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Glyphosate'sdisrup1onofmethyla1on/transsulfura1on

pathwaysasakeyfactorinau1smandotherdiseases

StephanieSeneff,MITCSAILMethyla9onSummit

July15,2018

Downloadtheseslides

hAp://people.csail.mit.edu/seneff/2018/SeneffJuly2018.pptx

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Outline•  Introduc9on•  GlyphosateandFolicAcidFor9fica9on•  CholesterolSulfateandHeparanSulfate•  Methyla9onandTranssulfura9onPathways•  GlyphosateDisplacingGlycineduringProteinSynthesis

•  HowGlyphosateDisruptsMethyla9onandSulfa9on

•  Summary

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RoundupandGMOCrops

Whatisglyphosate?

RoundupandGMOCrops

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RoundupandGMOCrops

GMORoundup-Readycorn,soy,canola,sugarbeetscoAon,tobaccoandalfalfa

RoundupasaDesiccant/RipenerjustbeforeHarvest

Wheat,Oats,Barley,Rye,Sugarcane,Beans,Len9ls,Peas,Flax,Sunflowers,Pulses,ChickPeas

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Glyphosate!!

•  Glyphosateisnowthe#1herbicideinuseintheU.S.andisincreasinglyusedaroundtheworld–  DevelopedandpatentedbyMonsantointhe1970’s

–  IntroducedintotheUSfoodchainin1974–  Cameoutfromunderpatentin2000

–  Inhibitsanenzymeintheshikimatepathwayinvolvedinthesynthesisoftyrosine,tryptophanandphenylalanine(thethreearoma1caminoacids)

•  HugeexpansionofGMOcorn,soy,coAonandcanolacropshasledtosharpincreasesinthelasttwodecades

Glyphosatevs.OtherPes1cides:UsageintheUnitedStates*

*hAp://sustainablepulse.com/wp-content/uploads/GMO-health.pdf

Glyphosate

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ShikimatePathwayDisrup1on

shikimate

chorismate

Phenylalanine,tryptophan,tyrosine

folate

vitaminK

Glyphosate à NeurotransmiAers,thyroidhormone

PaperShowingStrongCorrela1onsbetweenGlyphosateUsage

andChronicDisease

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EnvironmentalMedicineTraining||Copyright©2014ProgressiveMedicalEduca9on.AllRightsReserved.

Thyroidcancer Diabetes

Urinary/bladdercancer

Endstagerenaldisease

EnvironmentalMedicineTraining||Copyright©2014ProgressiveMedicalEduca9on.AllRightsReserved.

Thyroidcancer Diabetes

Urinary/bladdercancer

Endstagerenaldisease

In2015,WHOdeclaredglyphosatea“probablecarcinogen”

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QuotefromtheConclusion*

“Althoughcorrela9ondoesnotnecessarilymeancausa9on,whencorrela9oncoefficientsofover0.95(withp-valuesignificancelevelslessthan0.00001)arecalculatedforalistofdiseasesthatcanbedirectlylinkedtoglyphosate,viaitsknownbiologicaleffects,itwouldbeimprudentnottoconsidercausa9onasaplausibleexplana9on.”

*NLSwansonetal.JournalofOrganicSystems9(2),2014,p.32,

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TheBigPicture•  Glyphosatedisruptsfolatesynthesisbygutmicrobes(fromshikimatepathway)

•  U.S.mandatedfolicacidfor9fica9onin1998,simultaneouswiththewidespreadintroduc9onofRoundup-Readycrops

•  Folicacidisanoxidized,unmethylatedformofmethyl-tetrahydrofolate(5-MTHF)–  Itcoststheliverdearlyto“fix”it

•  Excessserumfolicacidleadstocerebralfolatedeficiencyduetofolicacidbindingtobrainreceptors–  Thisisariskfactorforau9sm

FolateandMethyla1onPathways*

•  Folatedonatesamethylgroupfornumerousbiochemicalpathways– NeurotransmiAersynthesis– DNAbiosynthesis– Regula9onofgeneexpression– Aminoacidsynthesisandmetabolism– Myelinsynthesisandrepair

•  5-MTHFimpactsmoodandcogni9onviacontrolofneurotransmiAersynthesis

methyl

*ALMiller.Alterna9veMedicineReview2008;13(3):216-226

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ABitofHistory•  Neuraltubedevelopmentaldefectslikespinabifidaand

anencephaly(nobrain)areduetoaveryrarebutcatastrophicdevelopmentaldisorderlinkedtolowfolateduringthefirsttrimesterofpregnancy

•  Excessre9noicacidexpressionduringdevelopmentcausesneuraltubedevelopmentaldefects

•  TheUSfirstconsideredaddingfolicacidsupplementstograinsin1996,andintroducedthemandatein1998

•  GMO“RoundupReady”cropswerejustbeginningtobeintroducedin1996andhadobtainedwidespreadadop9onby1998

SerumFolateDecreasedinWomenAged15-54aSerFolicAcid

For1fica1onwasIntroduced!*

Years SerumFolate (Caucasians)

1999-2000 13.42001-2002 12.12003-2004 11.3

•  Serumfolatedecreasedinwomenofreproduc9veageamongCaucasians,BlacksandHispanics

•  GMORoundup-Readycropsweredrama9callyrampingupatthesame9me

*CentersforDiseaseControlandPreven9on.MMWRMorbMortalWklyRep2007;55:1377-80.

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Adop1onofGMCropsinU.S.

HT=herbicide(glyphosate)tolerant

GlyphosateandSuperweeds:U.S.*

*hAp://sustainablepulse.com/wp-content/uploads/GMO-health.pdf

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GutMicrobesProvideFolatetoHost!*“Inconclusion,thefindingsfromthisstudysuggestthatthequan9tyofmicrobiallysynthesizedfolateinthelargeintes9neofhumaninfantsissufficientlylargetopoten9allyaffectthefolatestatusofthehost.“

*THKimetal.,JNutr.2004Jun;134(6):1389-94.

GutMicrobesProduceBioavailableFolate*

•  Strainsoflactobacillusandbifidobacteriawereshowntosynthesizefolate– Bothoftheseareespeciallysuscep9bletoglyphosatetoxicity

•  "Ratsfedaprobio9cformula9onoffolate-producingbifidobacteriaexhibitedincreasedplasmafolatelevel,confirmingthatthevitaminisproducedinvivoandabsorbed"

*MRossietal.,Nutrients2011,3,118-134

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GutMicrobesProduceBioavailableFolate*

•  Strainsoflactobacillusandbifidobacteriawereshowntosynthesizefolate– Bothoftheseareespeciallysuscep9bletoglyphosatetoxicity

•  "Ratsfedaprobio9cformula9onoffolate-producingbifidobacteriaexhibitedincreasedplasmafolatelevel,confirmingthatthevitaminisproducedinvivoandabsorbed"

*MRossietal.,Nutrients2011,3,118-134

Glyphosatedisruptstheshikimatepathway

ingutmicrobes.

Folate,producedbygutmicrobes,dependsontheshikimatepathway

USAggressiveCampaign:ADownSidetoFolicAcid?

•  Inaddi9ontofor9fica9on,USFDArecommendsfolicacid(FA)supplementsforwomenofchildbearingage

•  However,excessiveFAsupplementa9onhasbeenlinkedwithincreasedincidencesofasthma*andau9sm**amongchildren.

*MBBekkersetal.EurRespirJ2012;39(6):1468–1474.**CMBeardetal,MedHypotheses2011;77(1):15–17.

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“Highfolicacidconsump1onleadstopseudo-MTHFRdeficiency,alteredlipidmetabolism,

andliverinjuryinmice”*•  Fedmiceexcessiveamountsoffolicacid

•  Reducedmethyla9oncapacityinliver

•  CYP7A1levelwasdrama9callyreduced.(ratelimi9ngenzymeinbileacidsynthesis)

•  CausedliverdamageandfaAyliverdisease

*KEChristensenetal.,AmJClinNutr2015;101:646–58.

Workssynergis9callywithglyphosatetodisruptbileflow

“Contrarytoexpecta9ons,wefindthatthreegene9cmutantsrespondadverselytoFA[folicacid]supplementa9onwithincreasedincidenceofNTDs[neuraltubedefects]inhomozygousmutants,occurrenceofNTDsinheterozygousembryosandembryoniclethalitypriortoNTclosure.”

AssessmentofFolicAcidSupplementa1oninMice*

*AMareanetal.,HumanMolecularGene9cs2011;20(18):3678-3683.

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FolicAcidSupplementsinLatePregnancyincreaseRisktoAsthmainChildren*

•  Prospec9vecohortofAustralianfamilies•  Folicacidsupplementsinlatepregnancyincreasesriskofasthmainchildrenat3.5and5.5years

•  Supportspossibleroleoffolate-impairedmethyla9oninalteringfetalimmunephenotypetowardsTh2

*MJWhitrowetal.,AmericanJournalofEpidemiology2009;170:1486–1493

FolicAcidandAu1smRisk*•  Effectsofubiquitoussynthe9csupplementa9onof

vitaminsisunpredictable–  Blanketapproachmayharmthosewithspecificgenevariants

•  Folicacidsupplementa9onduringgesta9onisassociatedwithanincreasedriskforau9sm.

•  Unexpectedincreasesinasthmaandbreathingproblemsassociatedwithfolicaciduse

•  Excessmethyla9onduringgesta9onleadstoepigene9cchanges?

•  Folicacidsupplementsduringgesta9onlinkedtoprematurebirthandlowbirthweight

*MCDeSotoandRTHitlan,JournalofPediatricBiochemistry2(2012)251–261

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“Cerebralfolatedeficiencywithdevelopmentaldelay,au1sm,and

responsetofolinicacid”*

FolinicacidisaformofTETRAHYDRO-folate

*PMore=etal.,NeurologyMarch22,2005vol.64no.61088-1090

“Cerebralfolatedeficiencywithdevelopmentaldelay,au1sm,and

responsetofolinicacid”*

FolinicacidisaformofTETRAHYDRO-folate

*PMore=etal.,NeurologyMarch22,2005vol.64no.61088-1090

Folatereceptoran9bodiesduetoexcessfolicacidintheblood???

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TheBigPicture•  Connec9ve9ssuescontainlotsofsulfate•  Fetusdependsonmothertoprovidesulfate•  Sulfateisseverelydeficientinau9sm•  Cholesterolsupplytofetusdependsonsulfate–  Cholesterolsulfatenormallyaccumulatesinhighamountsintheplacentalvilliduringthirdtrimester

–  Cholesteroldeficiencyleadstoprojec9levomi9ngduetopyloricstenosis

•  Sulfateisessen9alforclearingcellulardebris•  Lowsulfateleadstohighoxalatewithmanysymptoms

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Connec1veTissueContainsLotsofSulfate

HeparansulfateChondroi9nsulfateKeratansulfate

SulfateinFetalDevelopment*•  Fetusdependsonmotherforsulfatesupply•  Sulfateisessen9alfortranspor9ngsterols(likeestrogenandDHEA)andsupplyingextracellularmatrixproteinseverywherewithsufficientnega9vecharge

•  Sulfatedetoxifiesxenobio9cslikeacetaminophen(Tylenol)andisessen9alforexcre9ngtoxinslikealuminumandmercury

•  Sulfateisseverelydeficientinau9s9cchildren(1/3thenormalleveloffreesulfateinbloodstream)

*PADawson.SeminCellDevBiol2011Aug;22(6):653-9.

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*Figure2inHCChris9ansonetal.,MatrixBiology2014;35:51-55

HeparanSulfateProteoglycans*

HeparanSulfateDeficiencyandAu1sm*

•  Experimentwith“designer”mice:impairedheparansulfatesynthesisinbrain

•  Miceexhibitedalltheclassicfeaturesofau9sm–bothcogni9veandsocial

*F.Irieetal.,Au9sm-likesocio-communica9vedeficitsandstereotypiesinmicelackingheparansulfate.PNASMar.27,2012,109(13),5052-5056.

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CholesterolSulfateinPlacentalVilli•  Placentalvilliarehighlyenrichedincholesterolsulfate,especiallyinthirdtrimesterofpregnancy

•  Mother’sserumcholesterolsulfatesteadilyrisesthroughpregnancy

•  Inthirdtrimester,villicontain24picomol/mgofcholesterolsulfate,comparedtoonly1.5inbloodserumofanon-pregnantwoman

*BLinetal.J.Chromatogr.B.Biomed.Sci.Appl.1997,704,99–104.

CholesterolSulfateinPlacentalVilli•  Placentalvilliarehighlyenrichedincholesterolsulfate,especiallyinthirdtrimesterofpregnancy

•  Mother’sserumcholesterolsulfatesteadilyrisesthroughpregnancy

•  Inthirdtrimester,villicontain24picomol/mgofcholesterolsulfate,comparedtoonly1.5inbloodserumofanon-pregnantwoman

*BLinetal.J.Chromatogr.B.Biomed.Sci.Appl.1997,704,99–104.

Hypothesis:cholesterolsulfateisamajorsupplierofbothcholesteroland

sulfatetothefetus

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PyloricStenosisandAu1sm•  Affects2outof1000births–  Pyloricvalveatbaseofstomachisenlarged,constric9ngflow

–  Severeprojec9levomi9nganddehydra9on,withelectrolyteimbalance.

–  Correc9vesurgeryisowenrequired•  Pyloricstenosisisassociatedwithlowserumcholesterol*

•  Au9smisassociatedwithincreasedrisktopyloricstenosis**

*FeenstraB,etal.JAMA2013;310(7):714-721.**M.L.Wieretal.,MedChildNeurol2006;48(6):500-507.

LowSulfate,HighOxalatePhenotype*•  GutDysbiosis

–  Decreasedsulfomucins,coli9s,IBD,leakygut–  Increasedsuscep9bilitytopathogens

•  FaAyliverdisease–  Reduceddetoxofheavymetalsandtoxicchemicals–  ElevatedserumLDL

•  Decreasedinsulinfunc9on•  Adrenalinsufficiency•  Increasedcancerrisk•  Stuntedgrowth,slowmetabolism•  Serotonindeficiencyinbrain•  Au9smlinkedtosulfatewas9nginkidneys

*Dr.Rostenbergwww.beyondmthfr.com/side-high-oxalates-problems-sulfate-b6-gut-methyla9on

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TheBigPicture•  Methionineisanessen9alsulfur-containingaminoacidproducedbygutmicrobesanddisruptedbyglyphosate

•  Methioninesitsatthecrossroadsofthemethyla9onandtrans-sulfura9onpathways

•  Bothmethyla9onandsulfa9onareessen9alfordevelopmentandneuronalfunc9on

•  GlyphosatealsosuppressesthesupplyoftheBvitamin,folate,essen9alformethyltransfer

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MethionineandCysteine

Methionine

THF

MTHFB12

Homocysteine

Cysteine

Sulfate

Glutathione

ProteinandDNAmethyla9on

MTHFR

*MBorisetal.,JournalofAmericanPhysiciansandSurgeons2004;9(4):106-108.

MTHFRgenevariantslinkedtoau9sm*

superoxide

Genera1ngMethioninefromHomocysteine

Methionine HomocysteineRequirements:WorkingMTHFRenzymeCobalamin(vitaminB12)ZincVitaminB6Methyltetrahydrofolate

Methioninesynthase

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Requirements:WorkingMTHFRenzymeCobalamin(vitaminB12)ZincVitaminB6Methyltetrahydrofolate

Folatetrap:Oneormoreoftheserequirementsare

missing;Methylgroupstaysstuckonfolate(inac9ve)

HomocysteineMethionineMethioninesynthase


Requirements:WorkingMTHFRenzymeCobalamin(vitaminB12)ZincVitaminB6Methyltetrahydrofolate

Folatetrap:Oneormoreoftheserequirementsare

missing;Methylgroupstaysstuckonfolate(inac9ve)

Thereisabeliefthatelevatedserumhomocysteineisbad,butthehomocysteineisdesperately

neededtoproducesulfate

HomocysteineMethionineMethioninesynthase

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Transsulfura1onPathway*

*Figure1,DAGeieretal.,NeurochemRes(2009)34:386–393.

PathwayfromHomocysteinetoSulfate*

homocysteinethiolactone

VitaminA

thiore9namide

VitaminC

alphaketobutyrate Sulfite

oxidase

re9noicacid

sulfate

sulfite

*McCully,AnnalsofClinicalandLaboratoryScience41:4,300-313,2011

PAPS

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VitaminA

thiore9namide

VitaminC


oxidase

re9noicacid

sulfate

sulfite


PAPS

WhenfolateandB12aredeficient,nearlyallhomocysteineisconvertedtohomocysteinethiolactone



VitaminA

thiore9namide

VitaminC


oxidase

re9noicacid

sulfate

sulfite


PAPS


Superoxide:Reac9ve

oxygenspecies(ROS)

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VitaminA

thiore9namide

VitaminC


oxidase

re9noicacid

sulfate

sulfite



PAPS

GAGs=Glycosaminoglycans=

sulfomucins

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WhatIfGlyphosateCouldInsertItselfIntoProteinSynthesis???

GGC

mRNA

Alanine Proline

--Anyproteinswithconservedglycineresiduesarelikelytobeaffectedinamajorway

......

CodeforGlycine


GGC

mRNA

glyphosate

Alanine Proline


......

CodeforGlycine

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GGC

mRNA

glyphosate

Alanine ProlineGlyphosate


......

CodeforGlycine

ExtraPieceS1cksOutatAc1veSite


Ac9veSite

Pep9dechain

Substratenolongerfitsinac9vesite

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glycine

Ac9veSite

Pep9dechain




glycine

Ac9veSite

ExtraStuff

Pep9dechain


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glycine

Ac9veSite

ExtraStuff

Pep9dechain


Thisexplainshowglyphosatedisrupts

EPSPSintheshikimatepathway:Mul9plebacteriahavedevelopedresistancebyreplacingac9vesiteglycinewithalanineandthisisthe

basisforGMORoundupReadycrops*

*TFunkeetal.,MolecularbasisfortheherbicideresistanceofRoundupReadycrops.PNAS2006;103(35):13010-13015.

Inhibi1onofEPSPSbyglyphosate:ResistantEcolimutant*

*Figure3,SEschenburgetal.Planta2002;216:129-135.

Wildtypewithglycine96

Mutantwithalaninesubs9tutedforglycine96

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SomePredictedConsequences*•  Neuraltubedefects•  Au9sm•  Impairedcollagenàosteoarthri9s•  Steatohepa99s(faAyliverdisease)•  Obesityandadrenalinsufficiency•  Hypothyroidism•  Impairedironhomeostasisandkidneyfailure•  Insulinresistanceanddiabetes•  Cancer

*A.SamselandS.Seneff.JournalofBiologicalPhysicsandChemistry2016;16:9-46.

AnAnalogy:ALSinGuam

•  AnepidemicinALSinGuamwastracedtoanaturaltoxinfoundincycads

•  BMAAisanon-codingaminoacidthatgetsinsertedbymistakeinplaceofserine

•  Defec9veversionsofaglutamatetransporterhavebeenlinkedtoALS*

•  Thetransporterhasanessen9alserine-richregioninitssequence**

*An9oxidants&RedoxSignaling2009;11:1587-1602.**DJSlotboometal.,PNAS1999;96(25):14282-14287.

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AnotherAnalogy:MS&SugarBeets*

•  SugarbeetscontainananalogueofprolinecalledAze

•  Remarkablecorrela9onbetweenMSfrequencyandproximitytosugarbeetagriculture

•  Myelinbasicproteincontainsaconcentra9onofprolineresiduesthatareabsolutelyessen9alforitsproperfunc9on

*E.Rubenstein,JNeuropatholExpNeurol2008;67(11):1035-1040.

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HumanDiges1veSystemDisorders

•  AlarmingincreaseintheUSinmanydiseasesrelatedtothegut– Crohn’sdisease,inflammatoryboweldisease,coli9s,acidrefluxdisease,glutenandcaseinintolerance,celiacdisease,leakygut

•  Thegut-brainaxislinksneurologicaldisorderswithgutdisorders

•  Ibelievethatglyphosateisamajorcause

InflammatoryBowelDiseaseandGlyphosateUsage*

*PlotprovidedbyDr.NancySwanson

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IBDUnder5YearsOldinCanada:AnEpidemic*

•  Canadahasamongthehighestratesofchildhood-onsetIBDintheworld

•  Incidenceisrapidlyrisinginchildrenunder5(7.2%increaseperyearsince1999)– Suspectearly-lifeenvironmentaltriggers

•  Canadiangovernment'sextensivedatabaseofglyphosateresiduesinfoodsshowsbyfarhighestlevelsinfoodsfromCanadaortheUS

*EIBenchimoletal.,AmJGastroenterol2017;112(7):1120-1134.

glyphosate

glyphosate

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ProteinsSuppressedbyGlyphosateinE.coli*

PAPSreductase -3.75sulfitereductase,alphasubunit -3.23sulfitereductase,betasubunit -4.55periplasmicsulfate-bindingprotein-3.39sulfatetransportsystempermease -2.05

*W.Luetal.,MolBioSyst2013;9:522-530,SupplementaryTableS2.




Requiredforincorpora9onofinorganicsulfurfromsulfateinto

organicsulfur(methionine)

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Requiredfortransportofsulfateintothecell

SulfiteMetabolism:SulfurSensi1vity

Sulfite

Sulfiteoxidase

DissimilatorySulfitereductase

AssimilatorySulfitereductase

Methionine HydrogenSulfide

Sulfate

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Sulfite

Sulfiteoxidase




Sulfate

InhibitedinEcolibyglyphosate


Sulfite

Sulfiteoxidase




Sulfate


Desulfovibrioovergrowth

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Sulfite

Sulfiteoxidase




Sulfate


Desulfovibrioovergrowth

Dependsonessen9alglycineresiduetoformac9vedimer

“SulfideasaMucusBarrier-BreakerinInflammatoryBowelDisease?”*

*N.Ijssennaggeretal.,TrendsinMolecularMedicine2016;22(3):190-199.

"hydrogensulfideconcentra9onsrise,causingdenatura9onoftheouterandinnermucuslayers,therebyallowingpenetra9onandcontactofbacteriawiththehostepitheliallining.Thisinturntriggersinflamma9on."

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ConservedGlycinesinImportantSulfur-processingEnzymes

•  Thesulfotransferases*– GxxGxxKmo9frequiredforbindingPAPS

•  Sulfiteoxidase**– Changingglycineatresidue473withaspartatedestroysenzymeac9vity

– Aspartatehassimilarproper9esasglyphosate,beingbulkyandnega9velycharged

– Defec9veSOleadstoseverebirthdefectsandneurologicalproblemsthatusuallyresultindeathatanearlyage

*K.Komatsuetal.,BiochemicalandBiophysicalResearchCommunica9ons1994;204(3):1178-1185.

**H.L.Wilsonetal.,Biochemistry2006,45,2149-2160.

SulfateReducingMicrobes

•  Desulfovibrioisamicrobeinthecolonthatreducessulfatetohydrogensulfidegas– Desulfovibrioovergrowthislinkedtoau9sm

•  Hydrogensulfidetravelslikeaghostacrossall9ssues–  Itcantravelbydiffusionfromthecolontothespinalcolumn,thepancreas,theliver,etc.

–  Itcanbeoxidizedtoformsulfateatthedes9na9onsite,butthisrequiressuperoxide,leadingtolocal9ssuedamage

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SulfateReducingMicrobes

•  Desulfovibrioisamicrobeinthecolonthatreducessulfatetohydrogensulfidegas– Desulfovibrioovergrowthislinkedtoau9sm

•  Hydrogensulfidetravelslikeaghostacrossall9ssues–  Itcantravelbydiffusionfromthecolontothespinalcolumn,thepancreas,theliver,etc.

–  Itcanbeoxidizedtoformsulfateatthedes9na9onsite,butthisrequiressuperoxide,leadingtolocal9ssuedamage

Thisisanovelwaytotransportsulfate!

HowGlyphosateDamagesMitochondriaandLysosomes

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GlyphosatedisruptsCytochromeCOxidase



Glyphosatedepletesglutathioneàinsufficientan9oxidantcapacity

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Glyphosateimpairssulfatesupplyàinsufficientacidity




Glyphosateimpairssulfatesupplyàinsufficientacidity


Resultisbuild-upoflipofuscin

(directlinktoagingandsenescence)andimpairedabilitytorecycle

damagedmolecules

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Glycinedecarboxylasedeficiencycausesneuraltubedefectsandfeaturesofnon-keto1chyperglycinemiainmice*

•  Fascina9ngar9cleaboutmicewithadeficiencyinaproteininvolvedingenera9ngmethylgroupsfromglycine->methylfolatedeficiency

•  Thesemicehaveveryhighrateofneuraltubedefects

•  Thosethatareviablehaveswollenventricles(afeatureofau9sm)anddelayeddevelopment

•  Methyla9onpathwayimpairmentisacommonfeatureofau9sm

*YJPaietal.,NatureCommunica9ons2015;6:6388

Glycinedecarboxylasedeficiencycausesneuraltubedefectsandfeaturesofnon-keto1chyperglycinemiainmice*

•  Fascina9ngar9cleaboutmicewithadeficiencyinaproteininvolvedingenera9ngmethylgroupsfromglycine->methylfolatedeficiency

•  Thesemicehaveveryhighrateofneuraltubedefects

•  Thosethatareviablehaveswollenventricles(afeatureofau9sm)anddelayeddevelopment

•  Methyla9onpathwayimpairmentisacommonfeatureofau9sm

Glycinedecarboxylasehasaglycine-richregionthat

maintainsshapeandflexibilityofac9vesite**

**AKumeetal.,JBC1991;266(5):3323-3329

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Inflamma1onandHydrogenSulfide*

•  EnhancedH2Ssynthesisinmul9pleinflammatorydiseasesandcondi9ons–  arthri9s–  acutepancrea99s–  sepsis–  hemorrhagicshock–  burns

•  H2Sissynthesizedfromcysteineandthenoxidizedtoformsulfate

•  H2Sinducesinflammatoryresponsewhichsuppliessuperoxideneededforsulfateforma9on

*NMunirajetal.,IntJRheumDis.2017Feb;20(2):182-189.

Inflamma1onandHydrogenSulfide*

•  EnhancedH2Ssynthesisinmul9pleinflammatorydiseasesandcondi9ons–  arthri9s–  acutepancrea99s–  sepsis–  hemorrhagicshock–  Burns

•  H2Sissynthesizedfromcysteineandthenoxidizedtoformsulfate

•  H2Sinducesinflammatoryresponsewhichsuppliessuperoxideneededforsulfateforma9on

Isthisamechanismtorenew

sulfatesuppliestothevasculature?

*NMunirajetal.,IntJRheumDis.2017Feb;20(2):182-189.

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MicrocephalyandPrematurity*•  Datapooledfromhospitalsin11ci9esin5states•  1506prematureinfantswerestudied(GA23-28weeks)

•  Microcephalyoccursmuchmorecommonlythanexpectedamongbabiesbornprematurely–  2.2%expected,nearly10%observed

•  Extremelylowgesta9onalageandsevereintra-uterinegrowthrestric9onareriskfactorsformicrocephaly–  Intra-uterinegrowthrestric9oncausedbyinflamedanddamagedplacenta

*TFMcElrathetal.,AmJObstetGynecol.2010;203(2):138.e1–138.e8.

MicrocephalyandPrematurity*•  Datapooledfromhospitalsin11ci9esin5states•  1506prematureinfantswerestudied(GA23-28weeks)

•  Microcephalyoccursmuchmorecommonlythanexpectedamongbabiesbornprematurely–  2.2%expected,nearly10%observed

•  Extremelylowgesta9onalageandsevereintra-uterinegrowthrestric9onareriskfactorsformicrocephaly–  Intra-uterinegrowthrestric9oncausedbyinflamedanddamagedplacenta

*TFMcElrathetal.,AmJObstetGynecol.2010;203(2):138.e1–138.e8.

Hypothesis:Inflamedplacentaistryingtorecoveradequatesulfatebyoxidizingreducedsulfursources

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MagnesiumSulfateProtectsPlacentafromInflamma1on*

•  Ratmodel:injectLPStoinduceinflamma9oninplacenta

•  Placentasrespondedwithincreasedexpressionofinflammatorymarkers

•  Simultaneousadministra9onofmagnesiumsulfateprotectedplacentas

•  HumanplacentalculturesreactedsimilarlytobothLPSandmagnesiumsulfate

*ODowlingetal.Placenta2012;33(5):392-8.

ThisisGoodNews!*

*hAps://www.ams.usda.gov/press-release/2016-count-cer9fied-organic-opera9ons-shows-con9nued-growth-us-market

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Summary•  Glyphosateusagehasgrownexponen9allyoverthepasttwo

decades,instepwiththeintroduc9onofGMORoundup-Readycrops

•  Glyphosatecausesneuraltubedefectsandau9smthroughmul9plemetabolicdisrup9ons–  Folateandmethioninedeficiency–  Disruptedsulfatesynthesisandtransport

•  Methioninesitsatthecrossroadsofthemethyla9onandtranssulfura9onpathways

•  Folatedeficiencyduetoglyphosate’sdisrup9onofgutmicrobesledtoregula9ontorequirefolicacidfor9fica9onofwheat-basedfoods

•  Folicacidisadefec9veformoffolatethatcausesliverdiseaseandincreasedrisktoau9smandasthma

•  Cholesterolsulfate,heparansulfateandchondroi9nsulfateareessen9alforfetalbraindevelopment

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