This may contribute to the sheep's susceptibility to Cu poisoning

Sheep store excess Cu in the liver. Sudden breakdown of this storage releases Cu from the liver into the blood causing the "hemolytic crisis"

Excretion of Cu

1. Excretion of Cu in the bile may be a principal homeostatic control mechanism for Cu in nonruminants
   1. In nonruminants, Cu is excreted in bile via sequestration of protein-bound Cu (metallothionein) by the lysosomes
   2. Cu excreted into the small intestine in bile is poorly reabsorbed
   3. Urinary Cu excretion is low in nonruminants

Storage of Cu in the liver (hepatic metallothionein?)

1. Pigs have an unusually high storage capacity for Cu in the liver, lungs and kidneys. A high Cu concentration in these organs does not seem to have a deletrious effect
2. Cu toxicity in pigs is low compared to other species
3. Increased Cu intake increases Cu turnover in various organs of the pig
4. Sheep can store Cu in the liver up to a point

VI.  Interactions with Other Elements (See Suttle, N.F. 1991. The interactions between copper, molybdenum, and sulfur in ruminant nutrition. Ann. Rev. Nutr. 11:121-140)

1. Sulfur and molybdenum in ruminants
   1. S and Mo within normal dietary range (0.1 - 0.4% S and 0.4 - 4.5 ppm Mo, dry basis, can affect Cu availability
      1. S exerts a predominant and independent effect
      2. Mo has a lesser and S-dependent effect
      3. Mo depletes liver Cu severely only when adequate S is present
   2. Both S and Mo must be elevated for sheep to develop dystrophic wool (a sign of Cu deficiency)
   3. Mo and S together elevate plasma total Cu without affecting ceruloplasmin
   4. Increase is due to TCA insoluble Cu.
   5. Several mechanisms have been proposed to explain the 3-way interaction
      1. Blocking of Cu transport across membranes
      2. Competition for a common carrier system
      3. Lower Cu absorption due to insoluble Cu sulfides or Cu-Mo complexes
      4. These mechanisms are all consistent with reduced liver Cu but why is plasma Cu elevated?
2. Effect of other dietary components
   1. Selenium: different effects have been reported in ruminants and nonruminants
      1. Small oral doses of Se improved growth and tissue Cu in lambs
      2. Rats fed diets low in Se appear to have a lowered threshold of Cu toxicity
   2. Manganese: Supplemental Mn may also improve Cu absorption in lambs
   3. Iron: Ceruloplasmin is a molecular link between Cu and Fe metabolism
      1. Cu, as ceruloplasmin, is necessary for Fe utilization
      2. Plasma Fe of Cu deficient lambs is often low
      3. Excess dietary Fe (800 ppm) can reduce plasma ceruloplasmin in calves to levels indicative of severe Cu deficiency
   4. Cobalt: Supplemental Co for lambs with Co deficiency combined with Mo/S induced Cu deficiency, reduced gains and lowered liver Cu.  In rat, cobalt increased urinary Cu excretion 4-fold (J. Nutr. 119:1259-1268. 1989)
   5. Zinc: Zn at 10x dietary requirement reduces Cu toxicity
      1. Reduces total Cu content of liver
      2. Increases Cu content of sheep liver metallothionein
   6. Tin: Rats fed high Sn diets accumulated less Cu in plasma, kidney & liver (J. Nutr. 115:615. 1985)
   7. Magnesium. Fertility of cows was improved when they were supplemented with both Mg and Cu but not with Cu or Mg alone (J. Dairy Sci. 70:167.1987)
      

      Control	Cu	Mg	Cu+	Mg
      First conception rate (%) Conception by 150d postpartum (%) Services per conception (no.)	33 59 1.9	27 62 1.9	38 63 2.0	57 84 1.6

   8. Cadmium: Cu absorption is decreased when supplemental Cd is fed.  Decreased Cu absorption is associated with Cu incorporation into metallothionein induced by Cd
   9. Protein: Solubility of Cu in rumen and abomasal contents decreases proportionally with increasing dietary protein
   10. Ascorbic acid (J. Nutr. 117:2109-2115. 1987)
       1. Papers are cited which showed apparent antagonism of ascorbic acid toward Cu metabolism
       2. In humans, moderate intakes of ascorbic acid reduced ceruloplasmin oxidase activity specifically
       3. However, ascorbic acid did not depress Cu absorption or overall body Cu status
   11. Ascorbate enhanced uptake of Cu by cells from ceruloplasmin. (J. NUtr. 119:779-784, 1989).  Ascorbate may play a role in ceruloplasmins delivery of Cu to extrahepatic tissues
   12. Dietary fructose increases severity of Cu deficiency. Ingestion of fructose as compared to starch increases Cu requirement. (J. Nutr. 119:453-457. 1989)

VII.  Cu Requirements

1. If the Natl. Acad. Sci. recommendation of 2-3 mg Cu/d for adult human is correct, intakes of both men and women reported by Patterson et al. (Am. J. Clin. Nutr. 40:1297-1403. 1984) are low. They reported 1.4 mg/d for males and 1.1 mg/d for females.
2. Estimation of requirements
   1. Subjects are fed different amounts of Cu and some function of absorption or retention which when regressed on intake gives a straight line is determined.
      1. Maintenance = intake at 0 retention
      2. Endogenous loss - retention at 0 intake
   2. Suttle determined Cu requirements of cattle by an IV repletion technique based on the assumption that total net Cu requirement approximates the daily rate at which the injected dose of Cu is used by calves on an extremely Cu deficient diet
3. Measurement of Cu status
   1. Liver Cu is a good criterion of Cu status.
   2. Blood plasma is more easily obtained and can be used to indicate a deficiency but it does not closely reflect higher Cu stores in liver
   3. Serum ceruloplasmin is often used
4. Recommended allowances of Cu
   1. Human...............................2 mg/d
   2. Swine & poultry rations.....4 to 5 ppm
   3. Ruminant rations...............8 to 20 ppm
      1. Adequate when dietary conditions are optimal for utilization of Cu
      2. Requirement for ruminants may be increased by dietary Mo differences of only 1 ppm

VIII.  Dietary Sources of Cu

1. Most feeds. Plant materials contain Cu which has an affinity for-plant lipids
   1. Cu content of oil seed meals is relatively high (50-100 ppm).
   2. There is evidence that water-soluble complexes of Cu in herbage are used more efficiently by the rat than are many inorganic sources
   3. Cu proteinate may be used more efficiently than inorganic sources by cattle when excess Mo is a problem
   4. Cu availability to ruminants is closely related to forage quality
2. Inorganic Cu salts (in order of availability)- Cu chloride, sulfate, nitrate, carbonate, oxide
3. With high dietary Mo, Cu may be more available from the proteinate than from the sulfate

IX.  Cu Deficiency

1. Acute diarrhea can deplete Cu in infants (Nutr. Rev. 48:19. 1990)
2. Human diseases associated with hypocupremia
   1. Menkes syndrome
      1. Lethal X-linked inherited neurodegenerative disease
      2. Results from a defect in the low molecular weight ligand that transports Cu into cells
      3. Leads to accumulation of excessive Cu in (or on) the cells
      4. Overall Cu deficiency is imposed on this situation
   2. Wilson's disease
      1. Failure of use of Cu for ceruloplasmin biosynthesis
      2. Cu accumulates in the liver and brain but is lacking in other tissues
3. Cu status of human subjects decreased by Zn supplements (Fischer et al., 1984. Am. J. Clin. Nutr. 40:743-746)
   1. Plasma Cu levels or ceruloplasmin were not affected
      1. For ferroxidase (ceruloplasmin) activity to be lost, two of the six Cu atoms associated with ceruloplasmin must be lost
      2. Since most of the plasma Cu is associated with ceruloplasmin, and since plasma Cu did not change, sufficient Cu was available to maintain ferroxidase activity
   2. Plasma Zn was increased
   3. Cu, Zn-superoxide dismutase decreased after 6 wk
      1. Cu is added to the apoenzyme superoxide dismutase at the time of erythropoiesis only
      2. If Cu is not lost from SOD during the lifespan of the erythrocyte, then it is likely Cu status for Zn supplemented individuals decreased well before the 6 wk without being apparent, due to the-long half-life of erythrocyte (only newly formed RBC would reflect lower Cu status)
   4. These results support the hypothesis that functional nutritional indices, such as SOD activity in the case of Cu status, are more sensitive than static indicators, such as plasma or tissue Cu levels
      • See J. Nutr. 118:859, 1988. In studies with rats, a 10-fold reduction in hepatic Cu only resulted in a 2-fold reduction in SOD activity. In this regard, SOD appears to be given high priority with respect to the utilization of cellular Cu
      • See J. Nutr. 120:88,1990. Cu deficient rats has smaller norephinephrine pool possibly due to limiting dopamine-b-monooxygenase activity
      • See J. Nutr. 119:1259-1268, 1989. Co increased urinary excretion of Cu 4-fold without an accompanying loss of Zn such as accompanies use of pennicillamine. Zn retention occurred with Co treatment, most likely due to cobalt mediated induction of metallothionein in the liver. Use of small amounts of Co may have clinical potential in elm·nation of Cu in Cu-overload disorders.
4. Effects of Cu and/or Fe deficiency on Fe utilization by rats (Cohen et al., 198~. J. Nutr. 115:633-649) Data from 49th day
   

   Dietary		Status	Plasma		Liver		Ferroxidase (ceruloplasmin)	Ascorbate	Hemoglobin	Liver Xanthine Oxidase
   Fe	Cu	Fe/Cu	Cu	Fe	Cu	Fe
   			mg/g wet		IU/mol		Mg/dl
   120 25 10 120 25 10	10 10 10 0 0 0	A/A M/A L/A A/D M/D L/D	1.20 1.05 0.95 0.06 0.05 0.03	4.36 2.67 0.91 2.37 1.48 0.45	3.82 3.81 4.14 1.11 1.01 0.62	230.1 101.9 31.9 279.9 184.6 90.8	8.32 8.26 8.37 0.02 0.08 0.04	0.98 0.96 1.25 0.62 0.59 0.97	15.1 15.1 10.3 14.9 12.6 8.3	5.3 5.5 5.8 3.7 3.4 3.7

   1. At each dietary Fe level, plasma Fe was lower, but liver Fe was higher when Cu was deficient.
   2. Ferroxidase activity of Cu deficient groups was < 10% that of Cu-sufficient groups.
   3. When low or marginal levels of Fe were fed, hemoglobin levels in Cu deficient groups were lower than in Cu sufficient groups. When Fe was adequate, hemoglobin was similar in Cu deficient and Cu sufficient groups
   4. Cu deficiency tended to result in lower concentrations of ascorbate and activities of xanthine dehydrogenase
   5. These results show that Cu deficiency may impair liver Fe mobilization in the growing rat if dietary Fe is low
   6. Possible mechanisms include decreasd ferroxidase activity and/or decreased iron reduction by ascorbate or xanthine dehydrogenase
5. Cu deficiency symptoms
   1. Growth retardation
   2. Impaired feed conversion
   3. Diarrhea
   4. Rough hair coat; loss of crimp in wool due to loss of disulfide bond formation
   5. Faulty connective tissue due to lack of lysyl oxidase
      1. Leg abnormalities
      2. Thin, fragile bones that break easily
      3. Massive internal hemorrhages resulting from spontaneous rupture of a major blood vessel (falling disease)
   6. Anemia
   7. Reduced serum Cu and ceruloplasmin
   8. Reduced Cu and cytochrome oxidase in brain and liver tissue
      Increased liver Fe deposition
      Lack of pigmentation (decreased tyrosinase activity)
   9. Nervous disorders, neonatal ataxia in lambs - lack of myelination in the spinal cord

X.  Cu Toxicity

1. Nonruminants can tolerate more Cu than ruminants and effects of Cu toxicosis are less dramatic
   1. Maximum tolerable levels (NRC, 1980)
      1. Swine............250 ppm (Cu at this level can be growth stimulant)
      2. Horses..........800 ppm
      3. Chickens......300 ppm
      4. Turkey..........300 ppm
      5. Rabbit...........200 ppm
      6. Rats..............1,000 ppm
      7. Human..........10 mg/d
   2. Toxicity signs in nonruminants: Growth inhibition, anemia, muscular dystrophy, impaired reproduction, decreased longevity
   3. The range between inadequate and excessive Cu for ruminants can be relatively narrow. Maximum tolerable levels (NRC 1980)
      1. Sheep, 25 ppm; 10-15 ppm can be toxic to sheep if diets contain only 0.1 ppm Mo or if concentrates are fed for a prolonged period
      2. Cattle, 50-100 ppm; 50 ppm may be toxic to calves. Bovines are more resistant to Cu poisoning than sheep but are also more susceptible to Cu deficiency
   4. There are three relatively distinct stages in development of Cu toxicity in ruminants
      1. Gradual accumulation of Cu in the tissues, particularly the liver
         1. Blood Cu values are normal
         2. No clinical symptoms are evident
      2. Whole blood Cu may rise to twice normal levels
         1. Plasma bilirublin may increase
         2. Decreased liver function
         3. Increases in a variety of blood enzymes, plasma glutamic oxaloacetic transminase (PGOT), arginase
      3. The hemolytic crisis
         1. Whole blood Cu increases to 5-8 X normal
         2. Total hemoglobin drops but methemoglobin increases
         3. Increased oxidative state of blood
         4. Rise in serum creatine phosphokinase
         5. Erythrocyte distortion
         6. Blood glutathione concentration falls drastically
   5. Clinical symptoms
      1. Dullness
      2. Anorexia
      3. Dehydration
      4. Acute thirst
      5. Evidence of abdominal pain
      6. Jaundice
      7. Hemoglobinurea
   6. Postmortem findings
      1. Generalized jaundice, adipose tissue yellow
      2. Kidney has a distinctive black metallic sheen
      3. Urinary bladder and gall bladder are apt to be distended with dark-colored fluids
      4. Spleen is enlarged, soft and dark
   7. Histological changes
      1. Fatty liver
      2. Dilation and necrosis of renal tubules
      3. Petechial hemorrhages on the heart
      4. Splenic hemosiderosis
   8. Hemolytic crisis can be triggered by stress, change of environment, transportation, handling, etc.
2. Causes of Cu poisoning in ruminants
   1. Excessive Cu doses as anthelmintics
   2. Excessive Cu doses to correct Cu deficiency
   3. Accidental consumption of high Cu feed intended for swine
   4. Grazing too soon after application of Cu-containing fertilizer or high Cu swine or poultry manure to pasture
   5. Exposure to Cu-based fungicides or insecticides
   6. Hepatoxic plants may make the liver more susceptible to accumulation of Cu
   7. Prolonged feeding of concentrates to confined sheep can be dangerous, particularly if dietary Mo and S are low
3. Treatment or prevention of Cu poisoning in ruminants
   1. Supplementation of feed with 0.1 g ammonium molybdate + I g sodium sulfate/sheep/day to reduce liver Cu
   2. IV administration of thiomolybdate to reduce liver Cu
   3. Dietary Zn 5-10X requirement may have a protective effect against excessive dietary Cu

Trace Elements

• Boron
• Chromium
• Cobalt
• Copper

• Fluorine
• Iodine
• Iron
• Manganese

• Molybdenum
• Nickel
• Selenium
• Silicon

• Tin
• Vanadium
• Zinc
• Ultra Trace Elements

For individual consultation or questions about our products, call
1-800-628-0997

Click Here for a Printable Version of This Page

Site Map

Results Based Guarantee

Company Sites