![Sequential outcomes of tubular cell toxic injury of cadmium accumulation in kidneys. Cd inflicts tubular cell injury at low intracellular concentrations, and the toxicity intensifies as Cd concentration rises [65]. Tubular injury disables glomerular filtration, leading to nephron atrophy, glomerulosclerosis, and interstitial inflammation and fibrosis. A reduction in tubular reabsorption of filtered proteins, RBP and β2MG follows tubular atrophy and nephron loss. Abbreviation: KIM1, kidney injury molecule 1; NAG, N-acetyl-β-D-glucosaminidase, NGAL, neutrophil gelatinase associated lipocalin; RBP, retinal binding protein; β2M, β2-microglobulin.](https://www.researchgate.net/profile/Soisungwan-Satarug/publication/363568096/figure/fig2/AS:11431281084646149@1663301459253/Sequential-outcomes-of-tubular-cell-toxic-injury-of-cadmium-accumulation-in-kidneys-Cd_Q320.jpg)
![Heme-glucose crosstalk and mitochondrial target of cadmium. (a) Heme degradation catalyzed by HO-1 and HO-2 utilizes NADPH from pentose phosphate pathway. (b) Cadmium-induced kidney tubular cell death. Cd uses the Zn carrier metallothionein (MT) and transporters of Ca and Fe, mitochondrial calcium uniporter (MCU) and the divalent metal transporter 1 (DMT1) to reach the mitochondrial inner membrane [145]. There, Cd reduces ATP output and promotes reactive oxygen species (ROS) formation. Extensive damage causes a release of mitochondrial DNA (mtDNA). The DNA-sensing mechanism (cGAS-STING) and nuclear factor-kappaB (NF-кB) signaling pathways are activated, proinflammatory cytokines are released, and cell death ensues. Abbreviation: BVR, biliverdin reductase; PEP, phosphoenolpyruvate; cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; CdRE, Cadmium response element.](https://www.researchgate.net/profile/Soisungwan-Satarug/publication/363568096/figure/fig4/AS:11431281084638155@1663302515814/Heme-glucose-crosstalk-and-mitochondrial-target-of-cadmium-a-Heme-degradation_Q320.jpg)
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Stresses2022,2,355–372.https://doi.org/10.3390/stresses2030025www.mdpi.com/journal/stresses
Review
MitigationofCadmiumToxicitythroughModulation
oftheFrontlineCellularStressResponse
SoisungwanSatarug
1,
*,DavidA.Vesey
1,2
andGlendaC.Gobe
1,3,4
1
KidneyDiseaseResearchCollaborative,TranslationalResearchInstitute,Brisbane4102,Australia
2
DepartmentofNephrology,PrincessAlexandraHospital,Brisbane4102,Australia
3
SchoolofBiomedicalSciences,TheUniversityofQueensland,Brisbane4072,Australia
4
NHMRCCentreofResearchExcellenceforCKDQLD,UQHealthSciences,RoyalBrisbaneandWomen’s
Hospital,Brisbane4029,Australia
*Correspondence:sj.satarug@yahoo.com.au
Abstract:Cadmium(Cd)isanenvironmentaltoxicantofpublichealthsignificanceworldwide.Diet
isthemainCdexposuresourceinthenon‐occupationallyexposedandnon‐smokingpopulations.
Metaltransportersforiron(Fe),zinc(Zn),calcium(Ca),andmanganese(Mn)areinvolvedinthe
assimilationanddistributionofCdtocellsthroughoutthebody.Duetoanextremelyslowelimina‐
tionrate,mostCdisretainedbycells,whereitexertstoxicitythroughitsinteractionwithsulfur‐
containingligands,notablythethiol(‐SH)functionalgroupofcysteine,glutathione,andmanyZn‐
dependentenzymesandtranscriptionfactors.Thesimultaneousinductionofhemeoxygenase‐1
andthemetal‐bindingproteinmetallothioneinbyCdadverselyaffectedthecellularredoxstateand
causedthedysregulationofFe,Zn,andcopper.ExperimentaldataindicatethatCdcausesmito‐
chondrialdysfunctionviadisruptingthemetalhomeostasisofthisorganelle.Thepresentreview
focusesontheadversemetabolicoutcomesofchronicexposuretolow‐doseCd.Currentepidemio‐
logicdataindicatethatchronicexposuretoCdraisestheriskoftype2diabetesbyseveralmecha‐
nisms,suchasincreasedoxidativestress,inflammation,adiposetissuedysfunction,increasedinsu‐
linresistance,anddysregulatedcellularintermediarymetabolism.Thecellularstressresponse
mechanismsinvolvingthecatabolismofheme,mediatedbyhemeoxygenase‐1and‐2(HO‐1and
HO‐2),maymitigatethecytotoxicityofCd.Theproductsoftheirphysiologichemedegradation,
bilirubinandcarbonmonoxide,haveantioxidative,anti‐inflammatory,andanti‐apoptoticproper‐
ties.
Keywords:bilirubin;cadmium;carbonmonoxide;glycolysis;gluconeogenesis;heme;hemeoxy‐
genase‐1;hemeoxygense‐2;obesephenotype;hemeoxygenase‐2deficiency;stressresponse
1.Introduction
Theutilityofaredoxinertmetalcadmium(Cd)inmanyindustrialprocesses,and
theuseofphosphatefertilizerscontaminatedwithCdbytheagriculturalsectorhavere‐
sultedinwidespreaddispersionofthistoxicmetalintheenvironmentandsubsequently
thefoodchains[1–5].Volcanicemissions,biomassandfossilfuelcombustion,andciga‐
rettesmokeareadditionalsourcesofenvironmentalCdpollution[6–10].Cdincigarette
smokeasavolatilemetallicformandoxide(CdO)hasaparticularlyhightransmission
rate[10,11].Anexistenceofthenose‐to‐braintransportrouteoftoxicmetalsraisesthe
possibilitythatairborneCdmayenterthecentralnervoussystem(CNS)byutilizinga
Cd‐alteredblood–brainbarrier[12–14].
Foodsthatarefrequentlyconsumedinlargequantities,suchasrice,potatoes,wheat,
leafysaladvegetables,andothercerealcrops,formthemostsignificantdietarysourcesof
Cd[15–17].Seafood(shellfish),mollusks,andcrustaceansareadditionaldietaryCd
sources[18,19].Cdentersthebodyfromthegutandlungsviathemetaltransportersand
Citation:Satarug,S.;Vesey,D.A.;
Gobe,G.C.MitigationofCadmium
ToxicitythroughModulationofthe
FrontlineCellularStressResponse.
Stresses2022,2,355–372.https://
doi.org/10.3390/stresses2030025
AcademicEditor:DavidR.Wallace
Received:1September2022
Accepted:14September2022
Published:15September2022
Publisher’sNote:MDPIstaysneu‐
tralwithregardtojurisdictional
claimsinpublishedmapsandinstitu‐
tionalaffiliations.
Copyright:©2022bytheauthors.
Submittedforpossibleopenaccess
publicationunderthetermsandcon‐
ditionsoftheCreativeCommonsAt‐
tribution(CCBY)license(https://cre‐
ativecommons.org/licenses/by/4.0/).
Stresses2022,2,25356
pathwaysforzinc(Zn),calcium(Ca),iron(Fe),manganese(Mn),andpossiblyselenium
(Se)[17].Becauseofanextremelyslowexcretionrate,mostabsorbedCdisretainedin
cells,andthecellularcontentofCdincreaseswiththedurationofexposure(age)[17].
Evidencefromepidemiologicandexperimentalstudiessuggestthatlowenviron‐
mentalexposuretoCdmayincreasetheriskofdiseaseswithhighprevalence,suchas
chronickidneydisease(CKD),liverdisease,type2diabetes,andneurodegenerativedis‐
orders[15–17,20].Developingstrategiestopreventthesechronicailmentsisofglobalim‐
portanceintheabsenceofeffectivechelationtherapiestoreducetheCdbodyburden.
Inthepresentreview,wefocusontheeffectsofCdexposureoncellularintermediary
metabolismandthecytoprotectiveroleofmetal‐inducedstressresponses.Toxicmanifes‐
tationofCdinkidneys,liver,pancreas,andadiposetissuesarediscussedbecausethese
organsarecentraltothecontrolofbloodglucoselevels.BloodandurinaryCdlevelsthat
werefoundtobeassociatedwithadversemetabolicoutcomesareprovided.Evidencefor
Cd‐inducedoxidativestressandinflammatoryconditionsarereviewed.Theinterplaysof
hemeoxygenase‐1and‐2(HO‐1andHO‐)toregulateglycolysisandgluconeogenesisare
highlightedasistheirkeyroleasthefrontlinecellularstressresponsemechanismthat
neutralizesoxidativedamageandprotectsagainstabnormalglucosemetabolism,exces‐
siveweightgain,andobesity.
2.MeasuresofHumanCadmiumExposure
2.1.Entry,Distribuion,andExcretionofCadmium
AsFigure1depicts,ingestedCdisabsorbedbytheintestineandtransportedviathe
portalbloodsystemtoliver,whileinhaledCdistransportedtolungsandpossiblythe
CNSvianasal‐to‐brainroute.Cdinducessynthesisofmetallothionein(MT)andthe
CdMTcomplexesareformedintheseorgans[21,22].
Figure1.Entry,distribution,andexitofcadmium.IngestedCd
2+
ionsareabsorbedandtransported
toliver,whileinhaledCdoxideandmetallicCdaretransportedtolungs.Thefractionofabsorbed
Cd
2+
ionsnottakenupbyhepatocytesinthefirstpassreachessystemiccirculationandisassimilated
bycellsthroughoutthebody.Inliverandlungs,CdinducessynthesisofMTwithresultantfor‐
mationofCdMTwithsubsequentreleaseintothecirculationandreabsorptionbykidneytubular
cells.TheCdabsorbedbythegutandlungsiseventuallyaccumulatedinthekidneytubularcells
andisexcretedinurineasCdMTbyinjuredordyingtubularepithelialcellsofthekidneys.
ThefractionofabsorbedCd
nottakenupbyhepatocytesinthefirstpassreachesthe
systemiccirculationandistakenupbytissuesandorgansthroughoutthebody,including
FoodsAir
Cd
Cd
UrineCdMT
BloodPlasma
Cd2+Albumin
Cd2+GSH
Cd2+aminoacids
CdMT
Fatcells.
Stresses2022,2,25357
theadiposetissue[23,24],pancreas[25],lungs,liver,andkidneys[26].Allnucleatedcells
havethecapacitytoassimilateCd2+ionsthatarenotboundtoMTthroughthetransport‐
ersforthemetalsrequiredfornormalcellularmetabolismandfunction.
Mostcells,hepatocytesincluded,donotassimilateCdMTduetoalackofmecha‐
nismsforproteininternalization(endocytosis).Kidneytubularepithelialcellsarewell
equippedwithsuchmechanisms,whichfacilitatereabsorptionofvirtuallyallfilteredpro‐
teinsforreutilization[27,28].KidneytubularcellsalsoassimilateCdinnon‐MTforms
throughmanyotherkidneytubulartransportersystems.
2.2.EndogenousSuppliersofCadmium‐MetallothioneinComplexes
ThecellularformationofCdMThasbeenviewedasadetoxificationmechanismthat
preventsacutetoxicitybecausethe“free”Cd2+ionisthechemicallyreactivetoxicformof
thismetal.Intheory,eachMTmoleculecancarry7atomsofCd2+,7atomsofZn2+or12
atomsofCu2+,andthecomplexesaredenotedasCd7MT,Zn7MT,andCu12MT[29].How‐
ever,variousspeciesofmixedmetalcomplexes,suchasCd3Cu3ZnMT,Cd4CuZn2MT,and
Cd6CuMT,areformedinvivo,withthemolarcontentsofCddependentonlevelsofCd
exposure[29].
Thereareatleast16MTisoforms,andtheybelongtofourmajorfamilies,MT‐1–MT‐
4[30].Amongthesefamilies,MT‐1andMT‐2arethemostfrequentlyexpressedintissues,
includingleucocytesandkidneytubularepithelialcells[31–33].MT‐3hasahigherbind‐
ingaffinityforCuthanMT‐1/2,anditisexpressedinhighabundance,particularlyin
kidneysandneurons[34–36].CuboundtoMT‐3maybeinvolvedinthenephrotoxicity
andneurotoxicityofCdbecauseCuisaredoxactivemetalthatcancauseoxidativestress
[35].
TheCd2+ionssequesteredinhepaticCdMTcomplexesarethosefromthedietwhile
pulmonaryCdMTcontainsairborneCd.Liverandlungsserveasendogenousreservoirs
fromwhichCdMTcomplexesarereleasedascellsdie.CdMTcomplexesareredistributed
tokidneys.AlthoughtheformationofCdMTcomplexespreventacutecytotoxicity,itmay
increasetheriskoflong‐termtoxicitybecauseCd2+ionscanbereleasedundercertaincon‐
ditions,leadingtoanincreasedsynthesisofnitricoxide(NO)thatliberatestheCd2+ions,
previouslyboundtoMT[37–39].
2.3.BloodCadmiumasanIndicatorofRecentExposure
Inthecirculation,lessthan10%ofCdispresentinplasma,andtheremainderisin
erythrocytes,wheremostCdinwholebloodisfound.Thechloride/bicarbonateanionex‐
changer([Cl−/HCO3−])isresponsibleforCduptakebyerythrocytes[40].Inplasma,Cdis
boundtotheaminoacidhistidineandproteins,suchasMT,pre‐albumin,albumin,α2‐
macroglobulin,andimmunoglobulinsGandA[41–43].Atanygiventime,thewhole
bloodCdlevelisindicativeofrecentexposurebecausetheaveragelifespanoferythro‐
cytesis120days.Thebiologicalhalf‐lifeofbloodCdrangedbetween75and128days[44].
2.4.UrinaryCadmiumasanIndicatorofCumulativeLifetimeExposure
ThekidneyburdenofCdasμg/gtissueweightincreaseswithageproportionallyto
theamountassimilatedfromexogenoussourcesoveralifetime[26,45–47].Thebiological
half‐lifeofCdinthekidneycortexwasestimatedat30yearsfornon‐smokers[38,39,45,46].
UrineCdhaslongbeenusedasanindicatorofacumulativelifetimeexposurebecause
thisparameteriscorrelatedwiththekidneyburdenofCdandotherdeterminantsofab‐
sorptionratethatincludethebodystatusofFeandZn[26,48].However,theexcretionof
Cdisindicativeofinjurytotubularepithelialcellsofthekidneys,discussedinSection2.4.
Interestingly,astudyofenvironmentallyexposedChinesesubjectsaged2.8to86.8years
(n=1235)showedthatCdexcretionlevelsincreasedwithage,peakingat50yearsinnon‐
smokingwomenand60yearsinnon‐smokingmen[49].
Stresses2022,2,25358
2.5.RolesforZincTransportersintheBiliaryExcretionandCytotoxicityofCadmium
ASwedishautopsystudyreportedthatapproximately0.001–0.005%ofCdinthe
bodywasexcretedinurineeachday[45,46].ThiskidneyrouteofCdexcretionisex‐
tremelyslow.Incomparison,thebiliaryexcretionrateofCdappearedtobehigherandit
wassuggestedthatbilemightbeanimportantexcretionrouteforCd[46].Theeffectsof
GSHanddithiothreitolonCduptakeandonbiliaryreleaseofCdweredemonstrated
usingtheisolatedperfusedratliver[50].
ThebiliaryrouteofCdexcretionhasgainedsupportfromrecentresearchdatashow‐
ingthatZIP8,azinctransporter,wasinvolvedinhepaticexcretionofMnthroughbile
[51].BecauseZIP8alsomediatedCdtransport,itremainstobeseenifZIP8mediatesbil‐
iaryCdexcretion[51,52].ItisrelevantthattheexpressionoftheZIP8genewasmodulated
byintracellularglutathione(GSH)concentrations[53],andthehepatotoxicityofCdinrats
couldbeattenuatedbyGSHadministration[54].
EvidenceforZninfluxandZneffluxtransporters,notablyZIP8,ZIP14,andZnT1,as
thedeterminantsofCdcytotoxicityisincreasing[55–58].Afewaresummarizedherein.
Thepretreatmentoftheratliverepithelialcells(TRL1215)withcyproterone,asynthetic
steroidalantiandrogenwithastructurerelatedtoprogesterone,decreasedsensitivityto
CdthroughareductioninCdaccumulation[59].However,themolecularbasisforsucha
decreaseinCdaccumulationwasnotinvestigated.Itwasshowninanotherstudythat
silencingtheexpressionofaZn/Cdeffluxtransporter,ZnT1resultedinanincreasedCd
accumulationandenhancedCdtoxicity[60].AdecreaseinCdaccumulationtogetherwith
adecreaseinZIP8expression,assessedbyZIP8mRNAandZIP8proteinlevels,wasseen
inmetallothionein‐nullcellsthatwereresistanttoCdtoxicity[61,62].
2.6.UrineCadmiumasaWarningSignofToxicityinProgress
IthaslongbeenviewedthatexcretedCdincludedCdmoleculesthatpassthrough
theglomerularfiltrationmembraneintothefiltratebutarenotreabsorbed[63].However,
itisnoteworthythattheprincipalformofCdinurineisCdMT[64],andthattheexcreted
CdMToriginatesfrominjuredordyingtubularcells[65].Thus,Cdexcretionisamanifes‐
tationofthecytotoxicityofCdaccumulationinkidneys’tubularcellsevenatverylow
exposurelevels.OurconceptualframeworkaccountingforthepathogenesisofCd‐in‐
ducednephropathyoriginatingfromtubularcellinjuryisdepictedinFigure2.
Figure2.Sequentialoutcomesoftubularcelltoxicinjuryofcadmiumaccumulationinkidneys.Cd
inflictstubularcellinjuryatlowintracellularconcentrations,andthetoxicityintensifiesasCdcon‐
centrationrises[65].Tubularinjurydisablesglomerularfiltration,leadingtonephronatrophy,glo‐
merulosclerosis,andinterstitialinflammationandfibrosis.Areductionintubularreabsorptionof
filteredproteins,RBPandβ2MGfollowstubularatrophyandnephronloss.Abbreviation:KIM1,
Tubularcellinjury.NAG,CdUrineKIM1,NAG,NGAL.
Tubularatrophy,
Interstitialinflammation,
andfibrosis.
Nephronloss
GFRfall.
eGFR≤60mL/min/1.73m2
Tubularre‐absorptionoffilteredproteins.
UrineRBPandβ2M.
Cd2+
Cd2+
RBP,
β2M,NAG
Cd
Stresses2022,2,25359
kidneyinjurymolecule1;NAG,N‐acetyl‐β‐D‐glucosaminidase,NGAL,neutrophilgelatinaseasso‐
ciatedlipocalin;RBP,retinalbindingprotein;β2M,β2‐microglobulin.
Inahistopathologicalexaminationofkidneybiopsiesfromhealthykidneytransplant
donors[66],thedegreeoftubularatrophywaspositivelyassociatedwiththelevelofCd
accumulation.TubularatrophywasobservedatrelativelylowCdlevels[66].InJapanese
residentsofaCdpollutionarea,theaveragehalf‐lifeofthemetalamongthosewithlower
bodyburden(urinaryCd<5μg/L)was23.4years;inthosewithhigherbodyburden(uri‐
naryCd>5μg/L),theaveragehalf‐lifewas12.4years[67,68].Thus,thelowerthebody
burden,thelongerthehalf‐lifeofCd.Ahalf‐lifeof45yearswasestimatedfromaCd‐
toxicokineticmodelthatuseddatafromSwedishkidneytransplantdonorsexposedto
lowenvironmentallevels[69].
3.ManifestationofCadmiumToxicity
Population‐basedstudiesinmanycountriesandtheU.S.generalpopulationstudy
knownasNationalHealthandNutritionExaminationSurvey(NHANES)suggestad‐
verseeffectsofchronicexposuretoCdextendbeyondkidneysandbones.Table1pro‐
videsepidemiologicevidencefortheeffectsofCdinorgansinvolvedinthemaintenance
ofglucosehomeostasis,includingtheliver[70–72],pancreas[73–75],andkidneys[76–80],
Inthepostabsorptivestate,kidneyandliversupplyanequalamountofglucoseintothe
systemicbloodcirculation[81–83].
Table1.AdversehealtheffectsofcadmiumexposureinmultipleorgansevidentfromtheU.S.
NHANESdatasets.
OrgansNHANESDatasetsAdverseEffectsandRiskEstimatesReferences
Liver1988−1994
n12,732,≥20yrs
Inwomen,liverinflammationwasassociatedwithurinary
Cdlevels≥0.83μg/gcreatinine(OR1.26).
Inmen,liverinflammation,NAFLDandNASHwereassoci‐
atedwithurinaryCd≥0.65μg/gcreatininewithrespective
ORvaluesof2.21,1.30,and1.95.
Hyderetal.,2013
[70]
Liver1999−2015
n11,838,≥20yrs
ElevatedplasmaALTandASTwasassociatedwitha10‐fold
incrementofurinaryCdwithrespectiveORvaluesof1.36
and1.31.
Hongetal.,2021
[71]
Liver 1999−2016
n4411adolescents
ElevatedplasmaALTandASTwereassociatedwithurinary
Cdquartile4withrespectiveORvaluesof1.40and1.64.The
effectwaslargerinboysthangirls.
Xuetal.,2022
[72]
Pancreas1988−1994
n8722,≥40yrs
Risksofprediabetesanddiabeteswereassociatedwithuri‐
naryCdlevels1−2μg/gcreatininewithrespectiveORvalues
of1.48and1.24.
Schwartzetal.,2003
[73]
Pancreas2005−2010
n2398,≥40yrs
Anincreasedriskofprediabeteswasassociatedwithurinary
Cdlevels≥0.7μg/gcreatinineafteradjustmentforcovari‐
ates.
Walliaetal.,2014
[74]
Pancreas1999–2006
n4530adults
BMDL5andBMDL10ofurinaryCdlevelsderivedfromdia‐
betesendpointwereof0.198and0.365μg/gcreatinine,re‐
spectively.
Shietal.,2021
[75]
Kidneys1999−2006
n14,778,aged≥20yrs
ReducedGFRa(OR1.32),albuminuriab(OR1.92),andre‐
ducedGFRplusalbuminuria(OR2.91)wereassociatedwith
bloodCdlevels≥0.6μg/LwithrespectiveORvaluesof1.32,
1.92,and2.91.
Navas‐Acienetal.,
2009[76]
Kidneys1999−2006
n5426,aged≥20yrs
Albuminuria(OR1.63)wasassociatedwithurinaryCdlev‐
els>1μg/gcreatinineplusbloodCdlevels>1μg/L(OR
1.63).
Ferraroetal.,2010
[77]
Stresses2022,2,25360
ReducedeGFR(OR1.48)andalbuminuria(OR1.41)wereas‐
sociatedwithbloodCdlevels>1μg/LwithrespectiveOR
valuesof1.48and1.41.
Kidneys2007−2012
n12,577,aged≥20yrs
ReducedeGFR(OR1.80)andalbuminuria(OR1.60)wereas‐
sociatedwithbloodCdlevels>0.61μg/LwithrespectiveOR
valuesof1.80and1.60.
Madrigaletal.,2019
[78]
Kidneys2009−2012
n2926,aged≥20yrs
Anelevatedalbuminexcretionwasassociatedwithurinary
Cdlevels>0.220μg/LandbloodCdlevels>0.243μg/L.
Zhuetal.,2019
[79]
Kidneys2011−2012
n1545,aged≥20yrs
ReducedeGFR(OR2.21)andalbuminuria(OR2.04)wereas‐
sociatedwithbloodCdlevels>0.53μg/LwithrespectiveOR
valuesof2.21and2.04.
Linetal.,2014
[80]
NHANES,NationalHealthandNutritionExaminationSurvey;n,samplesize;HR,hazardratio;
OR,oddsratio;ALT,alanineaminotransferase;AST,aspartateaminotransferase;NAFLD,non‐al‐
coholicfattyliverdisease;NASH,non‐alcoholicsteatohepatitis;aReducedeGFR,estimatedglomer‐
ularfiltrationrate(eGFR)≤60mL/min/1.73m2;bAlbuminuria,urinaryalbumintocreatinineratio
≥30mg/g.
ThehepatoxicityofCdwasseeninbothchildrenandadults[70–72].Inadults,in‐
creasesinriskofliverinflammation,NAFLD,andNASHwereassociatedwithurinary
Cdlevels≥0.6μg/gcreatinine[70].Inchildren,hepatotoxicityofCdwasmorepro‐
nouncedinboysthangirls[72].InNHANEScyclesundertakenbetween1999and2016,
reducedeGFRandalbuminuriawereconsistentlyassociatedwithCdexposuremeasures
[76–80].
3.1.CadmiumandtheRiskofType2Diabetes
Prediabetesanddiabetesaredefinedasfastingplasmaglucose≥110mg/dLand126
mg/dL,respectively.Thenumberofpeoplewithprediabetesanddiabeteshavereached
epidemicproportionsglobally.Theepidemicisattributedtotheincreasingprevalenceof
obesity,leadingtoasearchforenvironmentalobesogenicsubstances.Incomparison,a
statisticallysignificantinverseassociationhasconsistentlybeenobservedbetweenCdex‐
posureandbodymassindexandothermeasuresofadiposity(Section3.2).Dietaryexpo‐
suretoCdisconsequentlytheleastexpectedandleastrecognizedenvironmentalriskfac‐
torfordiabetes.
IncreasesintherisksofprediabetesanddiabetesamongNHANES1988–1994partic‐
ipantswereassociatedwithurinaryCdlevelsof1–2μg/gcreatinine[73].Anincreased
riskofprediabetesamongNHANES2005–2010wasassociatedwithurinaryCdlevels≥
0.7μg/gcreatinineafteradjustmentforcovariates[74].Inariskanalysis,theprevalence
oftype2diabeteswaslikelytobesmallerthan5%and10%aturinaryCdlevelsof0.198
and0.365μg/gcreatinine,respectively[75].
IntheWuhan‐Zhuhaiprospectivecohortstudy[84],fastingbloodglucoselevels
werefoundtoincreasewithurinaryCdoverathree‐yearobservationperiod.Foreach10‐
foldincreaseinurinaryCd,theprevalenceofprediabetesroseby42%.Dose–response
relationshipsbetweenCdexposureandrisksofprediabetesanddiabeteswereobserved
intwometa‐analyses,[85,86].Inariskanalysisofpooleddatafrom42studies,therisks
ofprediabetesanddiabetesincreasedlinearlywithbloodandurinaryCd;prediabetesrisk
reachedaplateauaturinaryCdof2μg/gcreatinine,anddiabetesriskroseasbloodCd
reached1μg/L[86].
Stresses2022,2,25361
3.2.AnInverseRelationshipbetweenCadmiumBodyBurdenandObesity
TherelationshipsbetweenCdexposurelevelsanddiseaseshownbyassociativestud‐
ieshaveoftenbeenignored.However,itisimportanttorecognizesuchassociationsas
theymayindicatemechanismsofdiseasepathogenesis.Thus,reportsofaninverserela‐
tionshipbetweenCdbodyburdenandobesityprovidedevelopmentaldatathatmaylead
tofuturesignificantcorrelationsthatdefinediseasepathogenesisandaidintherapyde‐
velopment.Hereinwereportsuchassociativestudiesthatreplicateanassociationob‐
servedbetweenCdandreducedriskofobesity.Thesedatacanbeinterpretedtosuggest
thatCdmayhavecausedthedysregulationofthecellularintermediarymetabolism(a
furtherdiscussioninSection4.3)andthattype2diabetesassociatedwithCdisindepend‐
entofobesity.
UrinaryCdlevelswereinverselyassociatedwithcentralobesityamongparticipants
ofNHANES1999–2002[87].AmongNHANES2003–2010participants,theirbloodCdlev‐
elswereinverselyassociatedwithbodymassindex(BMI)[88].Inanotheranalysisofdata
fromNHANES2001–2014,participantsaged20–80years(n=3982),withurinaryCdlevels
werenotassociatedwiththeriskofmetabolicsyndrome,buttheywereassociatedwitha
decreasedriskofabdominalobesity[89].Inameta‐analysisofdatafrom11cross‐sectional
studies,Cdexposurewasnotassociatedwithanincreasedriskofmetabolicsyndrome,
butitwasassociatedwithdyslipidemia,especiallyintheAsianpopulation[90].
UrinaryCdwasassociatedwithareductioninriskofobesityby54%inchildrenand
adolescentsenrolledinNHANES1999–2011;aninverseassociationbetweenurinaryCd
andobesitywasstrongerintheyoungeragegroup(6–12years)thantheolderagegroup
(13–19years)[91].UrinaryCdlevelswereinverselyassociatedwithheightandBMIin
Flemishchildren,aged14–15years[92].
Similarly,aninverseassociationbetweenbloodCdandBMIwasseeninnon‐smok‐
ersintheCanadianHealthSurvey2007–2011[93].AnegativeassociationbetweenCd
exposureandvariousmeasuresofobesitywereseeninbothmenandwomeninastudy
oftheindigenouspopulationofnorthernQuébec,Canada,whereobesitywashighly
prevalent[94].
AninverseassociationbetweenbloodCdandBMIwasnotedinagroupofKorean
men,40–70yearsofage[95].ThisKoreanpopulationstudyobservedaninversecorrela‐
tionbetweenfastingbloodglucoseandurinaryCdexcretionlevels,anda1.81‐foldin‐
creaseinriskofdiabetesamongmenwhohadurinaryCd>2μg/gcreatinine.
InaChinesestudy,urinaryCdexcretionrates≥2.95μg/gcreatininewereassociated
withreducedriskofexcessiveweightgainandreducedriskofobesity[96].Higheruri‐
naryCdlevelswereassociatedwithlowerBMIvaluesinastudyofresidentsofShanghai
withoutworkplaceexposuretoCd,showingthemedianurinaryCdexcretionof0.77μg/g
creatinine[97].
Ofinterest,lowerBMIfigureswereassociatedwithhigherCdaccumulationlevels
infattissuesinacohortstudyinSpain[23].Furthermore,anincreasedresistancetoinsu‐
linandhigherplasmainsulinlevelswereseeninsmokerswhoseadiposetissueCdlevels
wereinthemiddletertile,comparedtothosewithadiposetissueCdlevelsinthelowest
tertile1[24].
3.3.Cadmium‐InducedOxidativeStresssandInflammation
TheaforementionedstatisticallysignificantinverserelationshipbetweenCdbody
burdenandobesitysuggeststhataneffectofCdontheriskofdiabetesisindependentof
adiposityandinflammation,accompanyingexcessivebodyfats.Indeed,thereisevidence
thatCdmaycauseinflammationinadiposetissuesinaSwissautopsystudy,Cdaccumu‐
lationinomentumvisceralandabdominalsubcutaneousfattissueswerequantified[98].
Inaninvitrostudyusingtheadipose‐derivedhumanmesenchymalstemcells(FC‐0034),
Cdinthesamerangefoundinthosepostmortemfattissuesampleswasfoundtodisrupt
cellularZnhomeostasisandtocauseanincreaseintheexpressionofvariouspro‐
Stresses2022,2,25362
inflammatorycytokines[98].StudiesinmiceshowedthatCdcausedtheabnormaldiffer‐
entiationofadipocytes,resultinginsmalladipocytesandareductioninthesecretionof
adiponectin[99,100].
AsdatainTable2indicate,substantialevidenceforCd‐inducedoxidativestressand
inflammationcomesfromtheU.S.populationstudies,whichincludedNHANESIII
[101,102],astudyofhealthyNewYorkwomen[103];NHANES2003–2010[95];and
NHANES1999–2002[104,105].TheeffectsofCdontherisksofcardiovasculardiseaseand
all‐causemortalitywerealsoindicated[106].Inthesestudies,serumγ‐glutamyltransfer‐
ase(GGT),C‐reactiveprotein(CRP),andshorteningofleucocytetelomerelengthwere
quantifiedastheyweremeasuresofincreasedoxidativestressandinflammation.Insome
ofthesereports,aprotectiveroleofcertainnutrientswasobserved.
Table2.Cadmium‐inducedoxidativestressandinflammation.
BiomarkersDatasetsFindings References
SerumGGT.NHANESIII,
n10,098,aged≥20yrs.
SerumGGTwaspositivelyassociatedwithurinaryCd
levelsbetween0.002and23.4μg/gcreatinine.
SerumvitaminsCandEandcarotenoidswereinversely
associatedwithGGT.
Leeetal.,2006
[101]
SerumCRPand
fibrinogen
NHANESIII,
n6497,aged40‐79yrs.
ElevationsofserumCRPandfibrinogenwereassociated
withurinaryCdlevels≥0.93μg/gcreatininewithre‐
spectiveORvaluesof1.24and2.12.
Linetal.,2009
[102]
Serumbilirubin
Healthywomen,Buffalo,
NewYork
n259,aged18–44yrs.
Areductioninserumbilirubinby4.9%wasassociated
witha2‐foldincreaseinbloodCd.
MedianCdlevel(interquartilerange)was0.3(0.19–0.43)
μg/L.
Pollacketal.,2015
[103]
CRP,GGT,
ALP,bilirubin
andwhitecell
count.
NHANES2003–2010,
n3056women,
n3288men.
SerumCRP,GGT,andALPlevelswereincreased,re‐
spectively,by47.5%,8.8%and3.7%,inurinaryCdquar‐
tiles4vs.1.
Consumptionofanti‐oxidativeandanti‐inflammatory
nutrientswereassociatedwithanincreaseinserumbili‐
rubinby3%andreductions,respectively,inCRP,GGT,
ALP,andwhitebloodcellcountby7.4%,3.3%,5.2%,
and2.5%.
Colacinoetal.,
2014[104]
Telomere
length
NHANES1999–2002,
n2093withurinaryCd
data,n6796withblood
CdplusPbdata.
Telomereshorteningwasassociatedwithurinaryand
bloodCdlevelsbutnotbloodPb.
Zotaetal.,2014
[105]
Telomere
length
NHANES1999–2002,
n7120non‐smokers,
n2296smokers
AshortertelomerewasassociatedwithhigherCdexpo‐
sure,CRP,trunkfat,andinactivity.
Alongertelomerewasassociatedwithretinylstearate.
Pateletal.,2016
[106]
CRPandcardi‐
ovasculardis‐
ease
NHANES1999–2016
n38,223
CRP,triglycerides,totalcholesterol,andwhitecellcount
wereassociatedwithelevatedbloodCdlevels.Anin‐
creasedriskofcardiovasculardiseasewasassociated
bloodCd(OR1.45).
Maetal.,2022
[107]
Mortality
NHANES2001‐2010
Prospective,n20,221,
meanfollow‐up9.1
years,
n2945withdiabetes
Riskofdyingfromallcausedwasincreasedby49%,
comparingbloodCdlevels>0.6vs.<0.24μg/L.
Cd,CRP,and25(OH)Dwereassociatedwithall‐cause
mortalityamongthosewithtype2diabetes.
Liuetal.,2022
[108]
NHANES,NationalHealthandNutritionExaminationSurvey;n,samplesize;OR,oddsratio;GGT,
γ‐Glutamyltransferase;CRP,C‐reactiveprotein;ALP,alkalinephosphatase.
Stresses2022,2,25363
4.MitigationoftheCytotoxicityofCadmium
Owingtoitshightoxicityandcumulativepotential,minimizingtheCdcontamina‐
tionofthefoodchainsandreducingCdlevelsinfoodcropstothelowestachievablelevels
areessentiallypreventivepublicmeasures.Here,wediscussthefrontlinecellularstress
responsethatmaybeacomplementarymeasuretomitigateharmfuleffectsofinevitable
exposuretosuchatoxicantasCd.
4.1.HemeOxygenase‐1andHemeOxygenase‐2(HO‐1,HO‐2)
HO‐1andHO‐2areenzymesinvolvedinthedegradationofhemetoretrieveFefor
reusebycellsandtogeneratecytoprotectivemolecules,carbonmonoxide(CO)andbili‐
verdinIXαfromwhichbilirubinisrapidlygenerated[109–111].TheeconomyofFeutili‐
zationrequiresthesalvagingofFe,sothebulkofFereleasedbytheactionofHO‐1and
HO‐2isreutilizedinthesynthesisofhemoproteins,suchasnitricoxidesynthase,various
enzymesofthemitochondrialrespiratorychain,andthecytochromeP450superfamily
[112].Ineverynucleatedcellofthebody,hemedegradationanddenovobiosynthesisof
hemeareindispensableandsimultaneousinductionofMTandHO‐1occursinmostnu‐
cleatedcellsofthebodyinresponsetoCdexposure[32,109,110,113].
4.2.ProductsofthePhysiologicHemeDegrdation
4.2.1.Bilirubin
Serumbilirubin,aproductofnormalhemedegradationandthecatalyticactivityof
biliverdinXI‐αreductase,contributesmostlytothetotalantioxidantcapacityofblood
plasma[114‐116].Duetoitslipophilicproperties,bilirubinisalipidperoxidationchain
breakerthatprotectslipidsfromoxidationmoreeffectivelythanthewater‐solubleanti‐
oxidants,suchasglutathione[115,116].Theabilityofbilirubintoinhibittheoxidationof
low‐densitylipoproteinaccountsfortheassociationobservedbetweenhighertotalserum
bilirubinlevelsandlowerrisksofmetabolicsyndromeandnon‐alcoholicliverdisease
[117].Ofnote,recentexperimentaldatashowthatCd‐activatedHO‐1geneandhemedeg‐
radationdidnotresultinformationofbilirubin[118].AfurtherdiscussionisinSection5.
4.2.2.CarbonMonoxide
Syntheticcarbonmonoxide‐releasingmolecules(CORM)wereusedtostudyeffects
ofCOonmitochondrialbiogenesis[119–121].Inhighdoses,COhasanti‐inflammatory,
anti‐apoptotic,andvasodilatoryeffectsandiscardioprotective.Inlowlevelsachievable
throughinductionofHO‐1expression,COincreasesthegenerationofreactiveoxygen
species(ROS)bythemitochondria,presumablythroughtheinactivationofcytochromeC
oxidase(COX)[119].TheelevatedROSthenactivatesthePI3K/AKTsignalingpathway,
causingtheinhibitionofglycogensynthasekinase3β(GSK3β)andactivationofthenu‐
clearfactorerythroid2‐relatedfactor2(Nrf2)[122].CO,p62,andNAD(P)Hdehydrogen‐
asequinone1(NQO1)areallrequiredforthebiogenesisofmitochondriaandtheremoval
ofmitochondriawithseveredamage[122,123].MitochondrialROSproductionisamech‐
anismthatcellsusetoincreasetheircapacitytoadapttostress[124,125].Thus,HO‐1in‐
ductionrepresentsanimportantcellularstressresponsemechanism.Therepressionof
thisstressresponsegeneisequallyimportanttosustainthecellularredoxstate.
4.3.RoleofHO‐1,HO‐2,andPFKFB4intheHomeostasisofBloodGlucose
HO‐1andHO‐2areproductsoftwodifferentgenes[126].Thepromoterofthehu‐
manHO‐1geneisuniquebecauseitcontainstheGTrepeats,notfoundinrodentormu‐
rinespecies[109–111].Thegeneticpolymorphisms,suchaslongGTrepeats,areassoci‐
atedwithanelevatedriskforvariousdiseases,type2diabetesincluded[127,128].
CellularexpressionofHO‐1isregulatedbythetranscriptionfactor,including
CLOCK,Bmal,andPer,thatworktogethertogenerateday–nightcyclicalexpressionof
thegenesinvolvedinenergymetabolism[129–132].Disruptionofthediurnalcyclecaused
Stresses2022,2,25364
obesityinmice[133].ExpressionoftheHO‐1geneiscontrolledalsobyheme(itsown
substrate),thelevelsofglucose,oxygen,andshearstress[109,110,134,135].
ThecatalyticdomainsofHO‐1andHO‐2arehighlyhomologous,sharing93%of
theiraminoacidsequences.HO‐2,however,containsanadditionaldomain,whichhas
Cys‐Prodipeptidemotifsthatallowsbindingofhemeandinteractingwithotherproteins
thatincludeRev‐erbα,ahemesensorthatcoordinatesmetabolicandcircadianpathways
[136–138].
Inadditiontohemedegradationactivity,HO‐2hasaregulatoryrolethatwasunrav‐
eledfromobeseanddiabeticmicelackingHO‐2expression.HO‐2deficiencyinmice
causedneitherlethalitynorinfertility,andHO‐2deficientmiceunderwentnormaldevel‐
opmenttoadulthoodwhentheydisplaythesymptomaticspectrumofhumantype‐2di‐
abetes,hyperglycemia,increasedfatdeposition,insulinresistance,andhypertensionwith
aging[139–141].ThenormaldevelopmentandnormalfecundityintheabsenceofHO‐2
expressionsuggestedthatHO‐1couldcompensatefortheheme‐degradationactivityof
HO‐2.However,HO‐1didnotcompensatefortheanti‐diabetogenicityandanti‐obesity
ofHO‐2.
Inaproteinmicroarraystudy,HO‐2waslinkedtotheglycolyticpathwaythrough
itsinteractionwith6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase4(PFKFB4)
[142].Inliver,PFKFB4isthekeyregulatorofglycolysis[143],andalackofHO‐2expres‐
sioncausespersistenthyperglycemiaduetoanimpairedabilitytosuppressglucosepro‐
duction.CdmaymimicthiseffectofHO‐2deficiency,therebycausinghyperglycemia.
BothHO‐1andHO‐2arerequiredtopreventafallofbloodglucoseduringfastingora
riseinbloodglucoseinapost‐absorptiveperiod.HO‐2expressionensuresPFKFB4ex‐
pression.
AsFigure3a,bindicate,thehomeostasisofbloodglucoserequirescoordinatedacti‐
vationandrepressionofHO‐1,HO‐2,andPFKFB4.Failureinanyofthese(HO‐1,HO‐2
andPFKFB4)causeshyperglycemicandobesephenotypes.
(a)(b)
Figure3.Co‐ordinatedexpressionofHO‐1,HO‐2,andPFKFB4.(a)ChangesinexpressionofHO‐1
andPFKFB4inthefastingstate.;(b)ChangesinexpressionofHO‐1,HO‐2,andPFKFB4inthepost
absorptiveperiod.Abbreviations:PFKFB4,6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase4;
F‐2,6‐P
2
,fructose2,6‐biphosphate.
Intheliverofwild‐typemice,loweredglycolysiswithenhancedgluconeogenesis
couldbeachievedinfastingstatebyHO‐1up‐regulationplusPFKFB4down‐regulation.
Inthepost‐absorptivestate,highglycolysiswithsuppressedgluconeogenesiscouldbe
achievedbyHO‐1down‐regulationplusHO‐2andPFKFB4up‐regulation.HO‐1protein
expressionlevelsintheliverofHO‐2knockoutmicefellby35–40%[144].Apossiblecon‐
sequenceofareductioninexpressionlevelsofHO‐1isincreasedsusceptibilitytooxida‐
tivedamage.However,suchrepressionoftheHO‐1geneexpressionisanessentialmeta‐
bolicadaptationtosafeguardthecellularredoxstate.Thisisachievedbyutilizing
Fasting
IncreasedHO‐1expressionandreducedPFKFB4expression
preventafallinbloodglucose.
Minimizeuseofglucose.
Enhanceglucoseproduction.
Glucosereleaseintothecirculation.
ReduceF‐2,6‐P2.
Over‐productionofglucosecauseshighbloodglucose
infastingperiod.
PostAbsorption
RepressedHO‐1expressionandincreasedHO‐2expression
preventariseinbloodglucose.
Reduceglucoseproduction.
IncreasePFKFB4expression.
IncreaseF‐2,6‐P2.
Increaseglucoseuseviaglycolysis.
Increaseglycogensynthesis.
Reduceglucoseproduction.
Impairedsuppressionofglucoseproductioncauses
highbloodglucoseinpostabsorptiveperiod.
Stresses2022,2,25365
NADPH(H
+
)forregeneratingreducedglutathione(GSH)ratherthanforhemecatabolism
[142].GSHrecyclingisamechanismformaintainingcellularredoxstate.Itiscentralto
normalproteinfoldingandcellfunction(seeFigure4ainSection4.3).
(a)(b)
Figure4.Heme‐glucosecrosstalkandmitochondrialtargetofcadmium.(a)Hemedegradationcat‐
alyzedbyHO‐1andHO‐2utilizesNADPHfrompentosephosphatepathway.(b)Cadmium‐in‐
ducedkidneytubularcelldeath.CdusestheZncarriermetallothionein(MT)andtransportersof
CaandFe,mitochondrialcalciumuniporter(MCU)andthedivalentmetaltransporter1(DMT1)to
reachthemitochondrialinnermembrane[145].There,CdreducesATPoutputandpromotesreac‐
tiveoxygenspecies(ROS)formation.ExtensivedamagecausesareleaseofmitochondrialDNA
(mtDNA).TheDNA‐sensingmechanism(cGAS‐STING)andnuclearfactor‐kappaB(NF‐кB)signal‐
ingpathwaysareactivated,proinflammatorycytokinesarereleased,andcelldeathensues.Abbre‐
viation:BVR,biliverdinreductase;PEP,phosphoenolpyruvate;cGAS,cyclicGMP‐AMPsynthase;
STING,stimulatorofinterferongenes;CdRE,Cadmiumresponseelement.
4.4.ExogenousHO‐1Inducers
Severaltherapeuticdrugs,suchasstatins(lipidloweringagents),rosiglitazone(anti‐
diabeticdrug),aspirin(anti‐inflammatorydrug),paclitaxelandrapamycin(anti‐cancer
drugs),havebeenshowntoinduceHO‐1expression.Thetherapeuticefficacyofthese
drugsmaybeattributable,atleastinpart,toHO‐1induction[116,117].
Awiderangeofantioxidantsfromplantfoods,suchascurcumin,quercetin,tert‐
butylhydroquinone,andcaffeicacidphenethylester,areHO‐1inducers,asarecatechin
(ingreentea),α‐lipoicacid(inbroccoli,spinach),resveratrol(inredwine,grapes),carno‐
sol,sulforaphane(cruciferousvegetable),coffeediterpenescafestol,andkahweol[138–
140,146–148].Beneficialeffectsofconsumptionoftheseantioxidantscouldthusbemedi‐
atedinpartthroughtheinductionofHO‐1expression.
Diethighinanti‐oxidativeandanti‐inflammatorynutrientswasassociatedwithin‐
creasedserumbilirubinlevelsandreducedoxidativestressandsystemicinflammation
[104].GreenteaconsumedinusualamountswasfoundtoincreaseHO‐1expression[149–
151].Oneofthetrialsincludedonlynon‐smokingdiabeticsubjectswhohadnohistoryof
metaboliccomplicationsanddidnottakeregularfoodsupplements[150].Among43sub‐
jects,23hadthelongGTrepeats(GTrepeats≥25;L/Lgenotype)typeoftheHO‐1pro‐
moterandanother20hadshortGTrepeats(GTrepeats<25;S/Sgenotype).Accordingto
Westernblottingandthecometassay,HO‐1proteinlevelsincirculatinglymphocytes
wereincreasedby40%,whiletheleveloftheDNArepairenzyme8‐oxoguanineglycosyl‐
ase(hOGG1)wasincreased50%withDNAdamagebeingreducedby15%.Greentea
consumptionincreasedHO‐1proteinlevelsinlymphocytesinbothL/LandS/Sgenotype
Glucose
G‐6‐P
NADP
NADPH
Phosphogluconate
NADP
NADPH
Ribose‐5‐Phosphate
Oxaloacetate
TCA
Succinate
F‐6‐P
PFKFB4
−F‐2,6‐P2+
F‐1,6‐P2
PEP
Pyruvate
AcetylCoA
ATP+CO2+H2O
Glycogen
GSH
ROS
GSSG
Bilirubin
BVR
Biliverdin‐IXα,CO,Fe
HO‐1,HO‐2
Heme
δ‐AminolevulinicAcid
Glycine+SuccinylCoA
HO‐1,MT
NF‐кB
CdRE
DMT1,Fe
MCU,Ca
MT,Zn
Cd2+
mtDNA
cGAS‐STING
NF
‐
к
B
Acutemetal‐stressresponses
HO‐1,MT,SOD1(Zn/Cu),
Mn‐SOD
Ca,Fe,Zndysregulation
ROS
ATPoutput
In
j
ur
y
Cytokines
IFN‐γ,TNF‐α,
IL‐1,6,12,23
TheMitochondrialTargetofCadmiumCytotoxicity
Stresses2022,2,25366
groups,althoughtheS/SgroupshowedhigherHO‐1proteinlevelsatbaseline,compared
totheL/Lgroup.ThistrialshowedthatgreenteaconsumptionmayreducecellularDNA
damagethroughinducedexpressionofHO‐1.
5.DifferentHO‐1GeneActivationMechanisms
AllnucleatedcellsofthebodyhavethecapacitytotakeupCdfromthecirculation
andtheymustsynthesizetheirownhemefortheirownuse.Adenovobiosynthesisof
hemeisarequisiteforcellularresponsetostressors,andthishasbeendemonstratedfor
Cdasastressor[117].CurrentevidencesuggeststhatCdinducestheexpressionofHO‐1
bymechanismsdifferentfromthoseusedbyendogenous(physiologic)HO‐1activators
(Section4.3)andprostaglandinD2(PGD2)[152].
PGD2isamajorcyclooxygenasemediator,synthesizedbyactivatedmastcellsand
otherimmunecellsandisimplicatedinallergicdisorders[153].Inastudyofacellculture
modelofhumanretinalepithelialcells,PGD2wasfoundtoactivatetheHO‐1‐genepro‐
moterthroughD‐prostanoid2(DP2)receptorinanenhancermanner[152].Incontrast,Cd
activatestheHO‐1promoterviatheCdresponseelement(CdRE,TGCTAGATTTT)and
Mafrecognitionantioxidantresponseelement(MARE,GCTGAGTRTGACNNNGC),also
knownasstressresponseelement(StRE)[113].Cdalsosuppresseslysosomaldegradation
ofNrf2[154]andcausesnuclearexportoftheHO‐1generepressorBach1,whichallows
transactivationoftheHO‐1genebytheNrf2/smallMafcomplex[155]
Cd‐inducedexpressionoftheHO‐1increasesintracellularconcentrationofheme,a
stimulatorofgluconeogenesisandknowncauseofhyperglycemia.Thismayexplainhy‐
perglycemicstateinducedbyCd.However,Cd‐inducedexpressionofHO‐1doesnotre‐
sultintheformationofbilirubin[118].Thereasonforthisphenomenonremainsunclear,
butitmayexplainanincreasedcellularoxidativestressthroughloweringlevelsofthe
anti‐oxidativemolecule,bilirubin.
6.Conclusions
Thisnarrativereviewfocusedonadversemetabolicoutcomesofchronicexposureto
Cd.EpidemiologicdataindicatethatenvironmentalexposuretolowlevelsofCdincreases
theriskoftype2diabetesbyseveralmechanismsthatmayincludeoxidativestress,in‐
flammation,adiposetissuedysfunction,increasedinsulinresistance,andadysregulated
cellularintermediarymetabolism.HigherlevelsofCdaccumulationinadiposetissuesare
associatedwithlowerBMIandincreasedinsulinresistance.Astatisticallysignificantin‐
verseassociationbetweenCdexposureandobesityisuniversallyobservedinbothchil‐
drenandadults.Thus,Cd‐inducedtype2diabetesisindependentofadiposity.
Thecellularstressresponsemechanismsinvolvingthecatabolismofheme,mediated
byHO‐1andHO‐2,maymitigatethecytotoxicityofCd.Theproductsoftheirphysiologic
hemedegradation,bilirubin,andcarbonmonoxidehaveantioxidative,anti‐inflamma‐
tory,andanti‐apoptoticproperties.ExogenousHO‐1inducersmayraisethequantitiesof
theseprotectivemolecules,andthuscouldbeacomplementarymeasuretomitigatethe
cytotoxicityofCd.However,strategiesthatminimizeCdentryintothefoodchainsre‐
mainessentialpreventivepublicmeasures.
KnowledgegainedfromthephenotypicanalysesofHO‐2deficientmicethatdisplay
thesymptomaticspectrumofhumantype2diabeteshaveshownthatHO‐1,HO‐2,and
PFKFB4,thekeyregulatorsofglycolysis,arerequiredtopreventhyperglycemiaandan
obesephenotype.RepressionoftheHO‐1geneexpressionisanessentialmetabolicadap‐
tationofequalimportancetosafeguardthecellularredoxstate.
CdinducestheexpressionofHO‐1bymechanismsdifferentfromthoseofphysio‐
logicHO‐1geneactivators,andconsequentlyCd‐inducedHO‐1expressiondoesnotpro‐
ducebilirubinasaproduct.ThismayrepresentoneofthecytotoxicmechanismsofCd,
whichisinadditiontoahyperglycemicphenotype.
Stresses2022,2,25367
AuthorContributions:S.S.conceptualizedthereviewandpreparedaninitialdraftwithG.C.G.and
D.A.V.providinglogicaldatainterpretation.G.C.G.andD.A.V.reviewedandeditedthedraftman‐
uscript.Allauthorshavereadandagreedtothepublishedversionofthemanuscript.
Funding:Thisworkreceivednoexternalfunding.
InstitutionalReviewBoardStatement:Notapplicable.
InformedConsentStatement:Notapplicable.
DataAvailabilityStatement:Alldataarecontainedwithinthisarticle.
Acknowledgments:ThisreviewisdedicatedtothelateProfessorMichaelR.Moore,whowasDi‐
rectoroftheNationalResearchCentreforEnvironmentalToxicology(EnTox),Universityof
Queensland,between1994and2009.Hewasinstrumentalinestablishingtoxicologyresearchon
heavymetalsinAustralia,andhewasaninspirationtoallwhoworkedinthisfield.S.S.thanks
ProfessorShigekiShibaharaforhispatience,support,andguidanceonHO‐1andHO‐2research
undertakenbytheauthoratTohokuUniversity,Sendai,Japan.Thisworkwassupportedwithre‐
sourcesfromtheKidneyDiseaseResearchCollaborativeandtheDepartmentofNephrology,Prin‐
cessAlexandraHospital.
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
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