Metal Toxicity

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Metal Toxicity
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Cellular Injuries

• Diverse
• Many mechanisms
• Different biol levels
• Changes in activities
• Mostly direct
• Key bio molecules
• Biochem pathways

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Metals of Concern

• Lead (Pb)
• Mercury (Hg)
• Cadmium (Cd)
• Arsenic (As)
• Chromium (Cr)
• Zinc (Zn)
• Copper (Cu)

• Book notes last 3 essential nutrients for
  animals, humans
• Water soluble
• Readily absorbed
• Bind proteins, enzymes, nucleic acids in cells

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Metals Chemistry

• Most are electron acceptors
• Preferential reaction w/ -SH grps
• Also COOH, -PO4-2

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Metals Chemistry

• Most interactions w/ proteins, enzymes
• BUT in vitro data
• Not all competitive mols present
• Also metal mols may compete for binding sites
• May displace essential metal cofactors

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Lead (Pb)

• Routes of ingestion
• Lung
• Industry
• Wind (soil, vegetation)
• Gasoline engines
• Oral
• Food (vegetation (soils), pottery glaze, paint)
• Water (incl lead shot)

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Pb Toxicity to Plants, Animals

• From air, soil, lead shot
• Dependent on species
• Ex barley sensitive
• Ex goldfish insensitive
• May inhibit seed germination
• Paralyzes bird gizzard ? starvation, death
• Impt ingestion by animals further up food chain

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Toxicity to Humans

• Adult intake threshold 500 mg/d
• Children half
• 5-15 ingested dose absd (15-25 mg/d)
• 20-40 inhaled dose absd (8 mg/d)
• Unleaded gasoline decrd intake

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Lead Poisoning in Humans

• Nausea, anorexia
• Anemia
• Renal tubular dysfunction
• Joint pain
• Deposits in bone
• Equilib bone ?? blood

• Crosses placenta
• Miscarriage
• Crosses bbb
• Behavioral dysfunction
• Convulsions
• Delirium
• Encephalopathy

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Pb Toxicity within Cells

• Not fully known
• Highly reactive to SH grps
• ? Mercaptide
• RSPbSR
• Can inactivate enzs, other prots
• Book ex adenyl cylase (brain transmission)
• Book ex aminotransferase (aa metab)

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• Similar to Ca, competes
• At presyn receptor
• Now decrd Ca avail
• Bone
• Interacts w/ nucleic acids
• Decrs protein synth
• Decrd binding tRNA to ribosomes
• OR may incr prot synth

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Nucleus

• As, Pb, Hg, Se
• Produce intranuclear inclusion bodies
• BUT mechanisms varied/complex

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Nucleus

• Ex Pb best studied
• Renal tubule DNA, RNA, prot syntheses stimd
• So biochem changes in nuclear structure, function
• Karyomegaly
• Can ? renal adenocarcinoma w/ high dose
• Ex Methyl-Hg, Cd inhibit nucleic acid synth w/
  acute exposure

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• Interacts w/ Zn, Fe ? inhibn d-aminolevulinic
  acid dehydratase and ferrochelatase
• ? Decrd heme synth
• ? Decrd rbcs
• Book p. 224

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Cadmium (Cd)

• Routes of exposure
• Lung
• Highest concents industrialized cities, near
  smelters
• Tobacco smoke (more impt)
• 1.5-2.0 mg/cigarette 70 found in smoke

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• Routes of exposure contd
• Oral
• Water
• From industrial, mining wastes
• Soils
• From sewage sludge appld to agri fields
  phosphate fertilizers
• Food largest exposure source
• Accumd from plants (soil), fish (water)

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Cd Toxicity to Plants

• Accumd by all plants
• Soil pH, species impt
• Stunts growth, photosynth inhibits seed
  germination

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Cd Toxicity to Humans

• Toxicity _at_ 250-300 mg/day
• Pulmonary exposure not as impt to burden
• Except tobacco smoke
• BUT more dangerous route (direct)
• Greater percentage dose absd (25-40)
• Drinking water not as impt to burden
• 20-30 mg/day

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• Food most impt
• 35-90 mg/day
• Based on 5-10 absn
• Low prot in diet ? incrd absn, incrd toxicity
• Binds albumin in blood, taken up by liver
• Binds metallothionein, then ? blood ? kidney,
  bone, muscle
• Embryotoxic

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High Affinity Metal Binding Proteins

• In cytosol
• Intracellular sinks
• Hold toxic metals away from
• Sensitive organelles
• Metabolic sites
• Overwhelmed w/ very high metal exposure

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High Affinity Metal Binding Proteins

• Metallotheionine most impt
• Low MW
• Mammalian, nonmammamlian
• Cd, Zn, Hg, Ag, Cu, bismuth
• Also impt to regulating availability of metals in
  cell
• Nuclear inclusion bodies
• Lysosomes

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Example Cd in Mammals

• Ingestion through lungs, g.i. ?
• Blood, binds high MW proteins, transported ?
• Liver
• Cd induces synth MT
• Impt to availability of Cd in cell
• If high Cd dose, released back to blood as Cd-MT

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• Kidney
• Cd-MT taken up by prox tubule cells
• Damage if lysosomes cleave complex ? free Cd
• Hepatic cyt P450
• Acute Cd ? decrd cyt P450 content, activities
• Chronic Cd not same
• MT has time to be induced
• Can bind Cd
• MT can sequester from sensitive cell structures
• Other physio factors probably involved

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But

• Other metal binding proteins
• Some metals dont induce synth of metal binding
  prots

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Lysosomes

• Renal tubules
• Cd2, Hg (as Hg2 or methyl-Hg)
• Inhibit normal function
• ? cell injury
• Indirect effect due to dysfunction of other
  damaged organelles

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Cd Toxicity within Cells

• Energy prodn
• Chloroplast photophosphn
• Mitochondria ATP synth, NADH oxn, electron
  transport
• Enzyme inhibn
• Book ex alkaline phosphatase, myosin ATPases
• Binds SH grps
• Competes w/, displaces Zn

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• Binds SH grps in other impt cell prots
• Cell membr
• Mitochondria
• Uncouples oxidative phosphn
• Antimetabolite
• Competes w/ other metals (Zn, Cu, Se, Fe)

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Mitochondria

• Major intracell target of many metals
• Rapid transport metals across mitoch membrs
• Has high metab activity
• Sensitive to disruption

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Mitochondria

• Membranes
• Highly sensitive to metals toxicity
• Alterations in marker enz activities found
• Ex As, Pb, methyl-Hg
• Affect respiration
• Direct effect on enzymes
• Binding to cofactors
• Indirect effect on enzymes
• Perturbation of membrs (site of activity)

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Cd Poisoning in Humans

• Liver dysfunction
• Kidney damage
• ? Anemia
• ? Proteinuria
• Hypertension

• Emphysema
• Pneuomonitis
• GI disturbances
• Vomiting

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Mercury (Hg)

• Routes of exposure
• Lung
• Little in atmosphere harmful to health
• BUT vapor diffuses through alveolar membr ? brain
  quickly, directly
• Oral
• Little in drinking water harmful to health
• Food largest exposure source
• FDA guideline accumn lt0.5 mg/day

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Hg Toxicity to Plants, Animals

• In plants toxicity dependent on species
• Impairs germination, growth
• Fish may accum Hg gt FDA guideline
• In tissue, as methylmercury (CH3Hg)
• Ingested via water through gills food chain
• May be as CH3Hg or Hg
• Age, rate of exposure less impt than metabolic
  rate of indiv fish
• Incrd T ? incrd metab ? greater Hg in tissue in
  summer
• Toxicity to fish incrd w/ incrd T

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Hg Toxicity to Humans

• Critical intake 300 mg Hg as CH3Hg
• Almost all CH3Hg in diet from fish, meat
• Book Japanese Hg, CH3Hg discharges ? 11 mg Hg/g
  fish
• Fetal, newborn brains very sensitive to toxicity
• Tissue susceptibility related to formn Hg2 ion

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Hg Poisoning

• Chronic
• Salivation, loss appetite
• Anemia
• Tissue irritation, gingivitis
• Nutrional disturbances
• Renal damage
• Neurotoxicity

• Mercuric chloride
• Precipitates all prots
• Vomiting
• Severe thirst
• Nausea
• Severe GI irritation
• Loss fluids, electrolytes

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Hg Toxicity within Cells

• Inhibn enzymes
• Selective affinity to SH grps
• RSH CH3Hg ? RSHgCH3 H
• Incrs permeability Na, K
• Inhibits active transport mechs
• Disrupts fluid/electrolyte balance
• Affects chromosomes, mitosis ? mutagenesis

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Protection against Hg Toxicity

• Metallothionein
• Kidney damage when metallothionein saturated
• Se
• Mech unknown, but Se binds cysteine more tightly
  than Hg
• Vitamin E
• Mech unknown

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Cellular Injuries

• Dependent on individual physiological factors
• Developmental stage
• Sex
• Nutritional status
• Toxicant dose
• Toxicant combination

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Organelles/Structures Effected by Various Metals

• Nucleus
• Lysosomes
• Mitochondrion
• Cell membrane
• Endoplasmic Reticulum

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Cell Membrane

• Movement into cell dependent on
• Lipophilicity
• Metal binding to protein ? endocytosis
• Chem similarity of metal to nutrient
• Ex As

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• Metals may enter membr by
• Passive diffusion
• Binding cell membr, then endocytosis
• Ex Pb

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• Hg2, Cr6(chromate) strong oxidizers
• Acute high dose effects membranes
• Not seen w/ chronic low dose
• Some membrs adapt to chronic dosage
• Exceptions to metals trend
• Most dont directly damage cell membrane
• Most are intracellular toxicants

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Endoplasmic Reticulum

• Co, Cd, Sn, CH3Hg, In
• Metabolic enzs inhibd
• Cyt P450 and non-cyt P450
• Ex In disrupts e.r. structure
• Alters microsomal enz activities