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

organphosphoruscompounds-inducedneurotoxicity,mohamedb.abou-donia,ph.d.departmentofpharmacologyandcancerbiologydukeuniversitymedicalcenterdurham,northcarolina,usa919-684-2221,organophosphoruscompounds,usedinmedicine,industry,agricultureandaswarfareagents.haveawiderangeofacutetoxicity:a)lowacutetoxicitychemicalssuchastricresylphosphates(tcps)b)highlytoxicnerveagentssuchassarin,somanandtabun.,actionsoforganophosphoruscompounds,cholinergicneurotoxicity2.organophosphorusester-inducedneurotoxicity(opidn)3.organophosphorusester-inducedchronicneurotoxicity(opicn),1.cholinergicneurotoxicity,inhibitionofacetylcholinesterase(ache),anenzymeessentialforlife,organophosphate,manifestationsoforganophosphatepoisoning,opticsystempupilconstrictionblurredvisionlacrimation,respiratorysystembronchospasmbronchialsecretionpulmonaryedematightnessofchestwheezingcoughdifficultybreathing,gastrointestinaltractsalivationnauseacrampsabdominalpainvomitingdiarrheafecalincontinence,urinary-genitalurinaryincontinenceimpotenceuteruscontraction,brainheadachedizzinessvertigoanxietyapathyconfusionanorexiainsomnialethargyfatigueinabilitytoconcentratememoryimpairmentconvulsioncoma,cardiovascularsystemtachycardiaincreasedbloodpressure,musculatureweaknesstremorfasciculationstwitchingcrampsincreasedsweating,treatmentofcholinergictoxicity,1.2-pam(2-pyridinealdoximemethiodide)hydrolyzesphosphorylatedenzymethusacceleratingtheregenerationofactiveache;shouldbeadministeredrapidlywithin10to15minutesofexposure,beforeacheaging.2.atropine,anantagonistofmuscarinicachreceptor(achr),3.shieldingofache,organophosphorusnerveagents,suchassarinactbyirreversiblyinhibitingacheintheperipheralandcentralnervoussystems.2.pyridostigminebromide(pb)isadministeredtoprotectagainsttoxicity.pbisapprovedbythefdaforsoman.3.prophylaxisprincipleisthatpbactsbyshieldingacheinperipheralnervoussystemtoreversiblyinhibit30-40%oftheenzyme,protectingitfrompermanentinhibitionbythenervegas.4.enzymeactivityisrestoredfollowingspontaneousdecarbamyalationoftheache.resultfreeenzymeandnear-normalneuromuscularanautonomicfunctions.,4.bioscavengers,butyrylcholinesterase(bche)isanaturallyoccurringenzymeinblood.2.itsbloodconcentrationis2mg/liter.bchehasnoknownfunction;however,itfunctionsasthefirstlineofdefenseagainstpoisoningwithorganphosphoruscompounds.itactsasabioscavenger,likeaspongetoabsorbanddegradeorganphosphoruscompounds(e.g.,nerveagentsandinsecticides).,recombinantbche(rbche),recombinanthumanbche(rbche)isbeingdevelopedunderthetradenameprotexiaasapre-andpost-exposuretherapyfororganphosphoruscompoundpoisoning.protexiaisapegylatedrbche,thatisformedbyconjugationoftherbchewithpolyethyleneglycolinorderto:decreaserbcheimmunogenicityincreaserbchestabilityincreasecirculatingserumofrbche3.alimitedhumanstudyofprotexiahasstarted.,2.opidn,opidnisaneurodegenerativedisorder:1.alatentperiod;6and14days.2.neuropathologicallesions:medullaofthebrain,spinalcord,andsciaticnerve.3.degenerationoftheaxonandofmyelin4.speciesandagesensitivity.5.inhibitionofneurotoxicitytargetesterase(nte).,tri-ortho-cresylphosphate,syntheticpathwaysoftocp,tcps,usesoftricresylphosphatestcps,antiwearandadditiveinsyntheticlubricants.flameretardantplasticizer,neurotoxityoftcps,tocpisaweakinhibitorofacheitisapotentproducerofopidnotherisomershavenotbeenthoroughlytestedforopidn,isomersoftri-cresylphosphate(tcp),thereare10possibletcpstructures:isomersopidno,o,o+o,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-,chronologyoftocp-inducedopidn,yearcountryincidencecasesfrancecreosote59usacontaminatedgingerextractapprox.50,0001925-1934france,germany,apiolabortfacient200-500switzerland1937southafricacontaminatedcookingoil6001940switzerlandcontaminatedcookingoil801942britainmanufacturing3britaincontaminatedcottonseedoil171943-1947germanyusedascookingoil10-20switzerlandcontaminatedfood73switzerlandcontaminatedoliveoil80southafricacontaminatedwater11moroccousedascookingoil10,000indiacontaminatedcookingoil58rumaniacontaminatedalcohol12fijiislandscontaminatedflowermoroccoshoeglueexposure401977-1978srilankacontaminatedsesameoil231988indiacontaminatedcookingoil2,neurologicaldysfunctionofopidn,latentperiod:daystoweeksprogressivephase:symmetriccramping,numbnessandtinglinginfeetandlegs,bilateraldraggingoftoes(foot-drop),flaccidparalysis.3.stationaryphase4.improvementphase:resultsfromregenerationofpns;cnsdamagebecomesunmaskedasspasticityandexaggeratedkneejerk.5.prognosis:dependsonseverityofinitialsymptoms,totalparalysisbelowkneeswithtoedrop.,factorsinvolvedinthedevelopmentofopidn,chemicalstructureanimalspecies:humansaremostsensitiveindividualdifferencesanimalagedoseorconcentrationatneurotoxicitysite:a.exposuredoseb.frequencyofexposurec.durationofexposured.routeofexposuree.otherchemicalexposuref.stress,factorsinvolvedinthedevelopmentofopidn,metabolicactivation:tocpisactivatedtosaligenincyclic-o-tolylphosphate.phosphorothioateinsecticidesareactivatedtophosphatescombinedexposuretochemicalsthatincreaseactivityofcyp450enhancestocpneurotoxicity.,activation,factorsinvolvedinthedevelopmentofopidn,routeofexposure:organophosphoruscompoundshavemoreaccesstothenervoussystemandneurotoxicitytargetthroughinhalationandskinpenetrationthanthegastrointestinaltract.inhalationisthemosteffectiverouteofentry,precededonlybyintravenousinjection.,factorsinvolvedinthedevelopmentofopidn,3.opicn,organophosphorusester-inducedchronicneurotoxicity(opicn)1.isaneurodegenerativedisorderthatresultsfromlargetoxicorsmallsubclinicaldosesofops.2.clinicalsigns,whichcontinueforweekstoyears,consistofneurologicalandneurobehavioralabnormalities.3.damageisgreaterinthecnsthanpns.4.neuronalcelldeathisseeninvariousbrainareasincludingcerebralcortex,hippocampalformationandcerebellum.5.celldeathresultsfromearlynecrosisordelayedapoptosis.6.opicnisexacerbatedbyconcurrentexposuretostressorotherchemicalsthatcauseneuronalcelldeathoroxidativestress.7.becausecnsinjurypredominates,improvementisslowandcompleterecoveryisunlikely.,opicnintheliterature,opicnhasbeenreferredtoas:“chronicneurobehavioraleffects”“chronicorganophosphate-inducedneuro-psychiatricdisorder(copind)”“psychiatricsequelaeofchronicexposure”“psychologicalandneurologicalalterations”“cnssystemeffectsofchronicexposure”“neuropsychologicalabnormalities”“long-termeffects”“neurobehavioraleffects”“chronicnervouseffectsofacuteorganophosphatepoisoning”“choreaandpsychiatricchanges”“delayedneurologicbehavioraleffectsoflong-termexposure”“centralcholinergicinvolvementinbehavioralhyperactivity”,organophosphorusester-inducedchronicneurotoxicity(opicn),individualsexposedtoasinglelargetoxicorsmallsubclinicaldosesofopshavedevelopedachronicneurotoxicitythatpersistsyearsafterexposureandisdistinctfrombothcholinergicandopidnaffects.,characteristicsofopicn1.neurologicalalterations,headache,drowsiness,dizziness,anxiety,increasedtension,apathy,restlessness,labileemotions,anorexia,insomnia,baddreams,weakness,lethargy,fatigue,inabilitytoconcentrate,cognitiveandmemorydeficits,depression,socialisolation,neurologicaldeficits,irritability,confusion,reducedmotorcoordination,andtremors.(noteverypatienthasallofthesesymptoms),characteristicsofopicn2.neuropathologicalchanges,alargetoxicdoseoforganophosphatesproducednecroticneuronalcelldeathinthefollowingregionsofexperimentalanimals:cerebralandpiriformcortices,basalganglia,thalamus,septum,hypothalamus,hippocampus,corticospinaltracandcerebellum.3.thelesionsdidnotresemblethosepresentinhypoxiaoropidn.,characteristicsofopicn2.neuropathologicalchanges,exposuretoopscauseddelayedapoptoticneuronalcelldeathinthefollowingregions:motorcortexhippocampuscerebellumandcervicalspinalcord,humancasesofopicn,1.threeyearsandninemonthsafterthetokyoattack,somevictimscomplainedofchronicdeclineofmemory(nishiwakietal,2001).threeyearsafterthematsumotoattack,somevictimscomplainedoffatigue,shoulderstiffness,weakness,blurredvision(nakajimaetal.,1999)3.otherscomplainedofinsomnia,hadbaddreams,huskyvoice,slightfever,andpalpitation.,neuronalcelldeathconsequences,significantdeathofcerebralcortexneuronsresultsinmuscularweaknessandlossofstrength.alossofsignificantamountofhippocampalneuronsleadstoprogressivelossofmemoryandresultsinlearningdisabilities.3.lossofpurkinjecellsinthecerebellummaycause:a.delaysininitiatingandterminatingmovements.b.terminaltremorattheendofthemovement.c.disordersinthespatialcoordinationofhandandfingermuscle.,specificaims,thisstudywasdesignedtoinvestigatethelong-term,chroniceffectsfollowingasingledoseofsarinthatdoesnotproduceclinicalsignsinmalesprague-dawleyrats.,experimentals,1.groupsof15animalsweretreatedwithasingleintramuscularinjectionofsarin(ld50=100g/kg):a)1.0g/kg(0.01xld50)orb)10.0g/kg(0.1xld50)2.thefollowingparameterswerestudiedat24h,7days,onemonth,andoneyear.a.clinicalsignsb.neurobehavioralperformancec.brainacheandplasmabcheactivityd.integrityofthebloodbrainbarriere.neuropathologicalchangesinthebrain,clinicalsigns,24hours,7days,onemonth,oneyearaftertreatment1.allanimalslookedandbehavedsimilartocontrols.2.brainacheandplasmabcheactivitiesremainednormal3.bloodbrainbarrierwasintact4.m2achmuscarinicreceptorligandbindingwasincreasedinbrainstemafteroneyear.,neurobehavioralperformance,sensorimotorfunctionswereassessedusingthefollowingtests:1.beamwalkingandbeamscore2.inclinedplane3.forepawgriptimetheresultsshowedsensorimotordeficits3monthsaftertreatmentthatwereexacerbatedbytheendoftheyearaftertreatment.,0,01and0.1xld50sarinafteroneyear,histologicalassessmentsdemonstratedneuronalcelldeathin:1.motorcortex2.hippocampus3.cerebellumand4.cervicalspinalcord,sarin-inducedapoptosis,apoptosiswasconfirmedusing:1.apoptosis-specificstaintunnl.2.neuronalnitricoxidesynthase(nos)immunohistostaining.,mechanismsofneuronalcelldeathinopicn:highlevel,cholinergicpathwaysorganophosphatesacheinhibitionacherisemuscarinicreceptoractivationglutamatereceptoractivationnmdareceptoractivationca2+releaseca2+entryintoneuronalcellsnecroticneuronalcelldeath,mechanismsofneuronalcelldeathinopicn:lowlevel,oxidativestressorganophosphatesoxidativestressreactiveoxygenspecies(ros)+noperoxynitrile(onoo.)dnaprotein8-hydroxy-2-deoxy-guanosine3-nitrotyrosineapoptoticcelldeath,involvementofcamkiiinneuronalcelldeath,chemicalsincabinair,cabincontainedthefollowingchemicals:vaporsoflubricatingoilsandhydraulicfluids(tcps)2.insecticides.,componentsofsomeenginelubricatingoilsandhydraulicfluids,productcomponents(wt%)enginelubricatingoilsmobiljetoil254tricresylphosphate(tcp,1-5%)mobiljetoilitricresylphosphate,(n-phenyl-1-naphthalamine(1-5%)hydraulicfluidsskydrol5triisobutylphosphate,triphenylphosphate,(solutiainc.)epoxy-modifiedalkylesterskydrol500btributylphosphate,dibutylphenylphosphate(solutiainc.)butyldiphenylphosphate,epoxy-modifiedalkylesterbutyldi-phenylphosphate,2,6-di-tert-butyl-p-cresolskydrolld-4tributylphosphate,dibutylphenylphosphate(solutiainc)epoxymodifiedalkylesterhyjetiv-a+tributylphosphate(79%)(chevron)cyclicaliphaticepoxide(2.9%),additives(21%),pesticidesprays,apesticidesprayconsistsof:apesticide,apropellant,andsolvents.aerosolspray:2%d-phenothrin(immediate)and2%permethrin(residual).application:10g/ft3.action:pyrethroidsactbyslowingtheopeningofneuronalsodiumchannels,resultinginhyper-excitabilityofthenerves,andsubsequenttremors,ataxia,andparalysis.,permethrin,phenothrin(1r)-trans-isomer,d-phenothrin(amixtureofisomers),pyrethroid,unitedstateseliminateddisinsectionpracticein1979,in1979,thecentersfordiseasecontrolandprevention(cdc)concludedthatthedisinfsectionofaircraftswasineffectiveinpreventinginsectsfromenteringacountryandthatitwouldposeapotentialhealthrisktopassengersandcrew.,symptomsrelatedtocabinairrespiratory,irritationpain(eyes,nose,sinuses,throat)difficultybreathingbreathingdiscomfortpaininchestcoughingdry,stuffynose,symptomsrelatedtocabinairneurologicalandneurobehavioral,headachealteredvisiondizzinessinco-ordinationdisorientationlossofbalanceconfusionslurredspeechlightheadednessparesthesiasweaknessimpairedmemoryfatigueinabilitytoconcentratetroublecountingcognitiveproblems,symptomsrelatedtocabinairothersymptoms,dryskinrapidheartrateandpalpitationsreproductiveeffectslungfunctionseffectsacuteinfectionsimmunosuppressionhairloss,productsofo3/alkenereactionsidentifiedindoors,hydroxylradicalhydro-peroxyandalkyl-peroxyradicalshydrogenpero