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The Importance of Zinc in Animal Health

Published: June 6, 2013
By: Agranco
The Importance of Zinc in Animal Health - Image 1
The Importance of Zinc in Animal Health - Image 2
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History
  • 1509, recognized as element
  • Essentiality demonstrated
    • Plants: 1869
    • Animals: 1934
  • Deficiency
    • Considered unlikely until 1955
      • swine parakeratosis shown to be caused by Zn deficiency
      • conditioned human deficiency demonstrated in 1956
      • 1961, hypogonadal dwarfism suggested to be zinc deficiency
Facts
  • 30th element in the periodic table (IIB element)
    • MW = 65.37, completely filled d orbitals
  • In aqueous solutions
    • One oxidation state, namely Zn2+
    • Prefers tetrahedral complex formation
  • Not a redox active metal
    • readily complexes with amino acids, peptides, proteins and nucleotides
    • affinity for thiols, hydroxy groups & ligands with electron-rich nitrogen donors 
Distribution
The Importance of Zinc in Animal Health - Image 4
 
Sources
  • Relatively abundant mineral
    • Good sources: shellfish, beef and other red meats
    • Slightly less good: Whole-grains
      • most in bran and germ portions
      • 80% lost to milling
      • phytates, hexa & penta phosphates depress absorption
        • P/Zn ratios of 10 or more
    • Relatively good sources: nuts and legumes
  • Eggs, milk, poultry & fish diets lower than pork, beef, lamb diets
    • High meat diets enhance absorption
      • 280g or 10 oz fits right into food pyramid guide
      • cys & met form stable chelate complexes
 The Importance of Zinc in Animal Health - Image 5
Effect of trace mineral source on animal performance
The Importance of Zinc in Animal Health - Image 6
Relative bioavailability of trace mineral sources
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Whole Body Fluxes
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Dietary Factors that Affect Zn Absorption
  • Feed/Food source
  • Phytate (calcium-phytate-zinc complex)
    • Mainly hexa- and pentaphosphate derivatives
    • Highly dependent on calcium
  • Amino Acids
    • histidine, cysteine
  • Presence/Absence of other divalent cations
    • Fe, Ca
  • Efficiency of absorption can vary from 15-60%
    • Under normal conditions 1/3 of dietary Zn is absorbed
    • Zn status alters efficiency of absorption
  • Uptake and retention is > in growing animals 
Overview
  • Approximately 300 enzymes are associated with zinc
  • Biological functions of Zn are divided into three categories
    • Catalytic, Structural, Regulatory
  • Role in metabolism
    • Protein synthesis
    • Nucleic acid metabolism
    • Carbohydrate and energy metabolism
    • Lipid
    • Epithelial tissue integrity
    • Cell repair and division
    • Vitamin A and E transport and utilization
    • Immune function
    • Reproductive hormones
Absorption
  • Absorption takes place throughout the intestine
    • Glycocalyx
      • Barrier? Storage site?
    • Primarily in the jejunum
    • Some absorption in the rumen
    • No measurable amounts absorbed from stomach cecum or colon
  • In small intestine
    • Nonmediated (nonsaturable) process
      • Not affected by dietary Zn intake
    • Mediated (saturable) process
      • Stimulated by Zn depletion
The Importance of Zinc in Animal Health - Image 9
Transport in blood
  • Plasma contains approx .1% of the total zinc of the body
  • Albumin is major portal carrier
    • Binds to albumin by tetrahedral ligation to sulfur atoms
    • 70% of Zn is bound to albumin in plasma
    • 20-30% bound to α-2 macroglobulin
    • Other plasma proteins
      • Transferrin, histidine-rich glycoprotein, metallothionine
  • Plasma Zn concn's respond to external stimuli Intake fluctuations Fasting Acute stresses infection Plasma Zn levels do not influence absorption from mucosa
  • Most reductions in plasma levels reflect increased hepatic uptake
    • Hormonal control 
Transport
  • Rapidly cleared from plasma by liver
  • Fast component of 2 pool model (T1/2 = 12.3 da)
    • Single dose of zinc is taken up with T1/2 = 20 s
  • Slow component, other tissues (T1/2 = 300 da)
  • Bone and CNS uptake slow
  • Pancreas, liver and kidney most rapid
  • RBC & muscle in between
  • Exchangeable pool & zinc status 
Cellular Uptake
  • Hepatic uptake via a biphasic process
    • Contribution to overall Zn flux
      • Sequesters newly absorbed Zn
      • Removes Zn from the circulation
    • Saturable process – initial step
      • Temperature dependent
      • rapid
      • Stimulated by glucocorticoids
    • Linear accumulation – subsequent step
      • slow
      • Not affected by dietary Zn intake
    • Does not require energy
  • Erythrocytes
    • Depends upon bicarbonate ions
  • Fibroblasts, proximal tubule, lymphocyte
    • Biphasic uptake (same as liver) 
Intracellular Transport
  • Zinc transporters regulate Zn ion concentrations through import, export or sequestering Zn into vesicles
    • Storage, toxicity
  • 2 families exist:
    • ZnT- mainly exports Zn ions from cells
    • ZIP – important for Zn influx
  • Number of transporters
    • ZnT-1: all organs, small intestine (basolateral membrane), kidney (tubular cells), placenta
      • Efflux
    • ZnT-2: intestine, kidney, testis
      • Efflux & (?) intracellular vesicles
    • ZnT-3: brain (synaptic vesicles) & testis
      • Influx, intracellular retention
    • ZnT-4: mammary gland & brain
      • Efflux (into milk) Lethal mouse transgenic
  • ZIP family transporters:
    • Consist of:
      • hZIP1
      • hZIP2
      • hZIP3
    • Responsible for influx of Zn as well as Mn2+, Cd2+, and other divalent cations into cells
  • Number of transporters
    • DCT1: duodenum, jejunum, kidney, bone marrow, others
      • Non-specific: Zn, Cd, Mn & Cu actually have slightly higher affinity than Fe, the mineral for which the transport actions of this protein was first identified.
      • Competition between Fe & Zn & Cu
The Importance of Zinc in Animal Health - Image 10
Storage
  • Storage sites
    • No specfic storage sites are recognized
      • Within cells, amounts sequestered within metallothionine could be considered as stores
      • Anorexia, muscle catabolism, tissue zinc release
        • Metalloenzymes cling tenaciously to zinc
    • Serum/plasma zinc drops rapidly (~1 week) with zinc deficient diet
      • Zinc turnover is extensive and rapid
        • Two-components of turnover, fast ~12.3 days, and slow, ~300 days
      • Fast pool is also called the "exchangeable" pool
        • Usually amounts to 157-183 mg Zn 
Excretion
  • Lost via hair, sweat, desquamation, bile pancreatic secretions, seminal fluid, urine, feces
  • Main endogenous loss
    • Secretions into gut
      • Bile and pancreas
    • Mucosal cells
  • Urinary and integumental losses
    • < 20% under normal conditions
      • Losses increase with trauma, muscle catabolism, and administration of chelating agents (EDTA)
  • Primarily in fecal material
    • Unabsorbed Zn
    • Secreted Zn (endogenous sources)
      • From pancreatic and intestinal sources 
Regulation
  • Metallothionein
    • Concentrated in liver, kidney, pancreas, intestine
    • Acts as a Zn2+ buffer
      • Controls free Zn2+ level
      • Control intracellular Zn pool responsive to both hormones and diet
  • Zn-binding protein, metallothionein (MT), is involved in the regulation of Zn metabolism
  • MT is inducible by dietary Zn via the metal response element (MRE) and MTF-1 mechanism of transcriptional regulation
    • ↑ in cellular MT ↑ Zn binding within cells
  • Acute infections associated with proinflammatory cytokines increses Zn uptake into liver, bone marrow and thymus and reduces the amount going to bone, skin and intestine 
Metabolic Interactions
  • Interactions of other divalent cations in the intestinal lumen ?
    • ↑Fe, ? ↑Sn, ↑? Cd → ↓ Zn
    • ↑ Zn → ↓ Cu 
Interactions
  • Copper
    • High Zn diets reduce Cu absorption
      • electronic configuration competition
    • Metallothionine synthesis induced
      • sequesters Cu in mucosal cell preventing serosal transfer
        • Happens with 150mg Zn for two years
        • Can be used with Wilson's disease patients
        • High copper diets do not interfere with Zinc absorption
  • Iron
    • Supplements inhibit zinc absorption
      • Ferrous > Ferric, heme no effect
      • Pregnant and taking >60mg Fe/day should also take Zn
  • Calcium
    • High Ca diets reduce Zn absorption
      • effect enhanced in phytate rich diets
      • not sure how much of a problem in humans
        • post menopausal women yes, adolescent girls, no
  • Other
    • Tin (Sb), not usually high in diet, but diets high in Tin can increase fecal Zn excretion
    • Cadmium (Cd), alter Zn distribution in body rather than altering absorption
    • Folic acid, conjugase requires Zn
      • High doses sometimes impair Zn status further in low Zn situation - mechanism currently unclear 
Function
  • Zinc-containing enzymes
    • More than 70 enzymes
      • Secondary & tertiary protein structures
        • Metal stabilized active sites
    • Examples of general types
      • dehydrogenases
      • phosphatases
      • peptidases
      • kinases
      • deaminases
  • Insulin
  • Cu/Zn Superoxide Dismutase
    • General class of enzymes that protect against oxidative damage in the body.
  • Insulin
    • Zn important structurally
    • Zn needed for insulin "stored" in pancreas
      • Functionality drops rapidly so more of a "working store" than a static store
  • Nuclear transcription factors (>130)
    • Same protein structural role forms "zinc-fingers"
    • "Zn-fingers" bind DNA
      • allow different nuclear hormones to interact with DNA via different DNA binding proteins
        • up to 37 "fingers" have been found on a single transcription factor
        • Vit. A, Vit. D, steroid hormones, insulin-like growth factor-1, growth hormone, and others bind to zinc-finger proteins to modulate gene expression
      • Zn is responsible for thymidine incorporation
  • Cell Differentiation
    • Thymidine kinase activity
    • Creatine kinase activity 
Transcription Factors
  • Transcription factors
    • Regulate gene expression
    • Involved in virtually all biological processes:
      • Development, differentiation, cell proliferation, response to external stimuli
    • Consists of 2 domains
      • DNA Binding Domain (DBD) – recognizes and binds to specific DNA sequence elements in the promoter of target genes
      • Protein-interacting Transactivation Domain (TAD) – influences the rate of transcription 
Zinc Finger Proteins
  • Zinc finger proteins are characterized by their utilization of zinc ions as structural components
  • C2H2 zinc finger binding motif
    • Predominant motif in eukaryotic transcription
    • Involved in skeletal differentiation
    • Zinc binding motif is determined by the presence of 2 cysteine and 2 histidine residues that engage in a four coordinate bond with a singe Zn ion
    • Bind to response elements in the upstream promoters of genes transcribed by RNA poly 2
    • Binds to 5S ribosomal RNA gene, and 5S RNA, and activates transcription by RNA polymerase 3. 
Mech of Transcription
The Importance of Zinc in Animal Health - Image 11
The Importance of Zinc in Animal Health - Image 12
Function
The Importance of Zinc in Animal Health - Image 13
The Importance of Zinc in Animal Health - Image 14
The Importance of Zinc in Animal Health - Image 15
  • Zinc Fingers
    • Mutation c/ablation of binding
      • in case of Zif268, loss in sequence-specific DNA binding that allowed viral infection
    • Iron can replace Zn in "fingers"
      • Low Zn and high Fe
      • Fe gives rise to ROS more readily
        • DNA damage & carcinogenesis?
    • Cadmium can replace Zn in "fingers"
      • Non-functional, cytotoxic 
Transcription Factors
  • Revelation
    • Gene expression is controlled by specific proteins call transcription factors
      • Zinc containing transcription factors account for 1% of genome
    • Zinc plays key structural role in transcription factor proteins
    • Ligands for transcription factors include:
      • Vitamin A
      • Vitamin D
      • Bile acids
      • Thyroid hormones 
Membrane Stability
  • Membrane fractions contain high concentrations of Zn
    • Increases rigidity of cell
  • Protection from oxidative damage
    • Competition for binding sites with redox metals 
Membrane Function
  • In deficient animals:
    • Failure of platelet aggregation
      • Due to impaired Calcium uptake
    • Peripheral neuropathy
      • Brain synaptic vesicles exhibit impaired calcium uptake
    • Increased osmotic fragility in RBCs
      • Decreased plasma membrane sulfhydryl concentration 
Immune Function
  • After Zinc depletion
    • All functions within monocytes were impaired
    • Cytotoxicity decreased in Natural Killer Cells
    • Phagocytosis is reduced in neutrophils
    • Normal function of T-cells are impaired
    • B cells undergo apoptosis
  • High Zn supplementation shows alterations in cells similar to Zn depletion 
Vitamin A & Zinc
  • Zn influences Vitamin A metabolism
    • Absorption, transport, and utilization
      • Vitamin A transport is mediated through protein synthesis
        • Zn deficiency can depress synthesis of retinol-binding protein in liver
      • Oxidative conversion of retinol to retinal requires Zn-dependent retinol dehydrogenase enzyme
        • Retinol to retinaldehyde (retinal), for visual processes
  • Night Blindness
    • Hallmark deficiency sign for Vitamin A
      • Seen with Zn deficiency as well, why?
  • Stojanovic, Stitham and Hwa: Critical Rose of Transmembrane segment Zn binding I the structure and function of rhodopsin JBC 279(34):35932-35941, 2004
    • Rhodopsin proteins
Vitamin A
The Importance of Zinc in Animal Health - Image 16
Zn and Vitamin A Interaction
The Importance of Zinc in Animal Health - Image 17
Mechanisms of Toxicity
  • Excess accumulation within cells may disrupt functions of biological molecules
    • Protein, enzymes, DNA
      • Leads to toxic consequences
  • Anemia
    • Impaired copper availability
  • Acute excessive intakes
    • Local irritant to tissues and membranes
      • GI distress, nausea, vomiting, abdominal cramps, diarrhea
  • Relatively non-toxic
    • Sources of exposure – drinking water, feed, polluted air 
Deficiency
  • Signs
    • Growth retardation
    • Delayed sexual maturation & impotence
      • Impaired testicular development
    • Hypogonadism & hypospermia
    • Alopecia
    • Acroorifical skin lesions
      • Other, glossitis, alopecia & nail dystrophy
    • Immune deficiencies
    • Behavioral changes
  • More signs
    • Night blindness
    • Impaired taste (hypoguesia)
    • Delayed healing of wounds, burns, decubitus ulcers
    • Impaired appetite & food intake
    • Eye lesions including photophobia & lack of dark adaptation
  • Monogastric more susceptible
    • Chickens & pigs used to become deficient with high corn diets
      • Old enemy phytate
    • Ruminants resistant due to ability to break down phytates
  • Diabetes
    • Increases urinary zinc excretion
      • Can cause deficiency
  • Elderly
    • Poor intakes & altered physiology 
Deficiency During Pregnancy
  • Zn deficient rats failed to conceive
  • Abnormalities of blastocyst development
  • Offspring had high incidence of abnormalities
    • Deformities of brain, skull, limbs, eyes, heart, lungs
  • Low Zn intake during the third trimester may not have such profound effects
    • Main stages of differentiation are already complete
    • Can result in low birth weight, and prolonged and difficult parturition
The Importance of Zinc in Animal Health - Image 18
The Importance of Zinc in Animal Health - Image 19
Malformations in Zn deficiency
Cleft lip
Cleft palate
Brain (Hydrocephalus, anencephalus or exencephalus)
Micro- or agnathia
Micro- or anopthalmia
Clubbed feet
A- or syndactyly
Curly or stubby tail
Dorsal herniation
Heart (abnormal position)
Lung (missing lobes)
Urogentital (Hydronephrosis, missing kidney, or abnormal positions)
The Importance of Zinc in Animal Health - Image 20
Stress Response
  • Factors that decrease plasma Zn concentration
    • Infection
    • Bacterial endotoxins
    • Surgery
    • Burns
    • Pregnancy
  • IL-1 causes increased Zn uptake by liver thymus and bone marrow
  • Severe trauma or death can result from Zn supplementation to stressed animals 
2002 DRI's
  • Infants UL=(x)
    • 0-6 mo: 2 mg/d AI (4)
  • Children & adolescents
    • 7mos-1 yr: 3 mg/d (5)
    • 1-3 yrs: 3 mg/d (7)
    • 4-8 yrs: 5 mg/d (12)
    • 9-13 yrs: 8 mg/d (23)
    • 14-18 yrs: (34)
      • Males 11 mg/da
      • Females 9 mg/da
Adults: 19 yrs & older (40)
Men: 11 mg/da
Women: 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)
Footnote
Males need more than females due to high Zn content of seminal fluids & relatively low Zn loss through menstruation
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rajasekar
10 de febrero de 2017
I want know about dosage and excess result in detail
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