Organophosphorus EsterInduced Chronic …：有机磷酯诱导的慢性… .ppt

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1、Organphosphorus Compounds-Induced Neurotoxicity,Organophosphorus compounds,Used in medicine,industry,agriculture and as warfare agents.Have a wide range of acute toxicity:a)low acute toxicity chemicals such as tricresyl phosphates(TCPs)b)highly toxic nerve agents such as sarin,soman and tabun.,Actio

2、ns of Organophosphorus Compounds,Cholinergic Neurotoxicity2.Organophosphorus Ester-Induced Neurotoxicity(OPIDN)3.Organophosphorus Ester-Induced Chronic Neurotoxicity(OPICN),1.Cholinergic Neurotoxicity,Inhibition of Acetylcholinesterase(AChE),an enzyme essential for life,ORGANOPHOSPHATE,Manifestation

3、s of Organophosphate Poisoning,Optic SystemPupil ConstrictionBlurred VisionLacrimation,Respiratory SystemBronchospasmBronchial SecretionPulmonary EdemaTightness of ChestWheezingCoughDifficulty Breathing,Gastrointestinal TractSalivationNauseaCrampsAbdominal PainVomitingDiarrheaFecal Incontinence,Urin

4、ary-GenitalUrinary IncontinenceImpotenceUterus Contraction,BrainHeadacheDizzinessVertigoAnxietyApathyConfusionAnorexiaInsomniaLethargyFatigueInability to ConcentrateMemory ImpairmentConvulsionComa,Cardiovascular SystemTachycardiaIncreased Blood Pressure,MusculatureWeaknessTremorFasciculationsTwitchi

5、ngCrampsIncreased Sweating,Treatment of Cholinergic Toxicity,1.2-PAM(2-pyridine aldoxime methiodide)hydrolyzes phosphorylated enzyme thus accelerating the regeneration of active AChE;should be administered rapidly within 10 to 15 minutes of exposure,before AChE aging.2.Atropine,an antagonist of musc

6、arinic ACh receptor(AChR),3.Shielding of AChE,Organophosphorus nerve agents,such as sarin act by irreversibly inhibiting AChE in the peripheral and central nervous systems.2.Pyridostigmine Bromide(PB)is administered to protect against toxicity.PB is approved by the FDA for soman.3.Prophylaxis Princi

7、ple is that PB acts by shielding AChE in peripheral nervous system to reversibly inhibit 30-40%of the enzyme,protecting it from permanent inhibition by the nerve gas.4.Enzyme activity is restored following spontaneous decarbamyalation of the AChE.Result Free enzyme and near-normal neuromuscular an a

8、utonomic functions.,4.Bioscavengers,Butyrylcholinesterase(BChE)is a naturally occurring enzyme in blood.2.Its blood concentration is 2 mg/liter.BChE has no known function;however,it functions as the first line of defense against poisoning with organphosphorus compounds.It acts as a bioscavenger,like

9、 a sponge to absorb and degrade organphosphorus compounds(e.g.,nerve agents and insecticides).,Recombinant BChE(rBCHE),Recombinant human BChE(rBChE)is being developed under the trade name Protexia as a pre-and post-exposure therapy for organphosphorus compound poisoning.Protexia is a pegylated rBChE

10、,that is formed by conjugation of the rBChE with polyethylene glycol in order to:Decrease rBChE immunogenicityIncrease rBChE stability Increase circulating serum of rBChE3.A limited human study of Protexia has started.,2.OPIDN,OPIDN is a neurodegenerative disorder:1.A latent period;6 and 14 days.2.N

11、europathological lesions:medulla of the brain,spinal cord,and sciatic nerve.3.Degeneration of the axon and of myelin 4.Species and age sensitivity.5.Inhibition of neurotoxicity target esterase(NTE).,Tri-ortho-cresyl phosphate,Synthetic pathways of TOCP,TCPs,Uses of Tricresyl Phosphates TCPs,Antiwear

12、 and additive in synthetic lubricants.Flame retardantPlasticizer,Neurotoxity of TCPs,TOCP is a weak inhibitor of AChEIt is a potent producer of OPIDNOther isomers have not been thoroughly tested for OPIDN,Isomers of Tri-cresyl Phosphate(TCP),There are 10 possible TCP structures:Isomers OPIDNo,o,o+o,

13、o,m;o,o,p+o,m,m,;o,m,p;o,p,p+m,m,m;m,m,p;m,p,p;p,p,p-,Chronology of TOCP-Induced OPIDN,Year Country Incidence Cases France Creosote 59 USA Contaminated Ginger Extract Approx.50,0001925-1934 France,Germany,Apiol Abortfacient 200-500 Switzerland1937 South Africa Contaminated Cooking Oil 6001940 Switze

14、rland Contaminated Cooking oil 801942 Britain Manufacturing 3 Britain Contaminated Cottonseed Oil 171943-1947 Germany Used as cooking oil 10-20 Switzerland Contaminated food 73 Switzerland Contaminated Olive Oil 80 South Africa Contaminated Water 11 Morocco Used as cooking Oil 10,000 India Contamina

15、ted Cooking Oil 58 Rumania Contaminated Alcohol 12 Fiji Islands Contaminated Flower Morocco Shoe Glue Exposure 401977-1978 Sri Lanka Contaminated Sesame Oil 231988 India Contaminated Cooking Oil 2,Neurological dysfunction of OPIDN,Latent period:Days to weeksProgressive phase:Symmetric cramping,numbn

16、ess and tingling in feet and legs,bilateral dragging of toes(foot-drop),flaccid paralysis.3.Stationary Phase4.Improvement Phase:Results from regeneration of PNS;CNS damage becomes unmasked as spasticity and exaggerated knee jerk.5.Prognosis:Depends on severity of initial symptoms,Total Paralysis bel

17、ow knees with toe drop.,Factors involved in the Development of OPIDN,Chemical StructureAnimal Species:Humans are most sensitive Individual differencesAnimal AgeDose or Concentration at Neurotoxicity Site:a.Exposure doseb.Frequency of exposure c.Duration of exposured.Route of Exposuree.Other chemical

18、 exposure f.Stress,Factors involved in the Development of OPIDN,Metabolic Activation:TOCP is activated to saligenin cyclic-o-tolyl phosphate.Phosphorothioate insecticides are activated to phosphatesCombined exposure to chemicals that increase activity of CYP 450 enhances TOCP neurotoxicity.,Activati

19、on,Factors Involved in the Development of OPIDN,Route Of Exposure:Organophosphorus compounds have more access to the nervous system and neurotoxicity target through inhalation and skin penetration than the gastrointestinal tract.Inhalation is the most effective route of entry,preceded only by intrav

20、enous injection.,Factors involved in the Development of OPIDN,3.OPICN,Organophosphorus ester-Induced Chronic Neurotoxicity(OPICN)1.Is a neurodegenerative disorder that results from large toxic or small subclinical doses of Ops.2.Clinical signs,which continue for weeks to years,consist of neurologica

21、l and neurobehavioral abnormalities.3.Damage is greater in the CNS than PNS.4.Neuronal cell death is seen in various brain areas including cerebral cortex,hippocampal formation and cerebellum.5.Cell death results from early necrosis or delayed apoptosis.6.OPICN is exacerbated by concurrent exposure

22、to stress or other chemicals that cause neuronal cell death or oxidative stress.7.Because CNS injury predominates,improvement is slow and complete recovery is unlikely.,OPICN in the Literature,OPICN has been referred to AS:“Chronic neurobehavioral effects”“Chronic organophosphate-induced neuro-psych

23、iatric disorder(COPIND)”“Psychiatric sequelae of chronic exposure”“Psychological and neurological alterations”“CNS system effects of chronic exposure”“Neuropsychological abnormalities”“Long-term effects”“Neurobehavioral effects”“Chronic nervous effects of acute organophosphate poisoning”“Chorea and

24、psychiatric changes”“Delayed neurologic behavioral effects of long-term exposure”“Central cholinergic involvement in behavioral hyperactivity”,Organophosphorus Ester-Induced Chronic Neurotoxicity(OPICN),Individuals exposed to a single large toxic or small subclinical doses of Ops have developed a ch

25、ronic neurotoxicity that persists years after exposure and is distinct from both cholinergic and OPIDN affects.,Characteristics of OPICN1.Neurological alterations,Headache,drowsiness,dizziness,anxiety,increased tension,apathy,restlessness,labile emotions,anorexia,insomnia,bad dreams,weakness,letharg

26、y,fatigue,inability to concentrate,cognitive and memory deficits,depression,social isolation,neurological deficits,irritability,confusion,reduced motor coordination,and tremors.(Not every patient has all of these symptoms),Characteristics of OPICN2.Neuropathological Changes,A large toxic dose of org

27、anophosphates produced necrotic neuronal cell death in the following regions of experimental animals:cerebral and piriform cortices,basal ganglia,thalamus,septum,hypothalamus,hippocampus,corticospinal trac and cerebellum.3.The lesions did not resemble those present in hypoxia or OPIDN.,Characteristi

28、cs of OPICN2.Neuropathological Changes,Exposure to Ops caused delayed apoptotic neuronal cell death in the following regions:Motor cortexHippocampusCerebellum andCervical Spinal cord,Human cases of OPICN,1.Three years and nine months after the Tokyo attack,some victims complained of chronic decline

29、of memory(Nishiwaki et al,2001).Three years after the Matsumoto attack,some victims complained of fatigue,shoulder stiffness,weakness,blurred vision(Nakajima et al.,1999)3.Others complained of insomnia,had bad dreams,husky voice,slight fever,and palpitation.,Neuronal cell Death Consequences,Signific

30、ant death of cerebral cortex neurons results in muscular weakness and loss of strength.A loss of significant amount of hippocampal neurons leads to progressive loss of memory and results in learning disabilities.3.Loss of Purkinje cells in the cerebellum may cause:a.Delays in initiating and terminat

31、ing movements.b.Terminal tremor at the end of the movement.c.Disorders in the spatial coordination of hand and finger muscle.,Specific Aims,This study was designed to investigate the long-term,chronic effects following a single dose of sarin that does not produce clinical signs in male Sprague-Dawle

32、y rats.,Experimentals,1.Groups of 15 animals were treated with a single intramuscular injection of sarin(LD50=100 g/kg):a)1.0 g/kg(0.01 x LD50)or b)10.0 g/kg(0.1x LD50)2.The following parameters were studied at 24 h,7 days,one month,and one year.a.Clinical signsb.Neurobehavioral performancec.Brain A

33、ChE and plasma BChE activityd.Integrity of the blood brain barriere.Neuropathological changes in the brain,Clinical Signs,24 Hours,7 days,one month,one year after Treatment1.All animals looked and behaved similar to controls.2.Brain AChE and Plasma BChE activities remained normal3.Blood brain barrie

34、r was intact4.M2 ACh muscarinic receptor ligand binding was increased in brainstem after one year.,Neurobehavioral Performance,Sensorimotor functions were assessed using the following tests:1.Beam walking and beam score 2.Inclined Plane3.Forepaw grip timeThe results showed sensorimotor deficits 3 mo

35、nths after treatment that were exacerbated by the end of the year after treatment.,0,01 and 0.1 x LD50 Sarin after one Year,Histological assessments demonstrated neuronal cell death in:1.Motor cortex2.Hippocampus3.Cerebellum and4.Cervical Spinal cord,Sarin-Induced Apoptosis,Apoptosis was confirmed u

36、sing:1.Apoptosis-specific stain TUNNL.2.Neuronal nitric oxide synthase(NOS)immunohistostaining.,Mechanisms of Neuronal Cell Death in OPICN:High level,Cholinergic PathwaysOrganophosphatesAChE InhibitionAChE RiseMuscarinic Receptor ActivationGlutamate Receptor ActivationNMDA Receptor ActivationCa2+Rel

37、easeCa2+Entry into Neuronal CellsNecrotic Neuronal Cell Death,Mechanisms of Neuronal Cell Death in OPICN:Low Level,Oxidative StressOrganophosphatesOxidative StressReactive Oxygen Species(ROS)+NO Peroxynitrile(ONOO.)DNA Protein 8-Hydroxy-2-deoxy-guanosine 3-Nitrotyrosine Apoptotic Cell Death,Involvem

38、ent of CaMKII in Neuronal Cell Death,Chemicals in Cabin Air,Cabin contained the following chemicals:Vapors of lubricating oils and hydraulic fluids(TCPs)2.Insecticides.,Components of Some Engine Lubricating Oils and Hydraulic Fluids,Product Components(wt%)Engine lubricating oilsMobil jet oil254 Tric

39、resyl phosphate(TCP,1-5%)Mobil jet oil I Tricresyl phosphate,(N-Phenyl-1-naphthalamine(1-5%)Hydraulic fluids Skydrol 5 Triisobutyl phosphate,Triphenyl phosphate,(Solutia Inc.)Epoxy-modified alkyl ester Skydrol 500B Tributyl Phosphate,Dibutyl phenyl phosphate(Solutia Inc.)Butyl diphenyl phosphate,Epo

40、xy-modified alkyl ester Butyl Di-phenyl Phosphate,2,6-Di-tert-butyl-p-cresol Skydrol LD-4 Tributyl phosphate,Dibutyl phenyl phosphate(Solutia Inc)Epoxy modified alkyl ester HyJet IV-A+Tributyl phosphate(79%)(Chevron)Cyclic aliphatic epoxide(2.9%),Additives(21%),Pesticide Sprays,A pesticide spray con

41、sists of:a pesticide,a propellant,and solvents.Aerosol spray:2%d-phenothrin(immediate)and 2%permethrin(residual).Application:10 g/ft3.Action:Pyrethroids act by slowing the opening of neuronal sodium channels,resulting in hyper-excitability of the nerves,and subsequent tremors,ataxia,and paralysis.,P

42、ermethrin,Phenothrin(1R)-trans-isomer,d-Phenothrin(a mixture of isomers),Pyrethroid,United States Eliminated Disinsection Practice in 1979,In 1979,the Centers for Disease Control and Prevention(CDC)concluded that the disinfsection of aircrafts was ineffective in preventing insects from entering a co

43、untry and that it would pose a potential health risk to passengers and crew.,Symptoms Related to Cabin AirRespiratory,IrritationPain(eyes,nose,sinuses,throat)Difficulty breathingBreathing discomfortPain in chestCoughingDry,stuffy nose,Symptoms Related to Cabin AirNeurological and Neurobehavioral,Hea

44、dache Altered visionDizziness Inco-ordinationDisorientation Loss of balanceConfusionSlurred speechLightheadednessParesthesiasWeakness Impaired memoryFatigue Inability to concentrateTrouble countingCognitive problems,Symptoms Related to Cabin AirOther Symptoms,Dry skinRapid Heart Rate and palpitation

45、sReproductive effectsLung functions effectsAcute infectionsImmunosuppressionHair loss,Products of O3/Alkene Reactions Identified indoors,Hydroxyl radicalHydro-peroxy and alkyl-peroxy radicalsHydrogen peroxidesOrganic hydro-peroxides OzonidesFormaldehydeOther volatile aldehydes and ketonesProduct-con

46、taining hydroxyl,carbonyl,and/or carboxyl groups(Many of these chemicals cause oxidative stress),Neurobehavioral Effects of TCP isomers,Male Sprague-Dawley rats(250-300 g)were randomly divided into groups of 10 rats each.A daily dose of 2.5 mg/kg of test compounds was applied on a pre-clipped area o

47、n the back of the neck for 30 days as follows:1.Control:(vehicle,1 ml/kg/day)2.TOCP 3.TMCP 4.TPCP 5.TCP 6.TOCP+TMCP 7.TOCP+TPCP 8.TMCP+TPCP 9.TOCP+TMCP+TPCPTwenty hours after the last dose,the rats were subjected to behavioral evaluations following which they were sacrificed.,Beam-Walk Time(1),Beam-

48、Walk Time(2),Incline Plane(1),Incline Plane(2),GRIP TIME,PURPOSE:To assess forepaw grip strength PROCEDURE:Have the rats grip a 5-mm diameter wood dowelTime to release grip is recorded in seconds.,Grip Time(1),Grip Time(2),AChE Activity in the different brain regions(1),AChE Activity in the differen

49、t brain regions(2),Neuronal Cell Death in Brain,Pesticide Sprays,A pesticide spray consists of:a pesticide,a propellant,and solvents.Aerosol spray:2%d-phenothrin(immediate)and 2%permethrin(residual).Application:10 g/ft3.Action:Pyrethroids act by slowing the opening of neuronal sodium channels,resulting in hyper-excitability of the nerves,and subsequent tremors,ataxia,and paralysis.,Conclusions,Symptoms of cabin crew are consistent with exposure to concurrent exposure to chemicals including tri-cresyl phosphate isomers.,