| BackgroundIn acceleration environment,there will be dizziness,headache,cold sweats,nausea,vomiting,persistent fatigue and other symptoms,collectively referred to as motion sickness.It mainly includes seasickness,airsickness,motion sickness and visual induced motion sickness.Although the mechanism of motion sickness has not been fully elucidated so far,there were evidence indicated that the body’s exposure to abnormal acceleration environment caused stress response and autonomic nervous system dysfunction are the main reasons to promote the development of motion sickness.Many studies have confirmed that the existing variety of anti-motion sickness drugs,such as scopolamine,etc.,can relieve nausea,vomiting and other major symptoms of motion sickness,but the autonomic nervous system dysfunction and persistent fatigue can not be alleviated by these drugs.It is known that fatigue is the main and direct cause of the ability to operate,and the decline in operational capacity caused by fatigue tends to be directly related to the occurrence of a safety accident.Therefore,to clarify the characteristics of fatigue caused by acceleration exposure and its mechanism and the development of acceleration exposure induced personnel operating capacity maintenance measures are the focus of attention in marine medicine,especially in the field of military navigation medicine.Recent studies have confirmed that metabolomics is an effective tool to help analyze the changes in metabolites caused by various causes.Through the detection,analysis of changes in blood metabolites are helpful for us to understand a variety of disease pathogenesis and provide clues for prevention and treatment measures.To sum up,we believe that it is necessary to carry out the detection of changes in the metabolic products of the body after the acceleration exposure,analyze the possible causes of changes in brain function caused by the acceleration exposure,and provide clues for the development of maintenance measuresObjectiveIn this study,the metabolomics was used to understand the possible causes of fatigue induced by acceleration exposure on the basis of investigating and analyzing the fatigue characteristics of exposed personnel(serum pyruvate increased significantly).Then,the effect of serum pyruvate on the decline of brain function and its possible mechanism were observed by animal experiments,which provided clues for the development of maintenance measures for accelerating exposure people.MethodHuman experiment1.Investigation on seasickness and fatigue of navigation workers1.1 Evaluation of fatigue state of workersThe fatigue status and characteristics of the workers before and after expose to six levels of sea condition were investigated and analyzed by the fatigue syndrome questionnaire of the Japan Society of Industrial Hygiene.1.2 Evaluation of the degree of seasickness of workersThe severtity of crew’s motion sickness was tested by "Graybier scales".2 Effects of accelerated exposure on serum metabolites and hormone levels in Subjects2.1 Serum metabolites were measured before and after exposureThe changes of serum metabolites in subjects before and after exposure were analyzed by GC-TOF/MS.2.2 Detection of serum hormone levels before and after accelerated exposureSerum insulin,glucagon and glucocorticoid levels were measured by radioimmunoassay.ELISA was used to detect serum adrenaline content.Animal experiment1 The model rats of acceleration exposureMale Sprague-Dawley(SD)rat,weighing 250-300 g.During 18:00-21:00 everyday,the model animals were placed in plexiglass containers with the long axis of the body perpendicular to the horizontal rotation rod.This process was lasting for 2h.2 The evaluation criteria for motion sickness.Evaluation criteria for motion sickness index included the following: The particle count number was calculated as 1 points each feces;urination was counted as 1.2 points or 0;if there was a mild pilomotion reaction plan the score was recorded as 0.6 points,severe meter was 1.2 points,otherwise none;If there was a tremor response after acceleration treatment the socre was 1.2 point,otherwise no score.Motion sickness index was calculated by the sum of all the scores mentioned above.3.The investigation of brain-body function of rats3.1 Open Field Test(OFT)The OPT was used to test the brain body function of rats,and the total distance was recorded.3.2 Morris water maze(MWM)The WMW was used to test the cognitive function of rats,and the time to reach platform was recorded.3.3 Loaded swimming test(LST)The loaded swimming capacity test was employed in our study to evaluate the effects of acceleration expose on exercise durability of rats.The time of the animals subjected to the behavioral experiment were at 19:00? 22:00.4.Serum hormone,blood glucose,pyruvate and Beta-hydroxybutyrate determinationThe methods of radioimmunoassay was used to detect serum insulin,glucagon and cortisol levels in rats.The levels of β-hydroxybutyrate,epinephrine and norepinephrine in serum of rats were determined by enzyme-linked immunosorbent assay(ELISA).Detection of serum pyruvate by commercial kits.Blood glucose levels were determined by a glucose analyzer.5.The test of Pyruvate dehydrogenase(PDH)Activity and ATP concentration in hippocampus,prefrontal cortex,liver and muscle of rats.PDH activity was measured in the tissue according to manufacturer’s instruction(Abcam,Inc,Cambridge,MA).Tissue ATP levels were measured using a firefly luciferase based ATP assay kit(Beyotime,Nantong China)according to the manufacturer’s instructions.6.StatisticThe Graph Pad Prism v6.0.2(Graph Pad Prism Inc.,La Jolla,CA,USA)was used to analyze and present all the data.Multiple comparisons were performed using one-way ANOVA,followed by Tukey post-hoc test.The correlation coefficient(r)between the scores of fatigue and scores of motion sickness in human,as well as motion sickness index and Total distance.ResultHuman experiment1 Analysis on the characteristics of seizure fatigue of maritime operators60.9% of the crew had motion sickness and 94.3% of the crew had fatigue(mental fatigue and physical fatigue)after exposed for 2 hours in six levels.Further analysis of the percentage of physical fatigue and mental fatigue: Physical fatigue 0 points accounted for 10.3%,1-13 points accounted for 58.6%,13-26 points accounted for 20.7%,26-39 points accounted for 10.4%,while mental fatigue 0 points accounted for 14.9%,1-13 points accounted for 52.9%-26 points accounted for 20.7%,26-39 points accounted for 11.5%,which indicated that the incidence of fatigue was higher than that of seasickness after exposure to abnormal acceleration and had the characteristics of coexistence of brain fatigue.2 Effects of accelerated exposure on serum metabolites in subjectsThere were 35 metabolites in the serum of 60 subjects after accelerated exposure,29 of them were 1-2 times,6 of them were changed more than twice,and the changing fold of pyruvate concentration was the highest,Serum pyruvate levels increased by 4 times.3 Effects of accelerated exposure on serum hormones in subjectsThe serum insulin levels decreased by 28.8% and the levels of adrenaline,glucagon and glucocorticoid were increased by 50.2%,15.3% and 37.8%,respectively,in 60 subjects after accelerated exposure.Animal experiment1 Effect of acceleration exposure on brain-body function indexes of ratsThe total distance of the open field was shortened by 38.1%,the time of the water maze was prolonged by 88.3% and the time of swimming was shortened by 21.2% after the acceleration exposure.related hormones in rats.2 Effects of accelerated exposure on serum metabolites andThe content of 25 kinds of metabolites in the serum of rats was changed,and the changing fold of pyruvate concentration was the highest,which was 3.2 times higher after the exposure.The levels of serum insulin decreased by 33.3%,while the levels of glucagon,cortisol,adrenaline and norepinephrine were increased by 34.3%,190.6%,113.4% and 28.9%,respectively.3.The role of pyruvate in the changes of brain function related indexes after accelerated exposure.3.1 Effect of pyruvate on brain body function indexInjection of pyruvate resulted in a 3.9-fold increase in serum pyruvate concentrations in rats,with significant changes in brain function.Among them,the total distance of open field test shortened by 79.2%,the time to find the platform in Morris water maze prolonged by113.7% and load-bearing swimming time decreased by 23.0%..3.2 Exogenous insulin can inhibit the increase of serum pyruvate in rats with accelerated exposure and significantly relieve the decrease of brain body functionCompared with the exposed group,the insulin concentration in the insulin group was increased by 343%,the concentration of pyruvate decreased by 29.5%,the total distance of the open field was increased by 49.2%,and the time to find the platform in Morris water maze was shortened by 46.6%,Weight-bearing swimming time extended by 11.2%.3.3 Increased levels of endogenous insulin secretion inhibit the increase of serum pyruvate and increase the amplitude of brain function related indexesCompared with the group of exposure,Serum insulin levels were increased by 241.3% after gavage CPL(glucose,sucrose,tyrosine,leucine)before exposure and the content of pyruvic acid in the CPL group was decreased by 87.2%,the total distance of the open field test was prolonged by 69.7%,the time to find platform in water maze test was decreased by 47.0% and the weight-bearing swimming time was prolonged by 22.0%.There was no significant difference of the above indexes between scopolamine group and exposure group.function of brain-body 4.Effect of elevated serum pyruvate concentration on the4.1 Comparison of ATP concentration and PDH activity in hippocampus,prefrontal cortex,muscle and liver tissue and serum pyruvic acid of exposure group and experiment groupsCompared with the control group and exposure group,the PDH activity and ATP concentration in hippocampus,prefrontal cortex,muscle and liver tissue were decreased by 33.8% and 56.0%,25.0% and 48.5%,31.6% and 41.2%,38.6% and 48.3% respectively.The levels of serum pyruvate in the insulin group and the CPL group were significantly higher than those in the exposure group.The activity of PDH in the four tissues were increased by 46.3% and 63.4%,28.9% and 49.7%,25.5% and 23.2%,51.8% and 46.4%,while the ATP concentration increased by 81.7% and 74.0%、77.2% and 105.9%、87.5% and 36.5%、63.1% and 54.2%,respectively.4.2 There were increase of serum pyruvate and the decline of the concentration of ATP and the activity of PDH in hippocampus,prefrontal cortex,muscle and liver tissue in rats after intraperitoneal injection of pyruvateSerum pyruvate was significantly increased after the injection of pyruvate.Compared with the control group,the ATP concentration and PDH activity decreased by 45.4%,23.1%,31.3%,42.1%,28.6% and 21.2%,46.8% and 13.2%,respectively,in the hippocampus,prefrontal cortex,liver and muscle tissue.ConclusionsAbnormal acceleration exposure can cause both brain and body fatigue.Human experiments and animal experiments have found that accelerated exposure can cause a significant increase in serum pyruvate and animal experiments confirmed that elevated serum pyruvate caused by acceleration exposure plays an important role for the decline of brain-body function.inhibition of related tissue PDH activity,ATP synthesis and the impact of energy metabolism may be one of the reasons of the decline of brain body function caused by elevated pyruvate concentration. |
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