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Metal Toxicity
Cellular Injuries
• Diverse
– Many mechanisms
– Different biol levels
• Changes in activities
– Mostly direct
– Key bio molecules
– Biochem pathways
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
Metals Chemistry
• Most are electron acceptors
• Preferential reaction w/ -SH grps
– Also –COOH, -PO4-2
Metals Chemistry
• Most interactions w/ proteins, enzymes
– BUT in vitro data
– Not all competitive mol’s present
– Also metal mol’s may compete for binding sites
• May displace essential metal cofactors
Lead (Pb)
• Routes of ingestion– Lung
• Industry
•Wind (soil, vegetation)
•Gasoline engines
– Oral
•Food (vegetation (soils), pottery glaze, paint)
•Water (incl lead shot)
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
Toxicity to Humans
• Adult intake threshold ~ 500 mg/d
– Children half
• 5-15% ingested dose abs’d (15-25 mg/d)
• 20-40% inhaled dose abs’d (~8 mg/d)
• Unleaded gasoline decr’d intake
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
Pb Toxicity within Cells
• Not fully known
• Highly reactive to –SH grps Mercaptide
•R—S—Pb—S—R
– Can inactivate enz’s, other prot’s
•Book ex: adenyl cylase (brain transmission)
•Book ex: aminotransferase (aa metab)
• Similar to Ca, competes
– At presyn receptor
•Now decr’d Ca avail
– Bone
• Interacts w/ nucleic acids
– Decr’s protein synth
•Decr’d binding tRNA to ribosomes
– OR may incr prot synth
Nucleus
• As, Pb, Hg, Se
• Produce intranuclear inclusion bodies
• BUT mechanisms varied/complex
Nucleus
• Ex: Pb best studied
– Renal tubule DNA, RNA, prot syntheses stim’d
– 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
• Interacts w/ Zn, Fe inhib’n -aminolevulinic acid dehydratase and ferrochelatase Decr’d heme synth
Decr’d rbc’s
– Book p. 224
Cadmium (Cd)
• Routes of exposure
– Lung
•Highest concent’s – industrialized cities, near smelters
•Tobacco smoke (more impt)– 1.5-2.0 mg/cigarette; 70% found in smoke
• Routes of exposure – cont’d
– Oral
•Water– From industrial, mining wastes
•Soils– From sewage sludge appl’d to agri fields;
phosphate fertilizers
•Food – largest exposure source– Accum’d from plants (soil), fish (water)
Cd Toxicity to Plants
• Accum’d by all plants
– Soil pH, species impt
– Stunts growth, photosynth; inhibits seed germination
Cd Toxicity to Humans
• Toxicity @ 250-300 g/day
• Pulmonary exposure not as impt to burden
– Except tobacco smoke
– BUT more dangerous route (direct)
•Greater percentage dose abs’d (25-40%)
• Drinking water not as impt to burden
– 20-30 g/day
• Food most impt
– 35-90 g/day
– Based on 5-10% abs’n
– Low prot in diet incr’d abs’n, incr’d toxicity
• Binds albumin in blood, taken up by liver
– Binds metallothionein, then blood kidney, bone, muscle
• Embryotoxic
High Affinity Metal Binding Proteins
• In cytosol
• Intracellular “sinks”
– Hold toxic metals away from
•Sensitive organelles
•Metabolic sites
– Overwhelmed w/ very high metal exposure
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
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
• Kidney
– Cd-MT taken up by prox tubule cells
– Damage if lysosomes cleave complex free Cd
• Hepatic cyt P450
– Acute Cd decr’d 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
But…
• Other metal binding proteins
• Some metals don’t induce synth of metal binding prot’s
Lysosomes
• Renal tubules
• Cd+2, Hg (as Hg+2 or methyl-Hg)
– Inhibit normal function
cell injury
• Indirect effect due to dysfunction of other damaged organelles
Cd Toxicity within Cells• Energy prod’n
– Chloroplast photophosph’n
– Mitochondria ATP synth, NADH ox’n, electron transport
• Enzyme inhib’n– Book ex: alkaline phosphatase,
myosin ATPases
– Binds –SH grps
– Competes w/, displaces Zn
• Binds –SH grps in other impt cell prot’s
– Cell membr
– Mitochondria
•Uncouples oxidative phosph’n
• Antimetabolite
– Competes w/ other metals (Zn, Cu, Se, Fe)
Mitochondria
• Major intracell target of many metals
– Rapid transport metals across mitoch membr’s
– Has high metab activity
– Sensitive to disruption
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 membr’s (site of activity)
Cd Poisoning in Humans
• Emphysema
• Pneuomonitis
• GI disturbances
• Vomiting
• Liver dysfunction
• Kidney damage Anemia
Proteinuria
• Hypertension
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: accum’n <0.5 mg/day
Hg Toxicity to Plants, Animals
• In plants toxicity dependent on species
– Impairs germination, growth
• Fish may accum Hg > 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
• Incr’d T incr’d metab greater Hg in tissue in summer
• Toxicity to fish incr’d w/ incr’d T
Hg Toxicity to Humans
• Critical intake 300 mg Hg as CH3Hg
• Almost all CHHg 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 form’n Hg+2 ion
Hg Poisoning
• Chronic
– Salivation, loss appetite
– Anemia
– Tissue irritation, gingivitis
– Nutrional disturbances
– Renal damage
– Neurotoxicity
• Mercuric chloride
– Precipitates all prot’s
– Vomiting
– Severe thirst
– Nausea
– Severe GI irritation
– Loss fluids, electrolytes
Hg Toxicity within Cells
• Inhib’n enzymes– Selective affinity to –SH grps
– R—SH + CH3Hg R—S—Hg—CH3 + H+
• Incr’s permeability Na+, K+– Inhibits active transport mech’s
– Disrupts fluid/electrolyte balance
• Affects chromosomes, mitosis mutagenesis
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
Cellular Injuries
• Dependent on individual physiological factors
– Developmental stage
– Sex
– Nutritional status
– Toxicant dose
– Toxicant combination
Organelles/Structures Effected by Various
Metals
• Nucleus
• Lysosomes
• Mitochondrion
• Cell membrane
• Endoplasmic Reticulum
Cell Membrane• Movement into cell dependent on
– Lipophilicity
– Metal binding to protein endocytosis
– Chem similarity of metal to nutrient
– Ex: As
• Metals may enter membr by
– Passive diffusion
– Binding cell membr, then endocytosis
•Ex: Pb
• Hg+2, Cr+6(chromate) strong oxidizers
– Acute high dose effects membranes
– Not seen w/ chronic low dose
• Some membr’s adapt to chronic dosage
– Exceptions to metals trend
• Most don’t directly damage cell membrane
• Most are intracellular toxicants
Endoplasmic Reticulum
• Co, Cd, Sn, CH3Hg, In
• Metabolic enz’s inhib’d
– Cyt P450 and non-cyt P450
• Ex: In disrupts e.r. structure
– Alters microsomal enz activities