download these slides - mit csailpeople.csail.mit.edu/seneff/2018/seneffjuly2018.pdf · download...
TRANSCRIPT
![Page 1: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/1.jpg)
7/16/18
1
Glyphosate'sdisrup1onofmethyla1on/transsulfura1on
pathwaysasakeyfactorinau1smandotherdiseases
StephanieSeneff,MITCSAILMethyla9onSummit
July15,2018
Downloadtheseslides
hAp://people.csail.mit.edu/seneff/2018/SeneffJuly2018.pptx
![Page 2: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/2.jpg)
7/16/18
2
Outline• Introduc9on• GlyphosateandFolicAcidFor9fica9on• CholesterolSulfateandHeparanSulfate• Methyla9onandTranssulfura9onPathways• GlyphosateDisplacingGlycineduringProteinSynthesis
• HowGlyphosateDisruptsMethyla9onandSulfa9on
• Summary
![Page 3: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/3.jpg)
7/16/18
3
RoundupandGMOCrops
Whatisglyphosate?
RoundupandGMOCrops
![Page 4: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/4.jpg)
7/16/18
4
RoundupandGMOCrops
GMORoundup-Readycorn,soy,canola,sugarbeetscoAon,tobaccoandalfalfa
RoundupasaDesiccant/RipenerjustbeforeHarvest
Wheat,Oats,Barley,Rye,Sugarcane,Beans,Len9ls,Peas,Flax,Sunflowers,Pulses,ChickPeas
![Page 5: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/5.jpg)
7/16/18
5
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
![Page 6: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/6.jpg)
7/16/18
6
ShikimatePathwayDisrup1on
shikimate
chorismate
Phenylalanine,tryptophan,tyrosine
folate
vitaminK
Glyphosate à NeurotransmiAers,thyroidhormone
PaperShowingStrongCorrela1onsbetweenGlyphosateUsage
andChronicDisease
![Page 7: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/7.jpg)
7/16/18
7
EnvironmentalMedicineTraining||Copyright©2014ProgressiveMedicalEduca9on.AllRightsReserved.
Thyroidcancer Diabetes
Urinary/bladdercancer
Endstagerenaldisease
EnvironmentalMedicineTraining||Copyright©2014ProgressiveMedicalEduca9on.AllRightsReserved.
Thyroidcancer Diabetes
Urinary/bladdercancer
Endstagerenaldisease
In2015,WHOdeclaredglyphosatea“probablecarcinogen”
![Page 8: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/8.jpg)
7/16/18
8
QuotefromtheConclusion*
“Althoughcorrela9ondoesnotnecessarilymeancausa9on,whencorrela9oncoefficientsofover0.95(withp-valuesignificancelevelslessthan0.00001)arecalculatedforalistofdiseasesthatcanbedirectlylinkedtoglyphosate,viaitsknownbiologicaleffects,itwouldbeimprudentnottoconsidercausa9onasaplausibleexplana9on.”
*NLSwansonetal.JournalofOrganicSystems9(2),2014,p.32,
![Page 9: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/9.jpg)
7/16/18
9
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
![Page 10: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/10.jpg)
7/16/18
10
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.
![Page 11: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/11.jpg)
7/16/18
11
Adop1onofGMCropsinU.S.
HT=herbicide(glyphosate)tolerant
GlyphosateandSuperweeds:U.S.*
*hAp://sustainablepulse.com/wp-content/uploads/GMO-health.pdf
![Page 12: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/12.jpg)
7/16/18
12
GutMicrobesProvideFolatetoHost!*“Inconclusion,thefindingsfromthisstudysuggestthatthequan9tyofmicrobiallysynthesizedfolateinthelargeintes9neofhumaninfantsissufficientlylargetopoten9allyaffectthefolatestatusofthehost.“
*THKimetal.,JNutr.2004Jun;134(6):1389-94.
GutMicrobesProduceBioavailableFolate*
• Strainsoflactobacillusandbifidobacteriawereshowntosynthesizefolate– Bothoftheseareespeciallysuscep9bletoglyphosatetoxicity
• "Ratsfedaprobio9cformula9onoffolate-producingbifidobacteriaexhibitedincreasedplasmafolatelevel,confirmingthatthevitaminisproducedinvivoandabsorbed"
*MRossietal.,Nutrients2011,3,118-134
![Page 13: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/13.jpg)
7/16/18
13
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.
![Page 14: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/14.jpg)
7/16/18
14
“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.
![Page 15: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/15.jpg)
7/16/18
15
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
![Page 16: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/16.jpg)
7/16/18
16
“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???
![Page 17: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/17.jpg)
7/16/18
17
TheBigPicture• Connec9ve9ssuescontainlotsofsulfate• Fetusdependsonmothertoprovidesulfate• Sulfateisseverelydeficientinau9sm• Cholesterolsupplytofetusdependsonsulfate– Cholesterolsulfatenormallyaccumulatesinhighamountsintheplacentalvilliduringthirdtrimester
– Cholesteroldeficiencyleadstoprojec9levomi9ngduetopyloricstenosis
• Sulfateisessen9alforclearingcellulardebris• Lowsulfateleadstohighoxalatewithmanysymptoms
![Page 18: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/18.jpg)
7/16/18
18
Connec1veTissueContainsLotsofSulfate
HeparansulfateChondroi9nsulfateKeratansulfate
SulfateinFetalDevelopment*• Fetusdependsonmotherforsulfatesupply• Sulfateisessen9alfortranspor9ngsterols(likeestrogenandDHEA)andsupplyingextracellularmatrixproteinseverywherewithsufficientnega9vecharge
• Sulfatedetoxifiesxenobio9cslikeacetaminophen(Tylenol)andisessen9alforexcre9ngtoxinslikealuminumandmercury
• Sulfateisseverelydeficientinau9s9cchildren(1/3thenormalleveloffreesulfateinbloodstream)
*PADawson.SeminCellDevBiol2011Aug;22(6):653-9.
![Page 19: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/19.jpg)
7/16/18
19
*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.
![Page 20: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/20.jpg)
7/16/18
20
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
![Page 21: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/21.jpg)
7/16/18
21
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
![Page 22: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/22.jpg)
7/16/18
22
TheBigPicture• Methionineisanessen9alsulfur-containingaminoacidproducedbygutmicrobesanddisruptedbyglyphosate
• Methioninesitsatthecrossroadsofthemethyla9onandtrans-sulfura9onpathways
• Bothmethyla9onandsulfa9onareessen9alfordevelopmentandneuronalfunc9on
• GlyphosatealsosuppressesthesupplyoftheBvitamin,folate,essen9alformethyltransfer
![Page 23: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/23.jpg)
7/16/18
23
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
![Page 24: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/24.jpg)
7/16/18
24
Genera1ngMethioninefromHomocysteine
Requirements:WorkingMTHFRenzymeCobalamin(vitaminB12)ZincVitaminB6Methyltetrahydrofolate
Folatetrap:Oneormoreoftheserequirementsare
missing;Methylgroupstaysstuckonfolate(inac9ve)
HomocysteineMethionineMethioninesynthase
Genera1ngMethioninefromHomocysteine
Requirements:WorkingMTHFRenzymeCobalamin(vitaminB12)ZincVitaminB6Methyltetrahydrofolate
Folatetrap:Oneormoreoftheserequirementsare
missing;Methylgroupstaysstuckonfolate(inac9ve)
Thereisabeliefthatelevatedserumhomocysteineisbad,butthehomocysteineisdesperately
neededtoproducesulfate
HomocysteineMethionineMethioninesynthase
![Page 25: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/25.jpg)
7/16/18
25
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
![Page 26: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/26.jpg)
7/16/18
26
PathwayfromHomocysteinetoSulfate*
homocysteinethiolactone
VitaminA
thiore9namide
VitaminC
alphaketobutyrate Sulfite
oxidase
re9noicacid
sulfate
sulfite
*McCully,AnnalsofClinicalandLaboratoryScience41:4,300-313,2011
PAPS
WhenfolateandB12aredeficient,nearlyallhomocysteineisconvertedtohomocysteinethiolactone
PathwayfromHomocysteinetoSulfate*
homocysteinethiolactone
VitaminA
thiore9namide
VitaminC
alphaketobutyrate Sulfite
oxidase
re9noicacid
sulfate
sulfite
*McCully,AnnalsofClinicalandLaboratoryScience41:4,300-313,2011
PAPS
WhenfolateandB12aredeficient,nearlyallhomocysteineisconvertedtohomocysteinethiolactone
Superoxide:Reac9ve
oxygenspecies(ROS)
![Page 27: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/27.jpg)
7/16/18
27
PathwayfromHomocysteinetoSulfate*
homocysteinethiolactone
VitaminA
thiore9namide
VitaminC
alphaketobutyrate Sulfite
oxidase
re9noicacid
sulfate
sulfite
*McCully,AnnalsofClinicalandLaboratoryScience41:4,300-313,2011
WhenfolateandB12aredeficient,nearlyallhomocysteineisconvertedtohomocysteinethiolactone
PAPS
GAGs=Glycosaminoglycans=
sulfomucins
![Page 28: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/28.jpg)
7/16/18
28
WhatIfGlyphosateCouldInsertItselfIntoProteinSynthesis???
GGC
mRNA
Alanine Proline
--Anyproteinswithconservedglycineresiduesarelikelytobeaffectedinamajorway
......
CodeforGlycine
WhatIfGlyphosateCouldInsertItselfIntoProteinSynthesis???
GGC
mRNA
glyphosate
Alanine Proline
--Anyproteinswithconservedglycineresiduesarelikelytobeaffectedinamajorway
......
CodeforGlycine
![Page 29: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/29.jpg)
7/16/18
29
WhatIfGlyphosateCouldInsertItselfIntoProteinSynthesis???
GGC
mRNA
glyphosate
Alanine ProlineGlyphosate
--Anyproteinswithconservedglycineresiduesarelikelytobeaffectedinamajorway
......
CodeforGlycine
ExtraPieceS1cksOutatAc1veSite
Alanine ProlineGlyphosate
Ac9veSite
Pep9dechain
Substratenolongerfitsinac9vesite
![Page 30: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/30.jpg)
7/16/18
30
ExtraPieceS1cksOutatAc1veSite
Alanine ProlineGlyphosate
glycine
Ac9veSite
Pep9dechain
Substratenolongerfitsinac9vesite
ExtraPieceS1cksOutatAc1veSite
Alanine ProlineGlyphosate
glycine
Ac9veSite
ExtraStuff
Pep9dechain
Substratenolongerfitsinac9vesite
![Page 31: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/31.jpg)
7/16/18
31
ExtraPieceS1cksOutatAc1veSite
Alanine ProlineGlyphosate
glycine
Ac9veSite
ExtraStuff
Pep9dechain
Substratenolongerfitsinac9vesite
Thisexplainshowglyphosatedisrupts
EPSPSintheshikimatepathway:Mul9plebacteriahavedevelopedresistancebyreplacingac9vesiteglycinewithalanineandthisisthe
basisforGMORoundupReadycrops*
*TFunkeetal.,MolecularbasisfortheherbicideresistanceofRoundupReadycrops.PNAS2006;103(35):13010-13015.
Inhibi1onofEPSPSbyglyphosate:ResistantEcolimutant*
*Figure3,SEschenburgetal.Planta2002;216:129-135.
Wildtypewithglycine96
Mutantwithalaninesubs9tutedforglycine96
![Page 32: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/32.jpg)
7/16/18
32
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.
![Page 33: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/33.jpg)
7/16/18
33
AnotherAnalogy:MS&SugarBeets*
• SugarbeetscontainananalogueofprolinecalledAze
• Remarkablecorrela9onbetweenMSfrequencyandproximitytosugarbeetagriculture
• Myelinbasicproteincontainsaconcentra9onofprolineresiduesthatareabsolutelyessen9alforitsproperfunc9on
*E.Rubenstein,JNeuropatholExpNeurol2008;67(11):1035-1040.
![Page 34: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/34.jpg)
7/16/18
34
HumanDiges1veSystemDisorders
• AlarmingincreaseintheUSinmanydiseasesrelatedtothegut– Crohn’sdisease,inflammatoryboweldisease,coli9s,acidrefluxdisease,glutenandcaseinintolerance,celiacdisease,leakygut
• Thegut-brainaxislinksneurologicaldisorderswithgutdisorders
• Ibelievethatglyphosateisamajorcause
InflammatoryBowelDiseaseandGlyphosateUsage*
*PlotprovidedbyDr.NancySwanson
![Page 35: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/35.jpg)
7/16/18
35
IBDUnder5YearsOldinCanada:AnEpidemic*
• Canadahasamongthehighestratesofchildhood-onsetIBDintheworld
• Incidenceisrapidlyrisinginchildrenunder5(7.2%increaseperyearsince1999)– Suspectearly-lifeenvironmentaltriggers
• Canadiangovernment'sextensivedatabaseofglyphosateresiduesinfoodsshowsbyfarhighestlevelsinfoodsfromCanadaortheUS
*EIBenchimoletal.,AmJGastroenterol2017;112(7):1120-1134.
glyphosate
glyphosate
![Page 36: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/36.jpg)
7/16/18
36
ProteinsSuppressedbyGlyphosateinE.coli*
PAPSreductase -3.75sulfitereductase,alphasubunit -3.23sulfitereductase,betasubunit -4.55periplasmicsulfate-bindingprotein-3.39sulfatetransportsystempermease -2.05
*W.Luetal.,MolBioSyst2013;9:522-530,SupplementaryTableS2.
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)
![Page 37: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/37.jpg)
7/16/18
37
ProteinsSuppressedbyGlyphosateinE.coli*
PAPSreductase -3.75sulfitereductase,alphasubunit -3.23sulfitereductase,betasubunit -4.55periplasmicsulfate-bindingprotein-3.39sulfatetransportsystempermease -2.05
*W.Luetal.,MolBioSyst2013;9:522-530,SupplementaryTableS2.
Requiredfortransportofsulfateintothecell
SulfiteMetabolism:SulfurSensi1vity
Sulfite
Sulfiteoxidase
DissimilatorySulfitereductase
AssimilatorySulfitereductase
Methionine HydrogenSulfide
Sulfate
![Page 38: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/38.jpg)
7/16/18
38
SulfiteMetabolism:SulfurSensi1vity
Sulfite
Sulfiteoxidase
DissimilatorySulfitereductase
AssimilatorySulfitereductase
Methionine HydrogenSulfide
Sulfate
InhibitedinEcolibyglyphosate
SulfiteMetabolism:SulfurSensi1vity
Sulfite
Sulfiteoxidase
DissimilatorySulfitereductase
AssimilatorySulfitereductase
Methionine HydrogenSulfide
Sulfate
InhibitedinEcolibyglyphosate
Desulfovibrioovergrowth
![Page 39: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/39.jpg)
7/16/18
39
SulfiteMetabolism:SulfurSensi1vity
Sulfite
Sulfiteoxidase
DissimilatorySulfitereductase
AssimilatorySulfitereductase
Methionine HydrogenSulfide
Sulfate
InhibitedinEcolibyglyphosate
Desulfovibrioovergrowth
Dependsonessen9alglycineresiduetoformac9vedimer
“SulfideasaMucusBarrier-BreakerinInflammatoryBowelDisease?”*
*N.Ijssennaggeretal.,TrendsinMolecularMedicine2016;22(3):190-199.
"hydrogensulfideconcentra9onsrise,causingdenatura9onoftheouterandinnermucuslayers,therebyallowingpenetra9onandcontactofbacteriawiththehostepitheliallining.Thisinturntriggersinflamma9on."
![Page 40: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/40.jpg)
7/16/18
40
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
![Page 41: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/41.jpg)
7/16/18
41
SulfateReducingMicrobes
• Desulfovibrioisamicrobeinthecolonthatreducessulfatetohydrogensulfidegas– Desulfovibrioovergrowthislinkedtoau9sm
• Hydrogensulfidetravelslikeaghostacrossall9ssues– Itcantravelbydiffusionfromthecolontothespinalcolumn,thepancreas,theliver,etc.
– Itcanbeoxidizedtoformsulfateatthedes9na9onsite,butthisrequiressuperoxide,leadingtolocal9ssuedamage
Thisisanovelwaytotransportsulfate!
HowGlyphosateDamagesMitochondriaandLysosomes
![Page 42: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/42.jpg)
7/16/18
42
HowGlyphosateDamagesMitochondriaandLysosomes
GlyphosatedisruptsCytochromeCOxidase
HowGlyphosateDamagesMitochondriaandLysosomes
GlyphosatedisruptsCytochromeCOxidase
Glyphosatedepletesglutathioneàinsufficientan9oxidantcapacity
![Page 43: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/43.jpg)
7/16/18
43
HowGlyphosateDamagesMitochondriaandLysosomes
GlyphosatedisruptsCytochromeCOxidase
Glyphosateimpairssulfatesupplyàinsufficientacidity
Glyphosatedepletesglutathioneàinsufficientan9oxidantcapacity
HowGlyphosateDamagesMitochondriaandLysosomes
GlyphosatedisruptsCytochromeCOxidase
Glyphosateimpairssulfatesupplyàinsufficientacidity
Glyphosatedepletesglutathioneàinsufficientan9oxidantcapacity
Resultisbuild-upoflipofuscin
(directlinktoagingandsenescence)andimpairedabilitytorecycle
damagedmolecules
![Page 44: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/44.jpg)
7/16/18
44
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
![Page 45: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/45.jpg)
7/16/18
45
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.
![Page 46: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/46.jpg)
7/16/18
46
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
![Page 47: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/47.jpg)
7/16/18
47
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
![Page 48: Download these slides - MIT CSAILpeople.csail.mit.edu/seneff/2018/SeneffJuly2018.pdf · Download these slides hp:// people.csail.mit.edu/seneff/ 2018/SeneffJuly2018.pptx 7/16/18](https://reader033.vdocuments.us/reader033/viewer/2022060607/605cede470676f5eda1231ca/html5/thumbnails/48.jpg)
7/16/18
48
Summary• Glyphosateusagehasgrownexponen9allyoverthepasttwo
decades,instepwiththeintroduc9onofGMORoundup-Readycrops
• Glyphosatecausesneuraltubedefectsandau9smthroughmul9plemetabolicdisrup9ons– Folateandmethioninedeficiency– Disruptedsulfatesynthesisandtransport
• Methioninesitsatthecrossroadsofthemethyla9onandtranssulfura9onpathways
• Folatedeficiencyduetoglyphosate’sdisrup9onofgutmicrobesledtoregula9ontorequirefolicacidfor9fica9onofwheat-basedfoods
• Folicacidisadefec9veformoffolatethatcausesliverdiseaseandincreasedrisktoau9smandasthma
• Cholesterolsulfate,heparansulfateandchondroi9nsulfateareessen9alforfetalbraindevelopment