Health of dairy cattle

Health of the dairy cow has been the subject of intense research over the years. Several conditions, including pathogens and poor nutrition, invoke diverse mechanisms that facilitate poor growth and lower productivity, and when unrestrained might be implicated in the pathogenesis of diseases.

The impairment of dairy cow immunity is one of the fundamental reasons why these diseases occur (Mehrzad et al., 2001; Burvenich et al., 2003; Paape et al., 2003) and disruption of normal physiological processes is responsible for lowered productivity. For example, an increased vulnerability of dairy cows to intramammary infections (IMIs) has been attributed to a low status of selenium (Smith et al., 1984; 1987; Malbe et al., 1995; 2003; Weiss and Hogan, 2005).

Selenium is an essential trace element that serves several biological purposes as an integral component of a variety of proteins or enzymes known as selenoproteins. Selenium functions in the body as an antioxidant, in thyroid hormone metabolism, redox reactions, improves reproduction efficiencies and immune functions, and has anticarcinogenic properties (Rayman, 2000; Spears, 2000). It is also insulin mimetic (Stapleton, 2000).

Selenium deficiency therefore exerts profound effects on the dairy industry through lowered health status and productivity. Forages for dairy cows often do not contain adequate supplies of selenium. Therefore supplementation of selenium is now a common practice in many countries. Notwithstanding the beneficial effects of adequate amounts of selenium in dairy nutrition, the exact mechanism of this positive influence is not yet fully understood.

In this review, we will examine the influence of selenium on immune functions of the cow, highlight recent advances and discuss the physiological outcomes and consequences of selenium supplementation.


Selenium and selenoproteins

Selenium is a trace element that was first discovered in the late 19th century and considered toxic to plants and animals in the period between the 1930s and 1950s. Biomedical interest in selenium started in the late 1950s with reports that it was an essential trace element for mammals and also a component of the enzyme, glutathione peroxidase (GSH-Px) (Schwarz and Foltz, 1957; Flohé et al., 1973).

GSH-Px is an enzyme that provides antioxidative defense in mammals by converting hydrogen peroxide to water and lipid hydroperoxides to the corresponding alcohols. Selenium is integrated into GSH-Px as a selenocysteine residue, and is responsible for the catalytic efficiency of the enzyme (Forstrom et al., 1978; Wendel et al., 1978; Rocher et al., 1992; Aumann et al., 1997).

Selenium exerts its physiological influences as an integral part of several proteins known as selenoproteins, in the form mostly of selenocysteine, now recognized as the 21st amino acid in the genetic code (Stadtman, 1996; Hatfield and Gladyshev, 2002; Hatfield et al., 2006). The UGA codon, one of the so-called stop codons of the genetic code, now has the added function of signaling the incorporation of selenocysteine into selenoproteins after signaling the termination of normal protein synthesis. Thus, selenium is the raw material for production and smooth functioning of selenoproteins.

Although selenium is specifically incorporated into selenoproteins as selenocysteine, it can unspecifically join proteins as selenomethionine, which acts as a biological pool for selenium (Suzuki and Ogra, 2002). The important and varied physiological functions of selenoproteins now make selenium an essential dietary trace element in human and bovine nutrition.

Since the discovery of the first selenoprotein, about 50 mammalian proteins have been described, out of which about 25 are found in humans and 24 in rodents, and also about 30 in prokaryotes (reviewed by Köhrle et al., 2000; Kryukov et al., 2003). The first selenoprotein reported for bovine (brain) was selenoprotein P12 (SelP 12) (Saijoh et al., 1995). Lindmark- Månsson and Åkesson (2001) later demonstrated the presence of plasma GSH-Px (GSH-Px3) in both human and bovine milk. Recently, the mRNA of five more mammalian selenoproteins has been found in bovine mammary tissue (Bruzelius et al., 2007). Some of the selenoproteins (enzymes) have been assigned physiological functions but the mode of action of a good number of them is yet to be identified (Table 1).

Selenoproteins are found in many mammalian tissues and organs (Table 1) and their availability is regulated by the presence of selenium. Under a low selenium status, expression of some selenoproteins is prioritized whereas some, like GSH-Px isoforms, are strongly influenced (Brigelius-Flohé, 1999; Romanowska et al., 2007). The distribution and concentration of selenoproteins in animal tissues depends on dietary sources of the mineral (WHO, 1987; Gibson, 1990). On the other hand, the selenium content of plants and plant parts like grains and seeds is largely influenced by the selenium content of the soils in which they grow (WHO, 1987; Gibson, 1990). For dairy cattle, dietary selenium is mostly derived from plant sources.


Selenium and disease incidence in cattle

The influence of selenium on disease incidence and on immune functions is multifactorial and particular circumstances determine which systems are affected (Arthur et al., 2003).

Goff (2006) suggested that a strong correlation exists between malnutrition and the immune system, consequently causing disease conditions in cattle. Selenium appears to stimulate the immune system to boost host resistance to infection. In fact, selenium influences both the innate and the acquired immune systems (Spallholz, 1990; McKenzie et al., 2001). Selenium over-availability or under-availability has been shown to alter normal physiological processes, often leading to disease conditions, which implies that selenium as a trace element must be present in biological systems only at a certain threshold for proper functioning.

The first observed ill effects of selenium came when animals and humans alike consumed seleniferous plants and plant parts (grew in areas with high soil selenium content) and produced severe toxic symptoms such as loss of hoofs (in animals), changes in skin (red, swollen, and blistered), brittle, discolored and eventual loss of hair and nails, and nervous system failure (in humans) (Krehl, 1970; Yang et al., 1983).

Selenium deficiency on the other hand has been implicated in several disease conditions in cattle, such as ill-thrift, reduced growth rate, retained placenta and abortion, impaired fertility, cystic ovaries, metritis, white muscle disease in calves, mastitis and nutritional muscular dystrophy (Smith et al., 1984; Koller and Exon, 1986; Hemingway, 1999; 2003; Pehrson, 1993; Ndiweni and Finch, 1995; Kommisrud et al., 2005; Enjalbert et al., 2006). Augmentation of the selenium status of cattle has been shown to improve, reverse or prevent most of these conditions. Table 2 presents a summary of the effects of level of blood selenium status on cow health parameters.


Table 1. Some mammalian selenoproteins, their functions and tissue distribution.


To enlarge the image, click here

References: Holben and Smith, 1999; Köhrle et al., 2000; Gromer et al., 2005; Bruzelius et al., 2007.



Table 2. Blood selenium level and health parameters of cattle.





SELENIUM AND SOMATIC CELL COUNTS

Milk somatic sell counts (SCC) have over the years been used as a primary indicator of mastitis (or disease incidence) and milk quality in dairy herds. Several controlled trials and field studies have associated deficiencies in selenium with increased incidence and severity of IMIs, clinical mastitis cases, and higher SCC in individual cows and bulk tank milk (Erskine et al., 1987; Smith et al., 1987; Weiss et al., 1990; Hemingway, 1999). Smith et al. (1987) supplemented the diets of first lactation heifers with 0.3 mg Se/kg DM and reported a reduction in prevalence of infected quarters by 42%, clinical mastitis cases by 32.1%, and a significant reduction in SCC compared with nonsupplemented heifers.

Studies that examined the relationships among dietary and serum selenium concentration and bulk tank SCC associated high serum selenium concentrations with lower bulk tank SCC and lower rates of clinical mastitis (Erskine et al., 1987; Weiss et al., 1990). In the study by Erskine et al. (1987), higher GSH-Px activity was found in the herd with low SCC. Conversely, Norwegian herds with high selenium status were found to have higher frequencies of treatment for clinical mastitis and higher milk SCC than herds with low selenium status (Ropstad et al., 1987).

On the other hand, Erskine et al. (1990) found no difference in SCC from low selenium status cows (received 0.04 mg Se/kg DM) and high selenium status cows (received 2.04 mg Se/kg DM) after intracisternal challenge with Staphylococcus aureus. They, however, noted that peak SCC was reached much earlier in the low selenium status cows.


SELENIUM AND NEONATE IMMUNITY

At birth, a neonate is rapidly exposed to large numbers of potential pathogens. Hence, the ruminant mammary gland is responsible for providing protective immunity to neonates and for defending itself from invading pathogens (Kehrli and Harp, 2001).

Selenium inadequacy during this period leading up to calving is considered critical, because most disorders are thought to be selenium-responsive (retained placenta, mastitis, neonatal mortality, reduced milk production, impaired reproductive efficiency) (Gerloff, 1992; Hemingway, 2003). As demonstrated by Ndiweni and Finch (1995), low selenium status of cows may affect the levels of important immune cells in colostrum and consequently put calf health at risk.

Furthermore, several authors have confirmed that selenium supplementation resulted in a higher concentration of selenium in milk of suckler cows and also improved the selenium status of their calves (Pehrson et al., 1999; Gunter et al., 2003; Weiss and Hogan, 2005). High GSH-Px activities were also reported in calves from cows fed supplemental selenium (Gunter et al., 2003).


Potential mechanisms of action of selenium

Available information indicates that selenium consumption at safe levels affects positively the cow’s biological systems leading to improvements in health and reproduction parameters. The mechanisms of action of selenium in achieving these goals are mirrored in studies showing enhanced effects on the general immune system, the antioxidant system and in specific activities such as anti-pathogenic roles and influence on neutrophil functions.


SELENIUM AND THE DAIRY COW IMMUNE SYSTEM

Selenium availability is essential for an optimum response after pathogen attack in cattle, although the exact mechanisms of action are still being investigated. Selenium influences both the acquired and adaptive immune system of cows including antibody production, cell proliferation, cytokine production and neutrophil function (Larsen, 1993; Ndiweni and Finch, 1995; McKenzie et al., 1998).

Studies in humans indicate that selenium deficient lymphocytes were less able to proliferate in response to mitogens and also neutrophil chemotaxis was impaired (Turner and Finch, 1991; Beckett et al., 2003). Selenium deficiency also affects the humoral system whereby, IgG and IgA titers were decreased in rats and IgG and IgM in humans (Arvilommi et al., 1983; Turner and Finch, 1991; Beckett et al., 2003).

In cows suffering from selenium deficiency, Boyne and Arthur (1986) noted a decrease in the ability of neutrophils to kill phagocytosed Candida albicans. Also, a lack of selenium lowered the production of leucotrienes of polymorphonuclear leukocytes, which led to lowered chemotaxis of neutrophils (Aziz and Klesius, 1986).

Several reports associated increased concentration of blood selenium in cows with decreased rate in infections, including subclinical mastitis, clinical mastitis and infections by Actinomyces pyogenes and Corynebacterium spp. (Jukola et al., 1996; Ranjan et al., 2005). Furthermore, many epidemiological studies have also revealed positive association of selenium supplementation with cow udder health (Weiss et al., 1990; Hogan et al., 1993; Malbe et al., 1995; Kommisrud et al., 2005).

In other findings, both the severity and duration of infections as well as somatic cell count are associated with selenium status of animals (Smith et al., 1987; Erskine et al., 1990; Weiss et al., 1990; Hemingway, 1999).


THE ANTIOXIDANT EFFECTS OF SELENIUM

Beneficial health effects have been consistently associated with selenium supplementation in dairy cows (Pehrson et al., 1999; Rayman, 2004; Malbe et al., 2006). It is generally understood that these benefits are achieved through the action of selenium as a component of selenoproteins.

The GSH-Px and thioredoxin reductase groups of selenoproteins (Table 1) catalyze reduction of peroxides that can damage cells and tissues. Being a part of these proteins, selenium has the capacity to affect oxidative processes in the system and is considered an antioxidant nutrient. These antioxidants protect cells from oxidative damage from free radicals and peroxides (Rotruck et al., 1973). The activity of these enzymes is directly related to the concentration of selenium in the diet. In cattle, Bruzelius et al. (2007) demonstrated for the first time the activity of GSH-Px and thioredoxin reductase activity in bovine mammary tissue, which was influenced by selenium status.

This is an indication that selenium status of the mammary gland is an important regulator of selenoprotein expression and activities. Furthermore, several studies have demonstrated that oxidative stress of the cow contributes to lowering immunity and increases the risk of retained fetal membranes as well as mastitis (Hemmingway, 1999). Higher activity of GSH-Px has also been reported in the erythrocytes of cows receiving supplemental selenium compared with non-supplemented individuals (Ortman and Pehrson, 1999). Selenium therefore has a positive antioxidant effect in cattle.


SELENIUM-DEPENDENT ANTI-PATHOGENIC ACTIVITIES

Reports in cattle show that increased activity of GSH-Px, the result of selenium supplementation, inhibited growth of mastitis pathogens in cow’s milk (Ali-Vehmas et al., 1997; Malbe et al., 2003; 2006). Ali-Vehmas et al. (1997) observed that selenium supplementation of dairy cattle strengthens the inflammatory response to IMIs by inducing a change in whey, which either inhibited or restricted the growth of mastitis pathogens.

Similarly, 4 mg of supplemental selenium played an important role in maintaining quarter milks pathogen free (Malbe et al., 2003). A recent finding by Malbe et al. (2006) has established the presence of a selenium-dependent anti-pathogenic activity in cow’s milk.

In their study, selenium supplementation increased GSH-Px activity, which accounted for lower somatic cell counts and inhibited Staphylococcus aureus growth, especially when the activity level exceeded 4 μkat/g Hb. Bruzelius et al. (2007) also showed increased activity of cellular GSH-Px1, GSH-Px3, and selenoprotein P with increased mRNA abundance in the mammary gland, which is in line with the findings of Gierus et al. (2002) who demonstrated increased GSH-Px3 activity with selenium supplementation.

These findings give an insight into the mechanism of selenium action in udder defense, which reiterates the importance of adequate amounts of selenium in the diet of the dairy cow.


ROLE OF SELENIUM IN BOVINE NEUTROPHIL FUNCTION

Neutrophils are the first line of cellular defense against the aggression of invading pathogens. Thus, their recruitment to the site of pathogen attack will support defense mechanisms that favor reduction of the incidence of disease. The positive effect of selenium supplementation on the health of dairy cows has necessitated the elucidation of the role of selenium in neutrophil function. Neutrophils release free radicals when they reach sites of infection to take part in the killing of pathogens.

Oxygen free radicals such as superoxide anion, hydrogen peroxide and hydroxyl radical are generated in a process known as oxidative or respiratory burst. Although selenium deficiency has not been shown to affect neutrophil numbers in a range of species, it is clear that certain aspects of their function are affected (Turner et al., 1991).

In cattle, neutrophils collected from cows fed supplemental selenium diets had increased intracellular kill of bacteria, enhanced viability and reduced extracellular hydrogen peroxide concentration when compared with neutrophils from cows fed unsupplemented diets (Gyang et al., 1984; Hogan et al., 1990; Grasso et al., 1990).

The role of selenium in these studies was associated with the activity of GSH-Px in the neutrophils. Under deficient conditions, a lack of/or decreased GSH-Px activity seems to reduce the ability to kill bacteria. On the other hand, increased GSH-Px activity in the presence of selenium enabled the continued production of radicals and bacterial clearance. Furthermore, Cebra and co-workers (2003) reported that neutrophils from postparturient dairy cows with higher blood concentrations of selenium appear to have greater potential to kill microbes. Reported positive correlation between GSH-Px activity in the bovine mammary gland and milk and health benefits supports the positive role of selenium on neutrophil function in dairy cattle health.

Considering the potential mechanisms of action of selenium, we hypothesize that selenium adequacy leads to production and increased abundance of certain selenoproteins (depending on the system and conditions) that increase the ability of neutrophils to kill pathogens.

In addition, selenium adequacy will prolong the lifespan of neutrophils, thus enhancing their function. The antioxidant role of most selenoproteins already provides suitable conditions for neutrophil function. However, other unknown mechanisms may also be involved. Although several mammalian selenoproteins are known, their specific roles in cattle have not been investigated. Experiments are on-going or planned in our laboratory to test our hypotheses and characterize and determine the role of several selenoproteins in the bovine system.


Selenium and vitamin E

The positive action of selenium in biological systems is thought to be supported by vitamin E. Vitamin E is a fat soluble vitamin located in membranes where it protects polyunsaturated fatty acids from peroxidation. Like selenium, vitamin E also plays an oxidative role by protecting neutrophils from the destructive action of toxic oxygen molecules. Deficiencies in both nutrients have been implicated in impaired bactericidal activity of neutrophils and increased mastitis (Hogan et al., 1993).

Consequently, several reports in the past decades have examined the role of vitamin E and selenium on bovine health (Hogan et al., 1990; 1993; Ndiweni and Finch, 1995; Jukola et al., 1996; Sivertsen et al., 2005). The general consensus is that adequate amounts of these nutrients enhance the ability of bovine neutrophils to phagocytize pathogens and also enhance the functions of mammary gland macrophages and peripheral blood lymphocytes and consequently improve health, while their deficiency is associated with lower productivity and increased incidence of diseases.

Although the separate supplementation of these nutrients has resulted in the same positive effects, Sergerson et al. (1981) are of the opinion that, when used together, their effects are even more efficacious. However, Ndiweni and Finch (1995; 1996) found no evidence of additive or synergistic effects of vitamin E and selenium supplementation in health parameters in cattle.


Manipulating the selenium status of the cow and its milk, and bioavailability

Selenium deficiency can be corrected by supplementation. As a consequence of several analyses of selenium deficiency in livestock, humans and agricultural land, selenium supplementation of livestock feed or use of mineral fertilizers on crop lands is now a common practice in many parts of the world. In particular, the positive effects of selenium supplementation on the immune status and reproductive parameters of dairy cows have made the mineral a normal constituent of their rations.

Selenium supplementation is therefore necessary to maintain the selenium status of dairy cows and also increase the selenium concentration of milk (Knowles et al., 1999; Pehrson et al., 1999; Givens et al. 2004; Heard et al. 2004; Juniper et al., 2006). Selenium supplementation of dairy cows is also of significance in human nutrition since the main sources of human selenium supplies are from products of animal origin like meat and milk.

Selenium supplementation in cattle feed is usually in the form of organic (selenized yeast) or inorganic (sodium selenite or sodium selenate) selenium. Several studies have examined the effects of selenium sources on bioavailability and demonstrated varying capacities of the two forms at affecting dairy cow selenium status (in blood) and selenium content of milk (Knowles, et al., 1999; Weiss and Hogan, 2005; Juniper et al., 2006).

In general, the organic form of selenium shows higher capacity of assimilation and bioavailability, and in increasing the blood and milk selenium content when compared with the inorganic form (Ortman and Pehrson, 1999; Knowles et al., 1999; Mahan, 2000; Givens et al. 2004; Heard et al. 2004; Weiss and Hogan, 2005; Juniper et al., 2006). In a review by Weiss (2003) and subsequent studies (Givens et al., 2004; Heard et al., 2004; Juniper et al., 2006), the relative effect of organic selenium on the increase of milk selenium lies in the range of 34 to 90%.


Optimal dosage and toxic effects of selenium supplementation

The level of selenium supplementation in dairy cow diets varies from country to country and is mainly determined by the selenium content of feedstuffs, as influenced by soil selenium status. In Canada and the United States, both organic and inorganic sources of selenium can be supplemented at 0.3 mg/kg of DM. In the European Union, inorganic selenium is fed to cows at a recommended level of 0.5 mg/kg of DM (Ministry of Agriculture, Fisheries and Food, 2000) and was initially the only authorized form of selenium.

Recently, one source of organic selenium, Sel-Plex® (Alltech Inc.) has been approved for use in all livestock species in the European Union (EU regulation 1750/ 2006). In the US, Sel-Plex® first received approval for use in chicken diets in the year 2000, followed by turkey, swine, beef, dairy and equine feeds and most recently dog diets.

Since selenium was originally known to be toxic, it is imperative that care be taken not to reach toxic levels during supplementation. Rate of supplementation in most trials does not consider the selenium concentration in the other feed ingredients, implying that the final selenium intakes of animals is usually more than current recommended levels. However, little data exist to suggest toxic effects even when selenium was included at levels as high as 50 mg/d for 90 days or 100 mg/day for 28 days in diets of Holstein cows (Ellis et al., 1997).

Givens at al. (2004), as in most studies, observed increasing advantage of selenium inclusion levels on milk selenium concentration with the best results at a rate of 1.14 mg Se/kg as Sel-Plex® selenium yeast. These results demonstrate that current recommended levels of inclusion should be revisited in order to set the limits for favorable performance and to avoid toxicity. Since blood selenium concentration is a fairly good variable to measure individual or herd selenium status, Hogan et al. (1993) recommended its use in establishing selenium status. Their recommendation follows that blood selenium concentration should be at least 0.2 μg/ mL, but should not exceed 1 μg/mL.

On the other hand, Braun et al. (1991) considered blood selenium levels of 0.08 to 0.3 μg/mL as normal and 0.03 to 0.07 μg/mL as inadequate for cattle. To ensure that herd selenium intakes are within safe limits, it is imperative that intakes should not exceed the toxic threshold of selenium supplementation for dairy cows. Stating the selenium concentration on feed tags and routinely measuring concentration level in forages, hay and other feed materials may be one way of ensuring safe and favorable levels of inclusion and intakes.


Other unexplored effects of selenium in dairy cattle

A further area where selenium seems to play a role, but not yet examined in dairy cattle, is in apoptosis. The ultimate goal of a cell is to perform its function to the best of its ability in the maintenance of tissue homeostasis. Apoptosis is the process of deliberate life relinquishment by a cell in an organism. It is also commonly referred to as ‘cell suicide.’

In humans, an insufficient amount of apoptosis leads to uncontrolled cell proliferation, such as cancer whereas excessive apoptosis causes cell loss diseases such as ischemic damage (shortage of blood supply to an organism). Data in 1996 indicated that dietary supplementation of 200 μg of selenium in diets resulted in a decreased incidence of human prostate, lung and colorectal cancers (Clark et al., 1996).

The precise role of selenium in modulating cancers is much debated. Some authors are of the opinion that small molecules of selenium metabolites selectively promote apoptosis in transformed prostate epithelium (Jiang et al., 2004; Ip et al., 2000) while others believe that selenium supplementation prevents DNA damage that could lead to cell transformation by increasing levels of antioxidant selenoproteins (Diwadkar- Navsariwala and Diamond, 2004; Lu and Jiang, 2005).

A recent study with transgenic mouse models showed that selenoprotein deficient mice exhibited accelerated development of lesions associated with prostate cancer progression thus suggesting that selenium may function in cancer prevention by modulating the levels of selenoproteins (Diwadkar- Navsariwala et al., 2006). Another finding demonstrates that selenoprotein expression and selenium metabolism are regulated at multiple levels in prostate cells (Rebsch et al., 2006).

Selenium may therefore play a positive role in mediating useful apoptosis necessary for normal functioning of cells. Selenium’s role in this regard, is however, yet to be established in cattle.

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