ZincZinc

HistoryHistory

1509, recognized as element1509, recognized as element Essentiality demonstratedEssentiality demonstrated

Plants: 1869Plants: 1869 Animals: 1934Animals: 1934

DeficiencyDeficiency Considered unlikely until 1955 Considered unlikely until 1955

swine parakeratosis shown to be caused by Zn swine parakeratosis shown to be caused by Zn deficiencydeficiency

conditioned human deficiency demonstrated in 1956conditioned human deficiency demonstrated in 1956 1961, hypogonadal dwarfism suggested to be zinc 1961, hypogonadal dwarfism suggested to be zinc

deficiencydeficiency

FactsFacts

30th element in the periodic table (IIB 30th element in the periodic table (IIB element)element) MW = 65.37, completely filled d orbitalsMW = 65.37, completely filled d orbitals

In aqueous solutionsIn aqueous solutions One oxidation state, namely ZnOne oxidation state, namely Zn2+2+ Prefers tetrahedral complex formationPrefers tetrahedral complex formation

Not a redox active metalNot a redox active metal readily complexes with amino acids, readily complexes with amino acids,

peptides, proteins and nucleotidespeptides, proteins and nucleotides affinity for thiols, hydroxy groups & ligands affinity for thiols, hydroxy groups & ligands

with electron-rich nitrogen donorswith electron-rich nitrogen donors

DistributionDistribution Whole body: Whole body: 1.5g (female)-2.5g (male)1.5g (female)-2.5g (male)

Skeletal MuscleSkeletal Muscle 57% 57% BoneBone 29% 29% SkinSkin 6% 6% LiverLiver 5% 5% BrainBrain 1.5% 1.5% KidneysKidneys 0.7% 0.7% HeartHeart 0.4% 0.4% HairHair ~0.1%~0.1% Blood PlasmaBlood Plasma ~0.1%~0.1%

SourcesSources Relatively abundant mineralRelatively abundant mineral

Good sources: shellfish, beef and other red Good sources: shellfish, beef and other red meatsmeats

Slightly less good: Whole-grainsSlightly less good: Whole-grains most in bran and germ portionsmost in bran and germ portions 80% lost to milling80% lost to milling phytates, hexa & penta phosphates depress phytates, hexa & penta phosphates depress

absorptionabsorption P/Zn ratios of 10 or moreP/Zn ratios of 10 or more

Relatively good sources: nuts and legumesRelatively good sources: nuts and legumes Eggs, milk, poultry & fish diets lower than Eggs, milk, poultry & fish diets lower than

pork, beef, lamb dietspork, beef, lamb diets High meat diets enhance absorption High meat diets enhance absorption

280g or 10 oz fits right into food pyramid guide280g or 10 oz fits right into food pyramid guide cys & met form stable chelate complexescys & met form stable chelate complexes

Zinc MethionineZinc Methionine

Effect of trace mineral Effect of trace mineral source on animal source on animal

performanceperformance

Relative bioavailability of Relative bioavailability of trace mineral sourcestrace mineral sources

Whole Body Whole Body FluxesFluxesPlasma/

Serum 2.4 mga-2

macroglobulin (30%) albumin

(60%)

Target tissuesIncluding

Liver1.2 g

Urine: 0.4-0.6 mg/da

Other Losses: Sweat, Skin, Hair up to 1 mg/da

Milk: 2-3 ug/mL

Seminal Fluid: 196 ug/mL

IntestineZn++ (50-100mM)

1-2 mg/daMetallothionineChelating Agents

Phytates

Diet Zn++

4-15 mg/da(~0.15 mM)

Pancreatic & Biliary

Excretion: 4-5 mg/da

Feces: 3-14 mg/da

Menstrual Loss: 0.1-0.5 mg

Dietary Factors that Dietary Factors that Affect Zn AbsorptionAffect Zn Absorption

Feed/Food sourceFeed/Food source Phytate (calcium-Phytate (calcium-

phytate-zinc phytate-zinc complex)complex) Mainly hexa- and Mainly hexa- and

pentaphosphate pentaphosphate derivativesderivatives

Highly dependent Highly dependent on calciumon calcium

Amino AcidsAmino Acids histidine, cysteinehistidine, cysteine

Presence/Absence of Presence/Absence of other divalent cationsother divalent cations Fe, CaFe, Ca

Efficiency of Efficiency of absorption can vary absorption can vary from 15-60%from 15-60% Under normal Under normal

conditions 1/3 of conditions 1/3 of dietary Zn is absorbeddietary Zn is absorbed

Zn status alters Zn status alters efficiency of efficiency of absorptionabsorption

Uptake and retention Uptake and retention is > in growing is > in growing animalsanimals

OverviewOverview Approximately 300 enzymes are associated with Approximately 300 enzymes are associated with

zinczinc Biological functions of Zn are divided into three Biological functions of Zn are divided into three

categoriescategories Catalytic, Structural, Regulatory Catalytic, Structural, Regulatory

Role in metabolismRole in metabolism Protein synthesisProtein synthesis Nucleic acid metabolismNucleic acid metabolism Carbohydrate and energy metabolismCarbohydrate and energy metabolism LipidLipid Epithelial tissue integrityEpithelial tissue integrity Cell repair and divisionCell repair and division Vitamin A and E transport and utilizationVitamin A and E transport and utilization Immune functionImmune function Reproductive hormonesReproductive hormones

AbsorptionAbsorption

Absorption takes place throughout the Absorption takes place throughout the intestineintestine GlycocalyxGlycocalyx

Barrier? Storage site?Barrier? Storage site? Primarily in the jejunumPrimarily in the jejunum Some absorption in the rumenSome absorption in the rumen No measurable amounts absorbed from No measurable amounts absorbed from

stomach cecum or colonstomach cecum or colon

AbsorptionAbsorption In small intestineIn small intestine

Nonmediated (nonsaturable) processNonmediated (nonsaturable) process Not affected by dietary Zn intake Not affected by dietary Zn intake

Mediated (saturable) processMediated (saturable) process Stimulated by Zn depletionStimulated by Zn depletion

AbsorptioAbsorptionn

Mucosa Serosa

Zn++ Zn++

NSBP

MTI

MTI-Zn

CRIP

CRIP-Zn

Zn++ Zn++

Zn++-Albumin

Albumin

CRIP=cysteine-rich intestinal protein; MTI=metallothionine; NSBP, non-specfic binding protein

Non-saturable = Passive Diffusion

Saturable =Bound to

form transportligand Zn++-Albumin

Transport in bloodTransport in blood Plasma contains approx .1% of the total zinc of the bodyPlasma contains approx .1% of the total zinc of the body Albumin is major portal carrierAlbumin is major portal carrier

Binds to albumin by tetrahedral ligation to sulfur atomsBinds to albumin by tetrahedral ligation to sulfur atoms 70% of Zn is bound to albumin in plasma70% of Zn is bound to albumin in plasma 20-30% bound to 20-30% bound to αα-2 macroglobulin-2 macroglobulin Other plasma proteinsOther plasma proteins

Transferrin, histidine-rich glycoprotein, metallothionineTransferrin, histidine-rich glycoprotein, metallothionine Plasma Zn concn’s respond to external stimuliPlasma Zn concn’s respond to external stimuli

Intake fluctuationsIntake fluctuations FastingFasting Acute stressesAcute stresses

infectioninfection Plasma Zn levels do not influence absorption from Plasma Zn levels do not influence absorption from

mucosamucosa Most reductions in plasma levels reflect increased Most reductions in plasma levels reflect increased

hepatic uptakehepatic uptake Hormonal controlHormonal control

TransportTransport Rapidly cleared from plasma by Rapidly cleared from plasma by

liverliver Fast component of 2 pool model (TFast component of 2 pool model (T1/21/2

= 12.3 da)= 12.3 da) Single dose of zinc is taken up with TSingle dose of zinc is taken up with T1/21/2 = =

20 s 20 s Slow component, other tissues (TSlow component, other tissues (T1/21/2 = =

300 da)300 da) Bone and CNS uptake slow Bone and CNS uptake slow Pancreas, liver and kidney most rapidPancreas, liver and kidney most rapid RBC & muscle in betweenRBC & muscle in between Exchangeable pool & zinc statusExchangeable pool & zinc status

Cellular UptakeCellular Uptake

Hepatic uptake via a biphasic processHepatic uptake via a biphasic process Contribution to overall Zn fluxContribution to overall Zn flux

Sequesters newly absorbed ZnSequesters newly absorbed Zn Removes Zn from the circulationRemoves Zn from the circulation

Saturable process – initial stepSaturable process – initial step Temperature dependentTemperature dependent rapidrapid Stimulated by glucocorticoidsStimulated by glucocorticoids

Linear accumulation – subsequent stepLinear accumulation – subsequent step slowslow Not affected by dietary Zn intakeNot affected by dietary Zn intake

Does not require energyDoes not require energy

Cellular UptakeCellular Uptake ErythrocytesErythrocytes

Depends upon bicarbonate ionsDepends upon bicarbonate ions Fibroblasts, proximal tubule, Fibroblasts, proximal tubule,

lymphocytelymphocyte Biphasic uptake (same as liver)Biphasic uptake (same as liver)

Intracellular TransportIntracellular Transport

Zinc transporters regulate Zn ion Zinc transporters regulate Zn ion concentrations through import, concentrations through import, export or sequestering Zn into export or sequestering Zn into vesiclesvesicles Storage, toxicityStorage, toxicity

2 families exist: 2 families exist: ZnT- mainly exports Zn ions from cells ZnT- mainly exports Zn ions from cells ZIP – important for Zn influxZIP – important for Zn influx

Intracellular Intracellular TransportTransport

Number of transportersNumber of transporters ZnT-1: all organs, small intestine ZnT-1: all organs, small intestine

(basolateral membrane), kidney (basolateral membrane), kidney (tubular cells), placenta (tubular cells), placenta EffluxEfflux

ZnT-2: intestine, kidney, testisZnT-2: intestine, kidney, testis Efflux & (?) intracellular vesiclesEfflux & (?) intracellular vesicles

ZnT-3: brain (synaptic vesicles) & ZnT-3: brain (synaptic vesicles) & testistestis Influx, intracellular retentionInflux, intracellular retention

ZnT-4: mammary gland & brainZnT-4: mammary gland & brain Efflux (into milk)Efflux (into milk)

Lethal mouse transgenicLethal mouse transgenic

Intracellular TransportIntracellular Transport

ZIP family transporters:ZIP family transporters: Consist of: Consist of:

hZIP1hZIP1 hZIP2hZIP2 hZIP3hZIP3

Responsible for influx of Zn as well as Responsible for influx of Zn as well as MnMn2+2+, Cd, Cd2+2+, and other divalent cations , and other divalent cations into cellsinto cells

Intracellular Intracellular TransportTransport

Number of transportersNumber of transporters DCT1: duodenum, jejunum, kidney, DCT1: duodenum, jejunum, kidney,

bone marrow, othersbone marrow, others Non-specific: Zn, Cd, Mn & Cu actually Non-specific: Zn, Cd, Mn & Cu actually

have slightly higher affinity than Fe, the have slightly higher affinity than Fe, the mineral for which the transport actions mineral for which the transport actions of this protein was first identified.of this protein was first identified.

Competition between Fe & Zn & CuCompetition between Fe & Zn & Cu

StorageStorage Storage sitesStorage sites

No specfic storage sites are recognizedNo specfic storage sites are recognized Within cells, amounts sequestered within Within cells, amounts sequestered within

metallothionine could be considered as storesmetallothionine could be considered as stores Anorexia, muscle catabolism, tissue zinc Anorexia, muscle catabolism, tissue zinc

releaserelease Metalloenzymes cling tenaciously to zincMetalloenzymes cling tenaciously to zinc

Serum/plasma zinc drops rapidly (~1 Serum/plasma zinc drops rapidly (~1 week) with zinc deficient dietweek) with zinc deficient diet Zinc turnover is extensive and rapidZinc turnover is extensive and rapid

Two-components of turnover, fast ~12.3 days, and Two-components of turnover, fast ~12.3 days, and slow, ~300 daysslow, ~300 days

Fast pool is also called the “exchangeable” Fast pool is also called the “exchangeable” poolpool

Usually amounts to 157-183 mg ZnUsually amounts to 157-183 mg Zn

ExcretionExcretion Lost via hair, sweat, desquamation, bile Lost via hair, sweat, desquamation, bile

pancreatic secretions, seminal fluid, urine, pancreatic secretions, seminal fluid, urine, fecesfeces

Main endogenous lossMain endogenous loss Secretions into gutSecretions into gut

Bile and pancreasBile and pancreas Mucosal cellsMucosal cells

Urinary and integumental lossesUrinary and integumental losses < 20% under normal conditions< 20% under normal conditions

Losses increase with trauma, muscle catabolism, and Losses increase with trauma, muscle catabolism, and administration of chelating agents (EDTA) administration of chelating agents (EDTA)

Primarily in fecal materialPrimarily in fecal material Unabsorbed ZnUnabsorbed Zn Secreted Zn (endogenous sources)Secreted Zn (endogenous sources)

From pancreatic and intestinal sourcesFrom pancreatic and intestinal sources

RegulationRegulation MetallothioneinMetallothionein

Concentrated in liver, kidney, pancreas, intestineConcentrated in liver, kidney, pancreas, intestine Acts as a ZnActs as a Zn2+2+ buffer buffer

Controls free ZnControls free Zn2+2+ level level Control intracellular Zn pool responsive to both hormones and dietControl intracellular Zn pool responsive to both hormones and diet

Zn-binding protein, metallothionein (MT), is involved Zn-binding protein, metallothionein (MT), is involved in the regulation of Zn metabolismin the regulation of Zn metabolism

MT is inducible by dietary Zn via the metal response MT is inducible by dietary Zn via the metal response element (MRE) and MTF-1 mechanism of element (MRE) and MTF-1 mechanism of transcriptional regulationtranscriptional regulation ↑↑ in cellular MT in cellular MT ↑↑ Zn binding within cells Zn binding within cells

Acute infections associated with proinflammatory Acute infections associated with proinflammatory cytokines increses Zn uptake into liver, bone marrow cytokines increses Zn uptake into liver, bone marrow and thymus and reduces the amount going to bone, and thymus and reduces the amount going to bone, skin and intestineskin and intestine

Metabolic InteractionsMetabolic Interactions

Interactions of other divalent cations Interactions of other divalent cations in the intestinal lumenin the intestinal lumen Fe, Fe, SnSn, , CdCd → ↓ Zn → ↓ Zn ↑ ↑ Zn → ↓ CuZn → ↓ Cu

InteractionsInteractions CopperCopper

High Zn diets reduce Cu absorption High Zn diets reduce Cu absorption electronic configuration competitionelectronic configuration competition

Metallothionine synthesis inducedMetallothionine synthesis induced sequesters Cu in mucosal cell preventing sequesters Cu in mucosal cell preventing

serosal transferserosal transfer Happens with 150mg Zn for two yearsHappens with 150mg Zn for two years Can be used with Wilson’s disease patientsCan be used with Wilson’s disease patients High copper diets do not interfere with Zinc High copper diets do not interfere with Zinc

absorptionabsorption IronIron

Supplements inhibit zinc absorptionSupplements inhibit zinc absorption Ferrous > Ferric, heme no effectFerrous > Ferric, heme no effect Pregnant and taking >60mg Fe/day should Pregnant and taking >60mg Fe/day should

also take Znalso take Zn

InteractionsInteractions CalciumCalcium

High Ca diets reduce Zn absorption High Ca diets reduce Zn absorption effect enhanced in phytate rich dietseffect enhanced in phytate rich diets not sure how much of a problem in humansnot sure how much of a problem in humans

post menopausal women yes, adolescent girls, nopost menopausal women yes, adolescent girls, no OtherOther

Tin (Sb), not usually high in diet, but diets Tin (Sb), not usually high in diet, but diets high in Tin can increase fecal Zn excretionhigh in Tin can increase fecal Zn excretion

Cadmium (Cd), alter Zn distribution in Cadmium (Cd), alter Zn distribution in body rather than altering absorptionbody rather than altering absorption

Folic acid, conjugase requires ZnFolic acid, conjugase requires Zn High doses sometimes impair Zn status further High doses sometimes impair Zn status further

in low Zn situation - mechanism currently in low Zn situation - mechanism currently unclearunclear

FunctionFunction Zinc-containing enzymesZinc-containing enzymes

More than 70 enzymesMore than 70 enzymes Secondary & tertiary protein structuresSecondary & tertiary protein structures

Metal stabilized active sitesMetal stabilized active sites

Examples of general typesExamples of general types dehydrogenasesdehydrogenases phosphatasesphosphatases peptidasespeptidases kinaseskinases deaminasesdeaminases

InsulinInsulin

FunctionFunction

Cu/Zn Superoxide DismutaseCu/Zn Superoxide Dismutase General class of enzymes that protect General class of enzymes that protect

against oxidative damage in the body.against oxidative damage in the body. InsulinInsulin

Zn important structurallyZn important structurally Zn needed for insulin “stored” in Zn needed for insulin “stored” in

pancreaspancreas Functionality drops rapidly so more of a Functionality drops rapidly so more of a

“working store” than a static store“working store” than a static store

FunctionFunction

Nuclear transcription factors (>130)Nuclear transcription factors (>130) Same protein structural role forms “zinc-Same protein structural role forms “zinc-

fingers”fingers” ““Zn-fingers” bind DNAZn-fingers” bind DNA

allow different nuclear hormones to interact with allow different nuclear hormones to interact with DNA via different DNA binding proteinsDNA via different DNA binding proteins

up to 37 “fingers” have been found on a single up to 37 “fingers” have been found on a single transcription factortranscription factor

Vit. A, Vit. D, steroid hormones, insulin-like growth Vit. A, Vit. D, steroid hormones, insulin-like growth factor-1, growth hormone, and others bind to zinc-finger factor-1, growth hormone, and others bind to zinc-finger proteins to modulate gene expressionproteins to modulate gene expression

Zn is responsible for thymidine incorporationZn is responsible for thymidine incorporation

FunctionFunction

Cell DifferentiationCell Differentiation Thymidine kinase activityThymidine kinase activity Creatine kinase activityCreatine kinase activity

Transcription FactorsTranscription Factors

Transcription factorsTranscription factors Regulate gene expressionRegulate gene expression Involved in virtually all biological processes: Involved in virtually all biological processes:

Development, differentiation, cell proliferation, Development, differentiation, cell proliferation, response to external stimuliresponse to external stimuli

Consists of 2 domainsConsists of 2 domains DNA Binding Domain (DBD) – recognizes and DNA Binding Domain (DBD) – recognizes and

binds to specific DNA sequence elements in the binds to specific DNA sequence elements in the promoter of target genespromoter of target genes

Protein-interacting Transactivation Domain (TAD) Protein-interacting Transactivation Domain (TAD) – influences the rate of transcription– influences the rate of transcription

Zinc Finger ProteinsZinc Finger Proteins Zinc finger proteins are characterized by Zinc finger proteins are characterized by

their utilization of zinc ions as structural their utilization of zinc ions as structural componentscomponents

C2H2 zinc finger binding motifC2H2 zinc finger binding motif Predominant motif in eukaryotic transcription Predominant motif in eukaryotic transcription Involved in skeletal differentiationInvolved in skeletal differentiation Zinc binding motif is determined by the presence Zinc binding motif is determined by the presence

of 2 cysteine and 2 histidine residues that engage of 2 cysteine and 2 histidine residues that engage in a four coordinate bond with a singe Zn ionin a four coordinate bond with a singe Zn ion

Bind to response elements in the upstream Bind to response elements in the upstream promoters of genes transcribed by RNA poly 2promoters of genes transcribed by RNA poly 2

Binds to 5S ribosomal RNA gene, and 5S RNA, Binds to 5S ribosomal RNA gene, and 5S RNA, and activates transcription by RNA polymerase 3.and activates transcription by RNA polymerase 3.

Mech of TranscriptionMech of Transcription

FunctionFunction

Zinc-Finger

FunctionFunction

Zinc-finger Interacting with DNA

FunctionFunction

Zinc FingersZinc Fingers Mutation c/ablation of bindingMutation c/ablation of binding

in case of Zif268, loss in sequence-specific in case of Zif268, loss in sequence-specific DNA binding that allowed viral infectionDNA binding that allowed viral infection

Iron can replace Zn in “fingers”Iron can replace Zn in “fingers” Low Zn and high FeLow Zn and high Fe Fe gives rise to ROS more readilyFe gives rise to ROS more readily

DNA damage & carcinogenesis?DNA damage & carcinogenesis?

Cadmium can replace Zn in “fingers”Cadmium can replace Zn in “fingers” Non-functional, cytotoxicNon-functional, cytotoxic

Transcription FactorsTranscription Factors RevelationRevelation

Gene expression is controlled by specific Gene expression is controlled by specific proteins call transcription factorsproteins call transcription factors

Zinc containing transcription factors Zinc containing transcription factors account for 1% of genomeaccount for 1% of genome

Zinc plays key structural role in Zinc plays key structural role in transcription factor proteinstranscription factor proteins

Ligands for transcription factors Ligands for transcription factors include:include:

Vitamin AVitamin A Vitamin DVitamin D Bile acidsBile acids Thyroid hormonesThyroid hormones

Membrane StabilityMembrane Stability

Membrane fractions contain high Membrane fractions contain high concentrations of Znconcentrations of Zn Increases rigidity of cellIncreases rigidity of cell

Protection from oxidative damageProtection from oxidative damage Competition for binding sites with redox Competition for binding sites with redox

metalsmetals

Membrane FunctionMembrane Function

In deficient animals:In deficient animals: Failure of platelet aggregationFailure of platelet aggregation

Due to impaired Calcium uptakeDue to impaired Calcium uptake Peripheral neuropathyPeripheral neuropathy

Brain synaptic vesicles exhibit impaired Brain synaptic vesicles exhibit impaired calcium uptakecalcium uptake

Increased osmotic fragility in RBCsIncreased osmotic fragility in RBCs Decreased plasma membrane sulfhydryl Decreased plasma membrane sulfhydryl

concentrationconcentration

Immune FunctionImmune Function

After Zinc depletionAfter Zinc depletion All functions within monocytes were All functions within monocytes were

impairedimpaired Cytotoxicity decreased in Natural Killer CellsCytotoxicity decreased in Natural Killer Cells Phagocytosis is reduced in neutrophilsPhagocytosis is reduced in neutrophils Normal function of T-cells are impairedNormal function of T-cells are impaired B cells undergo apoptosis B cells undergo apoptosis

High Zn supplementation shows High Zn supplementation shows alterations in cells similar to Zn alterations in cells similar to Zn depletiondepletion

Vitamin A & Vitamin A & ZincZinc

Zn influences Vitamin A metabolismZn influences Vitamin A metabolism Absorption, transport, and utilizationAbsorption, transport, and utilization

Vitamin A transport is mediated through protein Vitamin A transport is mediated through protein synthesissynthesis

Zn deficiency can depress synthesis of retinol-binding Zn deficiency can depress synthesis of retinol-binding protein in liverprotein in liver

Oxidative conversion of retinol to retinal requires Zn-Oxidative conversion of retinol to retinal requires Zn-dependent retinol dehydrogenase enzymedependent retinol dehydrogenase enzyme

Retinol to retinaldehyde (retinal), for visual processesRetinol to retinaldehyde (retinal), for visual processes Night BlindnessNight Blindness

Hallmark deficiency sign for Vitamin AHallmark deficiency sign for Vitamin A Seen with Zn deficiency as well, why?Seen with Zn deficiency as well, why?

Stojanovic, Stitham and Hwa: Critical Stojanovic, Stitham and Hwa: Critical Rose of Transmembrane segment Zn Rose of Transmembrane segment Zn binding I the structure and function of binding I the structure and function of rhodopsin JBC 279(34):35932-35941, 2004rhodopsin JBC 279(34):35932-35941, 2004 Rhodopsin proteins Rhodopsin proteins

Vitamin AVitamin A

trans-Retinal + opsin

trans-Retinol

11-cis-Retinal

11-cis-Retinol

[11-cis-Retinal]Rhodopsin

Spontaneous i

n dark

+ opsin Light

Retinol isomeraseworks on vitamin A

bound to CRBP

Retinol isomerase

Alcohol dehydrogenase NADH (NADPH)NAD+ (NADP+)

Blood +Epithelium

“bleaching”

Zn-dependentProtein folding

Zn and Vitamin A Zn and Vitamin A InteractionInteraction

Mechanisms of ToxicityMechanisms of Toxicity Excess accumulation within cells may disrupt Excess accumulation within cells may disrupt

functions of biological moleculesfunctions of biological molecules Protein, enzymes, DNAProtein, enzymes, DNA

Leads to toxic consequencesLeads to toxic consequences AnemiaAnemia

Impaired copper availabilityImpaired copper availability Acute excessive intakesAcute excessive intakes

Local irritant to tissues and membranesLocal irritant to tissues and membranes GI distress, nausea, vomiting, abdominal cramps, GI distress, nausea, vomiting, abdominal cramps,

diarrheadiarrhea Relatively non-toxicRelatively non-toxic

Sources of exposure – drinking water, feed, Sources of exposure – drinking water, feed, polluted airpolluted air

DeficiencyDeficiency SignsSigns

Growth retardationGrowth retardation Delayed sexual maturation Delayed sexual maturation

& impotence& impotence Impaired testicular Impaired testicular

developmentdevelopment Hypogonadism & Hypogonadism &

hypospermiahypospermia AlopeciaAlopecia Acroorifical skin lesionsAcroorifical skin lesions

Other, glossitis, alopecia & Other, glossitis, alopecia & nail dystrophynail dystrophy

Immune deficienciesImmune deficiencies Behavioral changesBehavioral changes

More signsMore signs Night blindness Night blindness Impaired taste Impaired taste

(hypoguesia)(hypoguesia) Delayed healing of Delayed healing of

wounds, burns, wounds, burns, decubitus ulcersdecubitus ulcers

Impaired appetite & Impaired appetite & food intakefood intake

Eye lesions including Eye lesions including photophobia & lack of photophobia & lack of dark adaptationdark adaptation

DeficiencyDeficiency Monogastric more susceptibleMonogastric more susceptible

Chickens & pigs used to become deficient Chickens & pigs used to become deficient with high corn dietswith high corn diets Old enemy phytateOld enemy phytate

Ruminants resistant due to ability to break Ruminants resistant due to ability to break down phytatesdown phytates

DiabetesDiabetes Increases urinary zinc excretion Increases urinary zinc excretion

Can cause deficiencyCan cause deficiency ElderlyElderly

Poor intakes & altered physiologyPoor intakes & altered physiology

Deficiency During Deficiency During PregnancyPregnancy

Zn deficient rats failed to conceiveZn deficient rats failed to conceive Abnormalities of blastocyst developmentAbnormalities of blastocyst development Offspring had high incidence of Offspring had high incidence of

abnormalitiesabnormalities Deformities of brain, skull, limbs, eyes, heart, Deformities of brain, skull, limbs, eyes, heart,

lungslungs Low Zn intake during the third trimester Low Zn intake during the third trimester

may not have such profound effectsmay not have such profound effects Main stages of differentiation are already Main stages of differentiation are already

completecomplete Can result in low birth weight, and prolonged Can result in low birth weight, and prolonged

and difficult parturitionand difficult parturition

Deficiency During Deficiency During PregnancyPregnancy

ZincAdequate

ZincDeficient

3 days 4 days

From Hurley&Schrader, 1975

DeficiencyDeficiencyMalformations in Zn deficiencyCleft lipCleft palateBrain (Hydrocephalus, anencephalus or exencephalus)Micro- or agnathiaMicro- or anopthalmiaClubbed feetA- or syndactylyCurly or stubby tailDorsal herniationHeart (abnormal position)

Lung (missing lobes)

Urogentital (Hydronephrosis, missing kidney, or abnormal positions)

Stress ResponseStress Response Factors that decrease plasma Zn Factors that decrease plasma Zn

concentrationconcentration Infection Infection Bacterial endotoxinsBacterial endotoxins SurgerySurgery BurnsBurns PregnancyPregnancy

IL-1 causes increased Zn uptake by liver IL-1 causes increased Zn uptake by liver thymus and bone marrowthymus and bone marrow

Severe trauma or death can result from Severe trauma or death can result from Zn supplementation to stressed animalsZn supplementation to stressed animals

2002 DRI’s2002 DRI’s

InfantsInfants UL=(x)UL=(x) 0-6 mo: 2 mg/d0-6 mo: 2 mg/d AI AI (4)(4)

Children & adolescentsChildren & adolescents 7mos-1 yr: 3 mg/d 7mos-1 yr: 3 mg/d (5)(5) 1-3 yrs: 3 mg/d 1-3 yrs: 3 mg/d (7)(7) 4-8 yrs: 5 mg/d 4-8 yrs: 5 mg/d (12)(12) 9-13 yrs: 8 mg/d9-13 yrs: 8 mg/d (23)(23) 14-18 yrs: 14-18 yrs: (34)(34)

MalesMales 11 mg/da11 mg/da Females 9 mg/daFemales 9 mg/da

Adults: 19 yrs & older (40)

Men: 11 mg/daWomen: 8 mg/da

Pregnancy: 11-18 yrs: 12 mg/da (34)19-50 yrs: 11 mg/day (40)Lactation: 11-18 yrs: 13mg/da (34)19-50 yrs: 12 mg/day (40)

FootnoteMales need more than females due to high Zn content of seminal fluids & relatively low Zn loss through menstruation