Genetics and Animal Species Affect Copper Requirements
and Susceptibility to Copper Toxicosis
Jerry W. Spears, Ph.D.
North Carolina State University
Copper is a trace mineral required by all animals. It is needed by enzymes in the body that are involved in an array of functions such as energy metabolism, structural stability of collagen in bone and elastin in the heart and blood vessels, pigmentation of hair and wool, and the body’s antioxidant system. Although copper is essential in small amounts, copper toxicosis can be a problem, especially in sheep.
To understand why copper toxicosis occurs it is important to comprehend the critical role of the liver in regulating copper metabolism. A portion of the copper in the diet is absorbed from the small intestine and transported to the liver. In the liver copper can be stored, used by the liver, transported to other tissues for utilization in copper functions, or be excreted in the bile. Copper excreted in the bile goes back into the small intestine and is primarily excreted in the feces. Removal of liver copper by bile is the major way that liver copper levels are regulated. Swine and poultry are very efficient in regulating their liver copper levels. Ruminants have a limited ability to excrete copper in their bile, and as a result, are less able to regulate their liver copper levels. If ruminants are fed dietary copper well above their requirement, copper levels can increase in the liver to the point that toxicity occurs. This increase in liver copper usually occurs over a period of weeks or even months. When copper concentrations in the liver reach a high level (generally 1000 mg Cu per kg or higher on a dry matter basis) copper is suddenly released from the liver into the blood, and clinical signs of copper toxicosis become evident. The sudden release of copper from the liver is referred to as the hemolytic crisis because the release of copper into the blood causes damage and destruction of red blood cells. Liver damage occurs before the hemolytic crisis, but generally clinical signs are not apparent until after the hemolytic crisis. Clinical signs of copper toxicosis in sheep may include dullness, excessive thirst, anorexia, dark-colored urine, sunken eyes with a chocolate-brown color, and usually death (NRC, 2005).
It is well known that animal species differ in their requirement for copper and also in their susceptibility to copper toxicosis. With trace minerals, genetic differences within an animal species are generally not considered to be of practical importance. However, in the case of copper, genetic variation is an important factor in some animal species that can affect copper requirements, as well as, the likelihood of copper toxicosis.
Copper requirements of poultry and swine are relatively low, in the range of 4 to 8 mg Cu per kg of diet, and copper deficiency is unlikely (Suttle, 2010). Swine and poultry also can tolerate high dietary copper concentrations so copper toxicosis is not a problem. In fact, supplementing copper to swine and poultry diets at high levels (100 to 250 mg Cu/kg of diet), well in excess of their nutritional requirement, can stimulate growth and feed efficiency. Copper requirements of horses are not well defined but appear to be higher than for swine and poultry.
Absorption of copper from the small intestine is considerably lower in ruminants, once their rumen develops, than in nonruminants. Furthermore, high concentrations of sulfur, molybdenum, or iron in the diet reduce copper absorption in ruminants. As a result ruminant animals (cattle, sheep and goats) generally require more copper than poultry and swine, and they are more likely to develop copper deficiency. Since copper requirements of ruminants are greatly affected by the level of sulfur, molybdenum, and iron in the diet, it is impossible to give a precise requirement for ruminants. Requirements for copper in ruminants can vary from 4 to over 20 mg Cu/kg of diet. Copper requirements are higher in cattle and goats than in most breeds of sheep.
Sheep are much more likely to develop copper toxicosis than cattle or goats. Copper toxicosis is a practical problem in some breeds of sheep, and therefore, many commercial salt-mineral mixtures marketed forsheep do not contain any supplemental copper. If the level of molybdenum and sulfur in the diet is low, as little as 10 mg Cu/kg of diet can cause toxicosis in certain breeds of sheep (NRC, 2005).
A study conducted in Greece (Zervas et al., 1990) clearly indicated that goats can tolerate much higher levels of copper than sheep. In this study Boutsiko lambs and native breed goats, that were the same age (12-weeks-old), were fed a diet supplemented with 0, 30 or 60 mg Cu/kg of diet for 137 days. Based on blood analysis, lambs supplemented with 30 or 60 mg Cu/kg of diet were exhibiting liver damage, due to high liver copper levels, after day 64 of the study. Two of the six lambs supplemented with the high level of copper died from copper toxicosis on days 67 and 73, and one lamb fed 30 mg Cu/kg of diet died on day 88. Goats fed the same diets showed no signs of copper toxicosis during the 137-day study. At the end of the study, lambs had stored 6 to 9 times more copper in their liver than the goats. Crossbred (Boer x Brush) goats showed no signs of copper toxicosis or liver damage when fed a diet containing 36 mg Cu/kg for 88 days (Luginbuhl et al., 2000). Research with Nubian and Boer x Spanish goats also indicated that they can tolerate relatively high levels of copper (Solaiman et al., 2006).
GENETICS EFFECTS ON COPPER METABOLISM
The first evidence for genetic differences in copper metabolism came from clinical findings in humans (Cator and Mercer, 2005). Two genetic disorders of copper metabolism occur in humans. Menkes disease is a rare genetic disorder that results in severe copper deficiency due to an inability to absorb and utilize copper in the body. This disease occurs in infants with an estimated occurrence of between 1 in 100,000 to 1 in 298,000 live births. Even injections of copper are not successful in treating this disorder, and infants eventually die at a young age from copper deficiency.
Wilson disease in humans results in copper toxicosis due to impaired excretion of copper from the liver (Cater and Mercer, 2005). This condition is more common than Menkes disease with an estimated frequency of 1 in every 30,000 people. When liver damage occurs, Wilson disease is generally detected and can be treated by administering compounds that bind and remove copper from the liver.
A genetic disorder occurs in certain breeds of dogs that results in copper toxicosis. Genetic differences in copper metabolism of sheep and cattle are less dramatic than those associated with Menkes or Wilson disease. Genetic variation among animals is found in all breeds of sheep and cattle. However, differences in copper metabolism between breeds of sheep and cattle have been described that can affect copper requirements or susceptibility to copper toxicosis.
Genetic differences in copper metabolism among sheep breeds are important under practical conditions. Early observations indicated that the incidence of copper deficiency and copper toxicosis in sheep varied among breeds. Crossing of two sheep breeds results in offspring that are intermediate in copper status to that of the pure breeds. The Texel breed is one of the most susceptible to copper toxicosis (Suttle et al., 2002). Woolliams et al. (1982) evaluated liver copper levels in lambs born to Scottish Blackface ewes that were mated to sires of Scottish Blackface, East Friesland, Finnish Landrace, Suffolk or Texel breeds. At weaning lambs were fed diets containing 12 or 20 mg Cu/kg for 13 weeks. Texel-sired lambs had the highest liver copper concentrations followed by Suffolk-sired lambs at the end of the 13-week feeding period. Finnish Landrace and East Friesland-sired lambs were intermediate and Scottish Blackface had the lowest liver copper levels. Scottish Blackface sheep can tolerate higher copper levels than most breeds; however, they are also one of the most susceptible breeds to copper deficiency. In crossbred lambs fed diets low in copper (4 to 5 mg Cu/kg diet), Texel-sired lambs had the highest liver copper followed by Dorset- and Montadale-sired lambs with lambs from Finnsheep or Romanov rams being lowest (Littledike and Young, 1993).
Differences in copper metabolism between cattle breeds are not as dramatic as those observed in sheep. Simmental and Charolais cows and their calves had lower plasma copper concentrations than Angus when fed diets low in copper (Ward et al., 1995). When the diet was supplemented with 10 mg Cu/kg to provide adequate copper, plasma copper concentrations were similar for the three breeds. Mullis et al. (2003) evaluated the copper requirements of Angus and Simmental females. Based on liver and plasma copper concentrations, they concluded that the minimal copper requirement was higher in Simmental. Littledike et al. (1995) compared liver and plasma copper levels in beef cows of different breeds that were fed a common diet. The diet fed in this study was adequate in copper, based on liver copper stores at the end of the study. Limousin cows were found to have higher liver copper concentrations than Hereford, Charolais, Simmental, Braunvieh, Gelbvieh, Pinzqauer, and Red Poll cows. Liver copper also tended to be lower in Angus compared to Limousin cows. Plasma copper concentrations were not affected by breed.
Limited research suggests that breed may affect susceptibility of cattle to copper toxicosis. Jersey females accumulated more copper in their liver than Holsteins when fed diets high (80 mg Cu/kg of diet) in copper (Du et al., 1996). This suggests that Jerseys may be more sensitive to copper toxicosis than Holsteins. In a natural outbreak of copper toxicosis on a beef cow-calf operation with two different breeds, 32% of Angus calves were affected but only 5.5% of Charolais calves (Sargison and Scott, 1996).
An inherited copper toxicosis occurs in Bedlington terrier dogs (Hyun and Filippich, 2004). This genetic disorder is widespread and affects an estimated 69% of all Bedlington terriers in the US (Twedt et al., 1979). Copper toxicosis has also been reported in Sky terriers, West Highland White terriers, Doberman pinschers, and Dalmatians; but the disorder is much rarer in these breeds. With inherited copper toxicosis in dogs, copper accumulates to extremely high levels in liver resulting in liver damage. The disorder is due to a reduced ability to excrete copper in the bile. Copper toxicosis in dogs can be treated if detected in time. Treatment of copper toxicosis involves reducing copper intake and absorption, and reducing liver copper concentrations (Hyun and Filippich, 2004). Liver copper is reduced by injecting compounds that bind liver copper and cause it to be excreted. Once liver copper concentrations are reduced, dogs are fed a copper restricted diet. A high level of zinc is also frequently used to reduce absorption of copper from the diet.
Copper is required in small amounts by all animals. However, copper is also toxic at relatively low levels in some animals, especially sheep. Requirements for copper and susceptibility to copper toxicosis are affected by animal species and also genetics. Copper requirements are relatively low in poultry and swine, and these species can tolerate high levels of copper in their diets. Copper deficiency is more likely to occur in ruminant animals because their requirements are greatly affected by the level of sulfur, molybdenum, and iron in pastures or feed ingredients. Ruminant animals are also more susceptible to copper toxicosis. In sheep, copper requirements and susceptibility to copper toxicosis are affected by breed. Some breeds of sheep are extremely sensitive to copper toxicosis. Copper requirements as well as susceptibility to copper toxicosis also appear to be affected by breed in cattle. A genetic disorder occurs in some breeds of dogs (primarily Bedlington terriers) that results in copper toxicosis.
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