Selenium deficiency in ruminants (Proceedings)

The classic nutritional research of Schwarz and Foltz (1957), showing that selenium (Se) was the critical element in Factor 3 that prevented liver necrosis in rats, began the work that has subsequently proven Se to be an essential nutrient for man, cattle, other grazing ruminants, and all vertebrates examined to date. Subsequently, Muth (1963) and Hogue et al. (1962) reported that Se and vitamin E administration prevented white muscle disease in young ruminants. In recent years, several Se-responsive conditions have been described in cattle and these have been reviewed (Maas, 1983). The Se-responsive conditions in cattle include, nutritional myodegeneration (white muscle disease), retained placenta, abortions, neonatal weakness, diarrhea, ill-thrift, infertility, and immune system deficits. Minimum dietary requirements of cattle for Se were developed from feeding and response trials. In 1973, Rotruck et al. published work that outlined a basic biochemical mechanism that accounted for the role of Se as an essential nutrient. That work (Rotruck et al., 1973) showed that Se was a component of glutathione peroxidase (GSH-Px; E.C. 1.11.1.9) in erythrocytes. It was later shown that GSH-Px contained 4 grams atoms of Se per mole of GSH-Px. For many years this was the only known biochemical role of Se, and while GSH-Px was found to have important antioxidant activity, it was recognized that several tissues had high Se concentrations and low GSH-Px activities. In addition to the original GSH-Px, now referred to as cellular glutathione peroxidase (cGSH-Px) three other glutathione peroxidases have been characterized (Ursini, Maiorino, and Gregolin, 1985; Takahashi, et al., 1987; Chu, Doroshow, and Esworthy, 1993). Both type I and type II iodothyronine deiodinases that contain Se have been characterized (Behne, et al., 1990; Arthur, Nicol, and Beckett, 1990; Berry, Banu, and Larsen, 1991; Croteau, et al., 1995). Additionally, three other selenoproteins have been sequenced and characterized, but their biological role is unknown (Hill, et al., 1991; Karimpour, et al., 1992). Recently, a new 18-kD membrane bound selenoprotein has been reported (Kyriakopoulos, et al., 1996). All the Se-containing proteins described contain selenocysteine and all appear to be genetically controlled. While the various biochemical and physiologic functions of all of these proteins is not presently clear, it is evident that Se is an important antioxidant and this helps to explain its role in prevention of a number of disease conditions. At the present time, the only clinical use of Se-containing enzymes is the analysis of blood GSH-Px activity for diagnosis of Se status by some laboratories.

Several disease syndromes in cattle have been shown to be Se-responsive; Se administration will reverse the condition or prior Se supplementation will prevent the condition. In the original work by Muth (1963), not all of the Se-deficient forages would produce white muscle disease, and while Se administration would successfully prevent or treat white muscle disease, it was apparent that factor(s) other than Se deficiency were involved. The other Se-responsive syndromes are similar in that Se deficiency is the underlying problem to be addressed, while other factors involved with pregnancy, infectious diseases, exercise, or stress are important for the condition to become manifest. The Se-responsive syndromes can be put into four major disease categories; (1) musculoskeletal, (2) reproductive, (3) gastrointestinal, and (4) immunologic.

The musculoskeletal conditions include nutritional myodegeneration (NMD; white muscle disease), neonatal weakness, and myodegeneration of adult cattle. These diseases, particularly NMD are widespread throughout the world and affects both domestic and wild ruminants. It is a particular problem in the U.S., Canada, Australia, New Zealand, and Europe. The cardiac form of NMD can occur within two to three days of birth and is often associated with severe myocardial lesions and peracute to acute death. Calves or lambs affected at one to four weeks of age often appear lame or stiff and are reluctant to move. Elevated serum enzymes of muscle origin such as creatinine kinase are helpful in diagnosing the myopathy. On post mortem examination, pale streaks are seen in the muscles. The cardiac form of NMD is more severe, with necrosis and calcification of the heart muscle and the intercostal muscles. Neonatal weakness due to Se deficiency is a less severe clinical manifestation. Myodegeneration of adult cattle is often associated with exercise or parturition, and common clinical signs include paresis and myoglobinuria. The role of Se as an antioxidant is a key factor in these musculoskeletal conditions. Grazing ruminants are particularly susceptible to Se deficiency diseases as their diets often consist of feeds from a small geographic area; if the soil and plants are low in Se in that area, animals are particularly predisposed.

Selenium deficiency also can cause reproductive diseases such as abortion, retained placenta, and infertility in cattle. Cattle, sheep, and other grazing animals are susceptible to a number of infectious agents that can cause abortion, such as Brucella spp., Campylobacter spp., Leptospira spp. and numerous viral agents. Selenium deficiency has also been documented as a direct cause of abortion in cattle and sheep (Hedstrom, et al., 1986). These aborted fetuses often have lesions similar to NMD and may represent an in utero form of myodegeneration. Retained placenta is a multifactorial condition that is not specific to Se deficiency even though in some parts of the U.S. Se-responsive retained placenta is common. Infertility in cattle can be due to Se deficiency; however, infertility can also be caused by infectious agents (various protozoa, bacteria, and viruses), trauma, hormonal imbalances, and other nutritional or metabolic diseases.

The most common presenting signs of Se deficiency in cattle are diarrhea and "ill thrift", both of which are non-specific for Se deficiency. The diarrhea must be differentiated from the many causes of diarrhea in cattle which include bacteria (Salmonella spp., Mycobacterium paratuberculosis, etc.), viruses (bovine virus diarrhea, Rota virus, etc.), parasites (Trichostrongylus spp., Ostertagia spp.), or other nutritional and metabolic conditions. In addition to preventing Se-responsive diarrhea, Se added to the diet of Se deficient ruminants will allow for normal weight gains and can increase feed efficiency (Nunn, Turner, and Drake, 1995). The fact that normal Se nutrition optimizes feed efficiency in ruminants is a very important phenomenon. There are resource management implications both for domestic grazing ruminants and wild ruminants with respect to this aspect of Se nutrition. Marked Se deficiency could decrease feed efficiency by as much as 30% and this could have a major impact on carrying capacity and range utilization.

The effect of Se deficiency on the immune system of laboratory animals and man has been examined in detail and it has generally been concluded that Se deficiency decreases both the cellular and the humoral immune response to specific antigens. Additionally, genetic mechanisms which utilize Se to maintain the activity of immune system functions such as lymphocyte proliferation and T lymphocyte function, have been characterized (Roy, et al., 1994; Kiremidjian-Schumacher, et al., 1994). The research data for domestic ruminants is not as clear. Research on the immune system responses to Se deficiency in ruminants has been confounded by a number of factors. One of the major factors has been the vitamin E status of the experimental animals. Selenium and vitamin E have similar effects on the immune response and in many cases the responses overlap or are synergistic. Therefore, in situations with high levels of dietary vitamin E, such as would occur in animals grazing lush pastures, a decrease in immune function due to Se deficiency may not be observed because the very high vitamin E status preserves normal immune function. Conversely, if the experimental animals are deficient in both Se and vitamin E, adding nutritive levels of Se may not be enough to support the immune system for normal function. Selenium has been shown to be an important factor in the ability of neutrophils to exhibit microbicidal activity on ingested microorganisms. Selenium deficiency decreases the oxidative capacity of neutrophils. Also, normal Se status increases the mitogen response of lymphocytes in vitro versus lymphocytes from Se deficient ruminants. Selenium deficiency has been shown to be a major risk factor for mastitis in dairy cattle (Erskine, et al., 1987; Erskine, et al., 1989; Smith, et al., 1984) and while the precise immune mechanisms may not be currently known, Se deficiency seems to be very important in causing grazing ruminants to be more susceptible to a number of disease conditions.

A central consideration for Se deficiency, or Se toxicity, is accuracy in diagnosing Se status. While recognition of clinical disease is important, many losses can occur due to subclinical disease, decreased weight gains, or decreased feed efficiency. Most areas of the United States and Canada are at risk of having Se deficient grazing livestock and wildlife. The Pacific Coast, including most of California, the Intermountain West, the states and provinces bordering the Great Lakes, the Northeastern U.S., and the Eastern Coastal states are Se deficient. The central plains tend to have normal Se levels in the soils with localized areas of excess Se. Selenium concentration of plants, feeds, soil, and water can be determined; however, because of numerous dietary interactions, the Se status of animals is difficult to predict from these data. Nutritional Se status in cattle can be determined by measuring Se concentration (Olson, 1969; Tracy and Moller, 1990) or GSH-Px activity (Agergaard and Jensen, 1982; Maas, et al., 1993) in a number of tissues. The tissues most commonly used are blood, liver, and kidney. In a clinical setting, tissues of convenience include whole blood (EDTA or heparin tubes) and serum or plasma. Blood Se concentrations from 0.1 ppm to 1.0 ppm are considered normal, with most supplemented or Se normal ruminants having values of 0.1 ppm to 0.3 ppm (Maas, 1983). Blood Se concentrations below 0.05 ppm are frankly deficient and usually associated with clinical disease. Blood Se concentration of 0.05 to 0.1 ppm are considered marginal and subclinical disease can be common in these instances. While serum and/or plasma can be analyzed for Se concentration, it has been shown that diagnostic interpretation of these serum Se values is severely limited (Maas, et al., 1992). Serum Se concentrations that are 0.01 ppm or less are diagnostic of Se deficiency and serum Se concentrations of 0.10 ppm or greater are diagnostic of Se adequacy (Maas, et al., 1992). However, serum Se values between 0.01 ppm and 0.10 ppm (the vast majority of samples) can not be diagnostically interpreted with enough accuracy to make clinical decisions (Maas, et al., 1992). Blood Se concentrations of 5.0 ppm or greater are diagnostic of Se toxicosis. Blood GSH-Px activity (IU/mg hemoglobin/min) of 0 to 15, 15-25, and 25-100 correspond to blood Se levels of 0.01 to 0.05, 0.05 to 0.1, and 0.1 and above, respectively, in our laboratory (Maas, et al., 1993). However, it should be noted that methods for GSH-Px are rarely standardized and each GSH-Px method must be validated for each laboratory and for each species to be of diagnostic value.

The following elements have been shown to interfere with Se and vitamin E metabolism; silver, zinc, cadmium, tellurium, cobalt, copper, mercury, tin, lead, arsenic, iron, and sulfur, either alone or in combination (Van Vleet, 1982). Some of these elements are potent oxidants (cadmium, mercury, iron), while others interfere directly with Se metabolism (arsenic, sulfur, or tellurium). Selenium has been found to be protective against toxic doses of compounds such as monensin, a polyether ionophore, which can induce myopathy. One of the more important interactions on a clinical basis is that between Se and sulfur. Sulfur interferes with Se uptake by plants (Severson and Gough, 1992) and sulfur also interferes with Se metabolism in ruminants (Jones, et al., 1987). Therefore, sulfur fertilization of pastures and rangelands could significantly increase the interference with Se metabolism in animals and predispose them to Se deficiency. Another concern has been that Se could interfere with absorption and/or retention of copper. A recent report examined this possibility in pre-weaned and weaned beef heifers (Maas, et al., 1994). These young heifers were supplemented with 3 mg Se per day and it was found that no measurable interference occurred with Cu metabolism as characterized by hepatic and serum copper concentrations (Maas, et al., 1994). A similar study in lactating dairy cattle (Buckley, et al, 1986) had similar results and thus no apparent interference with copper metabolism seems to occur even with high levels of Se supplementation. The fact that numerous interactions between Se, other nutrients, drugs, other elements, and diseases can occur, increases the importance of accurate diagnostic criteria and careful interpretation of data related to Se deficiency or Se toxicity.

Salt mineral mixes for cattle can contain a maximum of 120 ppm Se and these types of mixtures could contain a maximum of 90 ppm Se for sheep. It is important to realize that the National Research Council of the National Academy of Sciences has determined the nutrient requirements for Se is between 0.1 ppm and 0.5 ppm for cattle and most other species. Therefore, 0.3 ppm is not adequate in all circumstances and that interference by other dietary components can increase the requirements greatly. The presence of sulfates in the feed or water, for example, can markedly interfere with Se absorption and utilization. The use of blood Se concentration as a diagnostic and management tool is very helpful in assessing the Se status of livestock. The need to supplement Se in grazing situations is common in the U. S. and Canada. Current laws and regulations recognize the scientific facts regarding Se as an essential nutrient for grazing animals and other species. One of the first methods of supplementation of Se used was via injection of sodium selenite solutions. This form of Se was particularly useful for treatment of NMD in calves, lambs, and other species. Data regarding pharmacodynamic aspects of Se injections in cattle has been reported (Maas, et al., 1993). It was found that peak blood Se concentrations, after using the label dose (2.5 mg/100 lb. bodyweight), occurred 5 hours post-injection. The peak blood Se concentration was above 0.1 ppm for 10 hours post-injection; however, the blood Se concentration continued to decrease rapidly and was less than 0.05 ppm by 28 days post-injection. The blood GSH-Px activity showed a significant increase by day 28 post-injection; however, the blood GSH-Px activity only achieved a level of about 40% of that considered to be adequate before declining sharply (Maas, et al., 1993). Some of the other significant conclusions of this study included: (1) the label dose of injectable Se does not achieve blood Se or blood GSH-Px activity considered to be adequate, (2) serum Se or serum GSH-Px are not accurate predictors of Se status or current Se injection history, (3) injectable Se is an excellent therapeutic agent and can be used for strategic supplementation, but should not be the sole method of long term supplementation unless repeated often, (4) the use of blood Se and blood GSH-Px can be used to retrospectively diagnosis Se status within 14 days of the time of an injection, and (5) approximately 30% of the injected Se dose is eliminated via the kidney within the first 48 hours post-injection (Maas, et al., 1993). Selenium injections are best considered as therapeutic agents and short term supplements. For grazing ruminants the use of sustained-release Se boluses are an excellent alternative. These products have been shown to be effective and safe for grazing animals (Campbell, et al., 1990; Coe, et al., 1993; Maas, et al., 1994). California currently has a sustained-release Se bolus approved for use under an investigational feed additive license that supplies adequate Se to cattle for 1 year. The use of boluses is particularly advantageous in extensive grazing or range situations. Another form of supplementation is the use of salt-mineral mixes with added Se. This can be a very effective method, but relies on voluntary consumption, which can vary greatly with season and individual animal. For feeding under more intensive situations, Se can be added to a premix and fed as part of a total mixed feed or a portion of a grain feeding program. Fertilization with Se is done in countries such as New Zealand, Australia, and Finland. This method has been used experimentally in California on range utilized by mule deer (Oliver, Jessup, and Norman, 1990). The need for Se supplementation is not limited to grazing domestic ruminants. Columbia black-tailed deer does given intraruminal Se boluses exhibited a 2.6 fold increase in fawn survival over a three year period (Flueck, 1989) versus controls. Blood samples (1,695) were collected from mule deer in 15 geographical regions of California and analyzed for Se content (Oliver, et al., 1990). Two-thirds of the herd groups had first quartile Se concentrations less than 0.05 ppm, indicating widespread Se deficiency in this species of grazing wildlife (Oliver, et al., 1990).

In summary, Se is an essential trace element for all vertebrates, including grazing ruminants. Selenium deficiency is widespread in the U. S. and Canada. Significant advances have been made in understanding Se deficiency problems and in our ability to diagnose Se deficiency and monitor Se supplementation.

References available upon request