, C11H10N2O3; MEQ) (Figure 1), a relatively new synthetic antibacterial agent developed for use in animal productions in China, considered as significant due to its antibacterial properties and growth promoting ability (Liu et al, 2012, 2017d; Wu et al, 2012; Li et al, 2014). 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). MEQ caused chromosomal aberrations in V79 cells and micronucleus formation in mice (Wang et al, 2011a,b; Liu et al, 2016). Despite many years of usage in food producing animals, the toxic characteristics of MEQ, including its major toxic effects on the reproduction and development, had not been adequately investigated
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