Metals and Metalloids II Flashcards
Chromium (Cr)
- metallic element that can exist in 6 valence states
- hexavalent chromium (CrVI/Cr+6) is a recognized carcinogen!
- exposure to CrVI in dust has increased risk of lung cancer and dermatitis
- trivalent Cr is not super concerning
- essential trace element that functions in a number of metabolic processes: potentiates activity of insulin!
cellular fates of chromium
- Cr VI gets access to the inside of cells: generates ROS, forms conjugates that bind to thiols, can move nucleus and mess with stuff, genotoxicity, etc
- enters thru active transport
acute chromium toxicosis
- inflammation and damage to the GI
- kidney damage
- liver damage
^ most blood flow: easy to see damage!
chronic chromium toxicosis
- gastroenteritis
- dermatitis
toxic events associated with chromium
- oil field contamination associated with death
- dairy cattle deaths from solution of strong oxidizing chromium was dripped on cattle and dermally absorbed
copper exposure (Cu)
ubiquitous in the diet, excess exposure is often due to over-supplementation
- some foods naturally high in copper: liver, whole grains
- over supplementation in mineral, feed, injection, palm kernal extract
what breed has a copper toxicity associated with chronic hepatitis
bedlington terriers: inherited metabolic defect resulting in impaired biliary copper excretion
COMMD1
bedlington terriers and copper
- inherited metabolic defect resulting in impaired biliary copper excretion
- gene responsible is COMMD1
- humans have genetic pre-disposition to toxicity with mutations in ATP7B (Wilson disease)
mechanism of copper toxicity
- normally, free copper concentrations in cell are kept low thru copper-binding proteins
- when they get too high and saturate the copper reservoirs, “free” copper ions exist in the cell
- free ions can undergo redox reactions leading to damage to membranes, proteins, and nucleic acids = through ROS!!
what does accumulation of copper in bedlington terriers lead to?
chronic hepatitis! may progress to cirrhosis
anorexia, lethargy, V+, weight loss
breeds susceptible to copper poisoning
- American Cocker Spaniels
- Bedlington Terriers – COMMD1 mutations
- Doberman Pinschers – ATP7A and ATP7B mutations
- Keeshonds
- Labrador Retrievers – ATP7B polymorphism and RETN mutations may play a role
- Skye Terriers – Defect in biliary copper transport
- West Highland White Terriers
all carry a genetic defect in copper deposition leading to high hepatic copper levels and chronic hepatopathy
major toxicosis of copper in dogs
chronic heptatitis
initial clinical signs of copper chronic hepatitis in dogs
salivation, vomiting, nausea
clinical signs of advanced copper toxicosis in dogs
- polyuria and polydipsia
- icterus and D+
- ascites
what is the most susceptible farm animal to copper poisoning?
sheep!! > goats > cows > pigs
sources of copper poisoning in sheep and goats
- trace mineral supplemented salt formualted for cattle or horses
- vitamin/mineral supplements intended for other animals
- Complete feed for swine, horses, poultry or cattle
- Pasture fertilized with swine manure
- Pasture fertilized with poultry litter
- Copper-containing foot baths for cattle
what plants can lead to copper toxicosis? how?
Senecio, ragworts, groundsels, contain alkaloids causing liver damage and can lead to copper release from damaged liver leading to elevated blood levels = hemolysis
signs of copper poisoning in ruminants
- weakness, panting, dull attitude
- pale mucous membranes
- icterus of mucous membranes
- dark brown/red urine
- abortion, death
how do you treat copper toxicosis in dogs?
- feed low copper diet (organ meat avoidance)
- use of oral chelating agents to enhance urinary elimination: D-penicillamine, Trientine Hydrochloride
- monitor liver enzymes every 6 months!
- liver biopsy
- add elemental zinc as dietary supplement
where will mobilized copper end up? (hint where you should look on necropsy)
mobilization of copper from liver may reduce levels to normal, but the mobilized copper will show up in the kidneys - bright red!
what are chelating agents that can help enhance urinary elimination of copper?
- D-penicillamine
- Trientine Hydrochloride
form cage around ions and carry them around
why would adding zinc to diet help with copper toxicosis?
increases expression of metallothionein to bind Cu2+ in enterocytes and increase excretion of Cu2+; poop it out!
- MT preferentially binds copper ions due to increased affinity = increased excretion of dietary copper in feces
treatment of copper toxicosis in ruminants
- not often successful :(
- fluid therapy, blood transfusion
- ammonium or sodium molybdate and sodium thiosulfate used as a drench
- ammonium tetrathiomolybdate
- increase molybdenum in diet to 5 ppm
- supplement zinc in diet to 100ppm
how does increasing molybdenum and sulfur in the diet of ruminants help copper toxicosis?
molybdenum and sulfur form thiomolybdate in the rumen and form an insoluble complex with copper. therefore adding molybdenum and sulfur to the diet of ruminants decreases copper toxicity
molybdenum
- low concentrations in most dietary constituents
- excess intake from plants with high concentrations
- grown in soils naturally high in Mo
- contamination by mining or smelting
toxicity of molybdenum (Mo) is intricately linked to
its interactions with copper and sulfur
predominant manifestations of Mo poisoning are associated with secondary copper deficiency
how can molybdenum lead to a secondary copper toxicity?
too much Mo = all Cu2+ bound up = secondary Cu2+ deficiency!
molybdenum ADME in monogastrics
- absorbed thru GI
- widely distributed, but has highest concentrations in kidney, liver and bone
- thiomolybdate will bind copper and make it an unavailable complex
- rapidly eliminated in both urine and biliary routes
molybdenum ADME in ruminants
- absorption DELAYED but quickly appears in blood: formation of thiomolybdates in the rumen is the reason for delayed absorption
- distribution and elimination is similar to that seen in monogastrics
acute poisoning of molybdenum
rare, different clinical signs than chronic
- ruminants more sensitive than monogastrics!
- feed withdrawal, lethargy, weakness, ataxia and recumbency hind limb –> front
pathology of acute molybdenum toxicity
- hydropic hepatocellular degeneration/necrosis
- hydropic degeneration/necrosis of the proximal and distal renal tubules
chronic molybdenum toxicity
- tiny amounts for sheep and cattle! 2.5-20 for sheep, 2-400 for cattle
- also dependent on dietary Cu and Sulfur! so therefore there are 3 classes of Mo poisoning in ruminants
ruminants succumb to molybdenosis with Mo intake is greater than _____________
20 ppm in diet
when that high, won’t get enough Cu2+!
what are the 3 classes of Mo poisoning in ruminants?
- Dietary Mo > 20 ppm
- Low Cu: Mo ratio (<2:1)
- high dietary sulfur with normal Cu and MO
teart
term used to refer to soil or plants with unusually high Mo, and thus the term “teart scours” is commonly used to describe the D+ associated with excessive Mo uptake
clinical signs of chronic Mo poisoning
- “teart”
- Poor weight gain
- Weight loss
- Anemia
- Poor immune function
- Decreased milk production
- Achromatrichia (loss of pigment in hair)
- Alopecia
- Limb deformities
- Bone fractures
- Periostosis
- Lameness
- Poor reproductive performance
in general, clinical signs can be treated with copper supplementation- but don’t induce copper toxicosis!!
what is the optimal Cu:Mo ratio in feed?
6:1 is optimal!
< 2:1 molybdenum toxicosis
> 15:1 chronic copper toxicosis
iron (Fe)
- essential element for animal and plant life
- 4th most abundant element on earth
- incorporated into many proteins where it plays a critical role: hemoglobin, myoglobin, P450 enzymes, electron transport proteins: energy metabolism!
where does iron (fe) play a critical role?
Incorporated into many proteins where it plays a critical role
* Hemoglobin – binds O2 in the blood
* Myoglobin – binds O2 in muscle
* P450 enzymes – critical role in metabolism
* Electron transport proteins in the mitochondria – energy formation
why don’t you want iron floating around?
Iron is highly regulated and controlled within living systems. Iron is essentially sequestered
with proteins everywhere in the body with essentially no “free” iron just floating around
- bound to transferrin in blood
- bound to lactoferrin in milk
- 80% to hemoglobin, myoglobin , etc
MOA of iron toxicity
- super active in reduction and oxidation (redox) reactions!! = very good at gaining and losing electrons
- but when electron exchange happens in an undirected fashion, the electron acceptor is often H2O2 which is formed from other ROS
= Fenton Chemistry/Fenton Reaction
exposures to iron toxicity
- ingestion of iron containing vitamins: dogs
- iron supplements: cattle, horses, pigs
- molluscicides with iron phosphate or EDTA
clinical signs of iron toxicity
- necrosis of GI cells: reacts with first thing it hits: GI!
- fluid loss
- cardiotoxicity
treatment of iron toxicity
- limit absorption: GI decontamination
- enhance urinary elimination: chelating agents like DFO: deforoxamine IV
- symptomatic and supportie care
manganese Mn
- essential element for maintaining function of biochemical and cellular rxns
- metalloenzymes contain Mn!
- manganese-superoxide dismutase
- arginase
- phosphoeonol-pyruvate carboxylase
- glutamine synthase
also good at moving e- around
manganese is found in
Food (nuts, cereals, grains, fruits, vegetables and teas) Water
Animal Feed
Dry Cell Batteries
Brick Coloring Fertilizers
how does manganese toxicity occur?
if dietary concentration exceeds max tolerable levels
- considered one of the least toxic elements
manganese toxicity in animals
Decreased growth in swine at 500-3000 ppm
* Lethal to pre-ruminant calves at 5000 pp
rats can tolerate the most, cattle the least
what are the primary toxic effects of manganese?
neurological: mechanism is varied: disruption of proteins in brain, mitochondrial calcium flux, sequestration
- oxidative stress and generation of ROS
clinical signs of manganese toxicity
- reduced appetite and growth rate
- anemia and abdominal discomfort
- abortions and cystic ovaries
- neuro syndrome of gait disorders in dogs
treatment of manganese toxicosis
- remove from further exposure
- chelation therapy: EDTA
- anti-oxidant therapy: vitamin E, N-acetylcysteine
- supportive and symptomatic care
zinc
- essential nutrient in mammals and birds
- component of 200 metalloproteins
- feed supplement
problems with toxicity generally occur with levels >1000ppm
when does toxicity of zinc occur?
at levels >1000pm
zinc toxicokinetics
- absorbed in GI by carriers
- stomach acid provides for rapid release from metal: pennies, galvanized steel, nuts and bolts
- often is in ointments for sunburn or diaper rash
- bioavailability is 25-50%: decreased by phosphates/calcium (bind it)
- peptides, amino acids and EDTA can increase absorption: don’t give!
MOA of zinc toxicity
- unknown: many roles in cell death and protection, as well as interactions with copper
- maybe oxidative stress?
clinical signs of zinc toxicity in dogs and cats
V+/D+, red urine, icterus, liver failure, kidney failure, anemia
most species display some degree of hemolytic anemia with an erythrocytic regenerative response
clinical signs of zinc toxicity in livestock
FOALS SUSCEPTIBLE!
- nonpainful joint enlargement that progresses to reluctance to rise, stiff gait and increased joint fluid
other livestock have lethargy, anorexia, anemia, icterus
zinc toxicity treatments
- zinc objects like pennies/bolts are mobilized due to acidity in stomach: so stop that!
- antacids
- proton pump inhibitors
- removal of foreign body
supportive care: IVF, blood, sucralfate for Gi bleeding, CBC and serum chem to monitor liver and kindeys
chelation therapy in zinc toxicity
controversial: addition of chelators can facilitate zinc ABSORPTION from the stomach if FB are still present and eluting zinc
once FB is removed, then chelation therapy might be good to increase renal elimination
chelator of choice: Ca-EDTA
monitor zinc levels in plasma
