Metals I Flashcards
Class A metals
Hard- highly stable and preferentially bind anions with O2 as electron donors
Class B metals
Soft metals- pronounced preference for S and N. certain soft acids bind strongly with Se
intermediate metals
ligand-binding characteristics that are intermediate to soft and hard, but still readily bind with S
Class B important metals
Mercury (Hg)
Cadmium (Cd)
Intermediate important metals
Arsenic (As)
Lead (Pb)
what do the relevant class B and intermediate metals all have in common (for this class purposes)
all of these elements bind with sulfur (thiols) in biological systems
thiol groups
- present in residues of proteins and enzymes
- important for structure and function: located within the active sites of enzymes, and directly involved in catalysis
molecular targets of Class B and Intermediate elements
thiols
metal ligand interactions
animal cells are heterogenous that have many sites for metal binding
also have metal binding proteins: metallothionein: which can detoxify metals to some extent
- if too prevalent, metals overwhelm antioxidant defenses and result in oxidative stress
metallothionein (MT)
- low molecular weight protein
- 30% of amino acid residues are cysteine (therefore MT has a large # of thiols)
- 1 molecule of MT can bind 7 atoms of Cd and other metals
- certain metals are strong inducers of MT
- MT can sequester heavy metals and prevent oxidation of critical protein
what is special about MT binding?
1 molecule of MT can bind 7 atoms of Cd and other metals
what is the purpose of binding “prevalences”?
- help determine how metals are distributed in animal cells
- used when treating patients in a clinical setting
- detoxification involves preventing inappropriate binding of non-essential metals with sensitive sites
adverse outcome pathway
framework for understanding toxic effects at various levels of biological organization
- effects to individuals and populations are anchored to toxicant/molecular interactions
Mercury (Hg) as a global contaminant
- emission sources include mining, coal combustion, volcanic eruptions
- elemental mercury vapor can travel for up to a year or more in the atmosphere!!
- deposits where it rains most!
various forms of Mercury (Hg)
- Metallic: Hg0
- Inorganic: Hg II, HgS, HgCl2
- Organic: MeHg
toxicity of these various forms differ (MeHg is most toxic)
what form of mercury is most toxic?
Methyl Mercury: MeHg: is bound to carbon
metallic mercury (Hg0)
- lipid soluble
- not well absorbed in Gi
- readily absorbed as vapor in lungs
- neurotoxicant!!
- oxidized to HgII in blood, then accumulates in kidneys
- toxicities rare because it is the “visible” form (liquid metal)
organic mercury
- highly bioavailable- cross the BBB!!!
- 90-95% absorbed in the GI
- potent neurotoxicant especially for the developing fetus
inorganic mercury
- damage to kidneys! filters and accumulates
- more readily absorbed in GI than metallic
- oral route damages GI and kidneys
what form of mercury crosses the BBB and is neurotoxic esp for the developing fetus?
organic: MeHg
what form of mercury is found highest in the kidneys?
inorganic
methylmercury uniqueness
- the structure resembles the essential amino acid methionine
- amino acid transporter helps cysteine-MeHg cross the BBB through “molecular mimicry”
methylmercury properties
- elemental Hg oxidized to inorganic Hg in atmosphere
- inorganic Hg is removed from atmosphere during dry or wet deposition
- inorganic Hg is converted by bacteria to MeHg (mainly in aquatic environments)
- MeHg bioaccumulates in organisms and biomagnifies in food webs
where does MeHg bioaccumulate?
in organisms and biomagnifies in food webs
“dancing cat” disaster in Japan - Minamata
- cats were eating fish and died of mercury poisoning because a factory had been contaminating water
- excessive salivation, convulsions, collapsed dead, jumped into sea to drown
Minamata - alerted world to MeHg toxicosis!
clinical signs of Hg toxicity
- ataxia
- salivation
- blindness
- tremor/convulsions
- GI disturbance (inorganic)
- kidney damage (inorganic and elemental)
treatment of mercury toxicosis
- acute exposure, inorganic Hg: egg white, charcoal followed by DMSA or Succimer: lots of thiols
- MeHg often futile by time of clinical signs: too much in brain
bind up and get it away!
Hg poisoning in domestic animals
uncommon, but related to obsolete products
- ex dog broke into a barometer: necrosis in liver and kidney
- sled dogs in Yukon exposed to MeHg thru consumpion of fish! MeHg is more bioavailable than inorganic or elemental Hg
Cadmium
- soft, silver-white metal
- cadmium oxide, cadmium chloride, cadmium sulfate
- used in batteries, semiconductors, solar cells, plastics
- enters environment from coal combustion, mining activities, zinc smelting, sewage sludge as fertilizers
how do animals get exposed to cadmium?
- Cd containing mineral supplements in feed and application of phosphate fertilizers and sewage sludge on pastures/fields increases Cd in soils
- cattle grazing on sewage sludge-treated pastures
cadmium + tobacco
- some plants concentrate Cd from soils (clover, willow, tobacco)
- cadmium exposure and accumulation in cats play a role in feline hypertension
- cigarette burning! generates high levels of calcium oxide
cadmium PK
- GI absorption low: 5-8%
- dietary deficiency of calcium can increase uptake
- cadmium may replace copper and zinc at binding sites, causing an induced copper deficiency?
what metal can cause an induced copper deficiency?
cadmium! may replace copper and zinc at binding sites
where does cadmium bind?
plasma proteins (thiols) and RBC and is distributed to liver and kidney
clinical signs of cadmium toxicity
aggression, anxiety, GI disturbance, mild anemia
treatment of cadmium toxicity
- minimize/reduce exposure
- EDTA, BAL, DMSA are not effective (chelating agents)
- BAL can increase nephrotoxicity!!!
arsenic properties
- metalloid, but often classified as a metal
- inorganic and organic forms
- binds to sulfur in cells
- toxicity varies with form
what form of arsenic is the most toxic?
Arsenite (As+3) is more toxic than Arsenate (as+5) and inorganic forms are more toxic than organic forms (opposite of mercury!)
what is more toxic, arsenate or arsenite?
arsenite: As+3
order of toxicity of arsenic from greatest to least
As+3 > As+5 > O As+3 > O As+5
sources/uses of As
- insecticides
- immiticide (heartworm)
- herbicides
- treated wood !
- water
what does Arsenite (As+3) do?
binds with lipoic acid (cofactor in TCA cycle) thus effecting energy metabolism
what does arsenate (As+5) do?
uncouples oxidative phosphorylation because it competes with phosphate during conversion of ADP to ATP
target tissues of Arsenic (AS)
those with high oxidative energy use: actively dividing cells:
- intestinal epithelium
- liver
- kidney
- spleen
- epidermis
clinical signs of As toxicity
sudden death, abdominal pain/colic, V+, staggering gait, watery D+, dehydration, resp distress
- alot to do with GI!
treatment of As toxicity
- minimize exposure
- GI decontamination
- IVF
- Dimercaprol (BAL- British)
- Dimercaptosuccinic acid (DMSA, Succiner)
get thiols in there to bind to arsenic!
how would animals get lead (Pb) toxicosis?
- batteries!!
- lead weights, curtains, fishing, paints, shot, pastures near Pb smelters, leaded gas
what is the highest frequency metal that causes toxicity in animals?
LEAD!!
Pb poisoning in domestic animals is encountered how often
OFTEN! greatest frequency compared to any other metal
what is the main source of lead poisoning in american cattle?
lead-acid batteries found on agricultural pasture land!
main entry thru GI
lead metabolism
- organic lead compounds are more bioavailable than inorganic or metallic
- calcium deficiency leads to increased absorption
- cattle and dogs are most commonly reported with Pb intoxication
clinical signs of Lead toxicity
neurotoxicity and blindness!
- aggression, blindness, head pressing, circling, roaring, anorexia, anemia
treatment of Lead (Pb) toxicity
- remove Pb objects from GI tract!
- Ca-EDTA: chelating agent!
- DMSA, Succimer
what abnormalities on a blood smear could make you suspicious of lead poisoning?
pyknotic nuclei, polychromasia, basophilic stippling
