| Quinoxalines,with the structure of quinoxaline-1,4-dioxides are synthetic antimicrobial agents,which have the characteristic for improving feed efficiency, promoting growth and increasing the rate of weight gain.For these reasons,they have been widely used as growth promoters in most countries of the world.However,carbadox and olaquindox,which the first were developed and used,have been banned or strictly limited to use due to their toxicities.Mequindox was synthesized by Lanzhou Institute of Animal and Veterinary Pharmaceutics sciences of CAAS in China,and used as antibacterial agent.Quinocetone and cyadox,which were new growth promoters of the quinoxalines family,had low toxicity,less side effect and obvious growth promotion in food-producing animals.But some researches showed that olaquindox can cause the stress hemorrhage syndrome with inappropriate use,and other researches considered that quinoxalines had the toxicity to impair kidney and adrenal tissues.But we don't know if quinocetone and cyadox had the same deleterious effects on stress responses with the similar structure and mechanism of growth promotion as olaquindox.So the current study was carried out to evaluate the effects of quinoxalines(cyadox,olaquindox and quinocetone) on hematological and physiological response parameters,antioxidant defenses and histopathology in carp(Cyprinus carpio L.) with fed diets containing different doses(50,150 and 500 mg/kg) of cyadox,olaquindox and quinocetone respectively for 4,8 and 12wk.1.The growth performance of test groups were all increased.In 4 wk,the growth improvement in 50,150 and 500 mg/kg cyadox groups were 25.7%(P＞0.05),64.3% (P＜0.05),92.9%(P＜0.05),and 24.3%(P＞0.05),48.6%(P＜0.05),67.1%(P＜0.05) in 50, 150 and 500 mg/kg olaquindox groups,and 34.3%(P＞0.05),74.3%(P＜0.05),91.4% (P＜0.05) in quinocetone 50,150 and 500 mg/kg groups respectively.In 8 wk,there were 25.5%(P＞0.05),56.2%(P＜0.05),64.2%(P＜0.05) in 50,150 and 500 mg/kg cyadox groups,22.6%(P＞0.05),44.5%(P＜0.05),40.9%(P＜0.05) in 50,150 and 500 mg/kg olaquindox groups,and 27.7%(P＜0.05),40.9%(P＜0.05),58.4%(P＜0.05) in quinocetone 50,150 and 500 mg/kg groups respectively.In 12 wk,there were 14.6%(P＞0.05),38.7% (P＜0.05),45.7%(P＜0.05) in 50,150 and 500 mg/kg cyadox groups,9.5%(P＞0.05), 31.2%(P＜0.05),18.1%(P＞0.05) in 50,150 and 500 mg/kg olaquindox groups,and 14.1%(P＞0.05),28.1%(P＜0.05),37.2%(P＜0.05) in quinocetone 50,150 and 500 mg/kg groups respectively.Only in 12wk,the growth improvement in 500 mg/kg olaquindox group was lower than 500 mg/kg cyadox and quinocetone groups(P＜0.05).The results showed that 50～500 mg/kg cyadox and quinocetone had effective growth promotion. 50～500 mg/kg olaquindox can also increase growth performance,but decreases were found in 500 mg/kg group in 8 and 12 wk.The growth performance was decreased in all groups as feeding time prolonged.2.The hematological changes showed that the red blood cell counts(RBC), hematocrit,hemoglobin decreased with increased doses of olaquindox,and significantly dropped in olaquindox 500 mg/kg group in all periods(P＜0.05).The RBC,HGB and HCT in cyadox and quinocetone 50 and 150 mg/kg groups had an increased tendency, while it was decreased in 500 mg/kg groups.The RBC in cyadox 500 mg/kg group was significantly lower than cyadox 50 mg/kg group in 8 and 12 wk(P＜0.05).In quinocetone 500mg/kg group,it was lower than its 50 mg/kg group in all periods(P＜0.05).The changes of hematological parameters revealed a possible anemic state and a toxic manifestation of 500 mg/kg olaquindox.While diets containing 50 and 150 mg/kg cyadox and 50 mg/kg quinocetone could enhance erythropoiesis to increase the oxygen supply to the major organs in response to the high metabolic demand.3.Effects of quinoxalines on cortisol and biochemical indices in serum of carp were investigated.150 and 500 mg/kg doses of cyadox and olaquindox,500 mg/kg quinocetone can increase cortisol level in serum in 4 wk(P＜0.05),while in 8 and 12 wk, all groups showed good accommodation.The glucose contents in groups of cyadox and quinocetone had increased tendencies,while in 500 mg/kg olaquindox group,it showed a descent(P＜0.05).The activities of AST,ALT,alkali phosphatase(ALP) and lactate dehydrogenase(LDH) in 500 mg/kg olaquindox group increased in all periods(P＜0.05). The increased phenomenon of total bulirubin(TB) and direct bulirubin(DB) was also found in olaquindox group in 8 and 12 wk.Total protein(TP) and albumin(ALB) decreased in 12 wk(P＜0.05).The contents of creatinine(CRE) increased in 150 and 500 mg/kg olaquindox groups only in 12wk(P＜0.05).Blood urea nitrogen(BUN) contents raised in 500 mg/kg olaquindox group in 8 and 12wk(P＜0.05).The concentrations of serum ion didn't change greatly in 4 and 8 wk(P＜0.05).In 12 wk,a decrease of Na~+ content was found in 500 mg/kg olaquindox group.The content of K~+ was increased in 500 mg/kg olaquindox group,the concentrations of P raised in cyadox 500 mg/kg group, 150 and 500 mg/kg olaquindox and quinocetone groups(P＜0.05).Values of other biochemical indices in serum,such as cholesterol(CHO),triglyeride(TG) and CL~-didn't change greatly(P＞0.05).4.Cortisol and glucose contents,AST,ALT,alkali phosphatase(ALP) and lactate dehydrogenase(LDH) activities in serum changed significantly after stress(P＜0.05),they can be used as indicators of stress response.In 4 wk,cortisol levels after stress in all groups were increased with the same tendency as basal levels.It revealed an undamaged HPI axis.In 8 and 12 wk,500 mg/kg olaquindox did not had effects on basal serum cortisol levels(P＞0.05).Hower,challenging fish with stress revealed an impairment of the capacity to raise cortisol.While eortisol level in olaquindox 500mg/kg group after 24h confined in 12 wk was not decreased as metioned after chasing stress,but an increase (P＜0.05),it might suggest that a decrease of plasma clearance rate of cortisol was happened as time prolonged.The glucose content had a decent tendency in 500 mg/kg olaquindox group,and in this group,AST,ALT and ALP activities were induced after stress in all periods(P＜0.05),it indicated that stress enhanced the damage to cell membrane and intercellular metabolism caused by olaquindox.While inductions of AST, ALT and ALP activities were also found in 500 mg/kg cyadox,500 mg/kg quinocetone and 150 mg/kg olaquindox groups in 12wk(P＜0.05).5.Activities of superoxide dismutase(SOD) and glutathione-S transferase(GST), malondialdehyde(MDA) level in liver of carp pre-stress were also determined.There was a clear increase of SOD activity at the doses of 150 and 500mg/kg of the three quinoxalines,500 mg/kg olaquindox especially(P＜0.05).GST activity was decreased only in olaquindox 500 mg/kg group in 4 and 12 wk,while it was increased in 50 mg/kg cyadox and 150 mg/kg quinocetone groups in 12 wk(P＜0.05).All the three additives had little influence on MDA level(P＞0.05),an increase was only found in 500 mg/kg cyadox group in 12 wk(P＜0.05).From the results,we can conclude that olaquindox at the dose up to 500 mg/kg had oxidative damage on carp,while at the dosage range of out test, cyadox and olaquindox can improve the function of antioxidant defense systems. 6.The histopathological effects of cyadox,olaquindox and quinocetone on head kidney,kidney,liver,intestine of carp were investigated.Results showed time-dependent histopathological changes of all the tissues in fish in 500 mg/kg olaquindox group.Slight damage was found in 500 mg/kg cyadox and quinocetone groups with the time prolonged, while histological structure was less influenced by cyadox and quinocetone below the dose of 500 mg/kg,and olaquindox below 150 mg/kg.In conclusion,this study had evaluated the effects of cyadox,olaquindox and quinocetone on hematological and physiological response parameters,antioxidant defenses and histopathology in carp.It demonstrated that high dose of olaquindox had adverse effects on physiological status accompanied with alterations of physiological stress response of fish,and firstly gave the reason for stress hemorrhage syndrome caused by olaquindox.While cyadox and quinocetone were less toxic,deleterious effects were only found at the dose of 500 mg/kg for long-term use,stress hemorrhage syndrome would not happened after appropriate use.These results give scientific guidances for reasonable and safe use of quinoxalines in aquiculture. |
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