Metal Toxicity Cellular Injuries • Diverse – Many mechanisms – Different biol levels • Changes in activities – Mostly direct – Key bio molecules – Biochem pathways.
Download ReportTranscript Metal Toxicity Cellular Injuries • Diverse – Many mechanisms – Different biol levels • Changes in activities – Mostly direct – Key bio molecules – Biochem pathways.
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 • Crosses placenta – Miscarriage • Crosses bbb – Behavioral dysfunction • Joint pain – Convulsions • Deposits in bone – Delirium – Equilib bone blood – 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 d- 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 mg/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 mg/day • Food most impt – 35-90 mg/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 CdMT • 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 • Liver dysfunction • Pneuomonitis • Kidney damage • GI disturbances – Anemia • Vomiting – 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 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 form’n Hg+2 ion Hg Poisoning • Chronic – Salivation, loss appetite – Anemia – Tissue irritation, gingivitis • Mercuric chloride – Precipitates all prot’s – Vomiting – Severe thirst – Nausea – Nutrional disturbances – Severe GI irritation – Renal damage – Loss fluids, electrolytes – Neurotoxicity 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