Acifluorfen Induced Learning And Memory Deficits In Kunming Mice And Its Mechanism

Acifluorfen is an important member of the family of diphenyl ether herbicides.Due to its excellent properties such as wide bioactivity spectrum,low toxicity and high efficiency,acifluorfen is widely used in residential and agricultural areas to control weeds,particularly in soybean,peanut,rice and other crops.A variety of exposure ways,including residues in food and drinking water and residential herbicides exposure,make the acifluorfen show potential threats to human and ecological environment,the biosafety of acifluorfen were also been great concern.Prior studies have failed to evaluate the neurotoxicity of acifluorfen in vivo,which is desiderated to be confirmed.In this paper,42 male Kunming mice were divided into 6 groups.The control used saline solution,4 treatment groups were gavaged with different concentrations of acifluorfen(0.13,1.3,13 and 130 mg·kg-1·d-1),and protective group was administrated with 130 mg·kg-1·d-1 acifluorfen combined with 100 mg·kg-1·d-1Vitamin E.After 14-day treatment,we assessed the effect of acifluorfen exposure on the behavior of mice and the degree of brain tissue damage though the results of Morris water maze and histopathological section(H&E staining and Nissl staining).Through the detection of oxidative stress indicators(Reactive oxygen species,ROS;Malondialdehyde,MDA;Glutathione,GSH),inflammation indicators(NLR family pyrin domain containing 3,NLRP3;Cysteine-aspartic acid protease 1,caspase-1;Interleukin-1 beta,IL-1?)and learning and memory-related indicators(N-methyl-D-aspartate receptor,NMDAR;phosphorylatcd cAMP response element binding protein,pCREB;Brain derived neurotrophic factor,BDNF)to explore the effect on learning and memory of mice and the mechanism induced by acifluorfen.Vitamin E was added as a protective agent to explore the protective effects of Vitamin E and the mechanism.Our results of this paper showed that the mice oral exposure to acifluorfen showed cognitive deficit in the water maze experiment which was manifested in a significant increase in the escape latency of mice,a significant reduction in swimming time in the target quadrant,and an irregular trajectory.The pathological section of the mouse brain showed that the arrangement and size of the hippocampal neurons were changed,and the Nissl bodies in the cell bodies and dendrites were reduced or even disappeared.The oxidative stress was appeared through increased ROS and MDA levels and the decreased GSH levels.Also,the level of inflammation(NLRP3,caspase-1 and IL-1?)were significantly increased and the expression of learning and memory-related proteins(NMDAR,pCREB and BDNF)were significantly inhibited.The levels of oxidative stress and inflammation were significantly reduced in the brain tissue of mice exposed to acifluorfen with the protective agent Vitamin E,the learning and memory impairment in the behavior of mice was improved to a certain extent,the pathological damage of the brain tissue of mice was reduced,and the expression of learning and memory-related proteins was increased to a certain extent.The study shows that 13 and 130 mg·kg-1·d-1 acifluorfen exposure can induce Kunming mice cognitive deficit and brain tissue damaged.However,exposure to 0.13 and 1.3 mg·kg-1·d-1 acifluorfen did not have a significant negative effect on mice,indicating that the exposure concentrations of 0.13 and 1.3 mg·kg-1·d-1 were relatively safe for mice.Oxidative stress,inflammation,and the decreased neuroprotective function of the NMDAR-CREB-BDNF pathway in brain tissue may be one of the mechanisms of brain tissue damage.Down-regulation of oxidative stress,inflammation and up-regulation of NMDAR-CREB-BDNF neuroprotective pathway level was proposed to explain the neuroprotective effects of Vitamin E.In this paper,the behavioral changes,brain tissue damage,oxidative stress and other mechanisms as well.as the protection of Vitamin E to Kunming mice after acifluorfen exposure were analyzed,which could help us to evaluate the neurotoxicity of acifluorfen and to provide theoretical basis and experimental support for the possible mechanisms of damage and safe application of acifluorfen.