Vitamin E Deficiency in Experimental Animals

Vitamin E deficiency in experimental animals was first described by Evans and Bishop in 1922, when it was discovered to be essential for fertility. It was not until 1983 that vitamin E was demonstrated to be a dietary essential for human beings, when Muller and coworkers (1983) described the devastating neurological damage from lack of vitamin E in patients with hereditary abe-talipoproteinemia. 

Vitamin E deficiency in experimental animals results in a number of different conditions, with considerable differences between different species in their susceptibility to different signs of deficiency. As shown in Table 4.2, some of the lesions can be prevented or cured by the administration of synthetic antioxidants, and others respond to supplements of selenium. 

Vitamin E-deficient female animals suffer death and resorption of the fetuses. This was the basis of the original biological assay of the vitamin female rats were maintained for 2 to 3 months on a vitamin E-free diet and then mated. Impregnation and implantation proceed normally but, if they are not provided with vitamin E, the fetuses die and are resorbed. Five days after mating, the animals were killed, and the number of surviving fetuses gave an index of the biological activity of the test compound, relative to standard doses of a-tocopherol. Synthetic antioxidants can replace vitamin E for this function, but selenium cannot. 

Necrotizing myopathy/white muscle disease Variable + — 

In male animals, deficiency results in testicular atrophy, with degeneration of the germinal epithelium of the seminiferous tuhules. This lesion responds to vitamin E or selenium, but not to synthetic antioxidants. 

Vittimin E deficiency results in the development of necrotizing myopathy, sometimes including cmdiac muscle. This has heen called nutritional muscular dystrophy, an unfortunate teim, because deficiency of the vitamin is not a factor in the etiology of human muscular dystrophies, and supplements of the vitamin have no beneficial effect. The myopathy responds to selenium, but not to synthetic emtioxidtmts. 

The nervous system is tilso affected in deficiency, with the development of centred nervous system necrosis (nutritional encephalomacia), a condition that cem be exacerbated by feeding a diet especially rich in polyunsaturated fatty acids. There is edso axonal dystrophy in animals maintained for prolonged periods of time on vitamin E-deficient diets. Synthetic emtioxidcmts, but not selenium, can prevent these changes. The neuropathy begins from axonal membrane injury, and then develops as a distal and dying-back type of axonopathy. 

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Deficiency symptoms In vitamin E deficiency in experimental animals the manifestations are seen in several systems... 

For a long time, it was considered that, unlike the other vitamins, vitamin E had no specific functions rather it was the major Upid-soluble, radicaltrapping antioxidant in membranes. Many of its functions can be met by synthetic antioxidants however, some of the effects of vitamin E deficiency in experimental animals, including testicular atrophy and necrotizing myopathy, do not respond to synthetic antioxidants. The antioxidant roles of vitamin E and the trace element selenium are closely related and, to a great extent, either can compensate for a deficiency of the other. The sulfur amino acids (methionine and cysteine) also have a vitamin E-sparing effect. 

Vitamin E functions as a lipid antioxidant hoth in vitro and in vivo a numher of synthetic antioxidants will prevent or cure most of the signs of vitamin E deficiency in experimental animals. Polyunsaturated fatty acids undergo oxidative attack by hydroxyl radicals and superoxide to yield alkylperoxyl (alkyl-dioxyl) radicals, whichperpetuate a chain reactionin the lipid-withpotentially disastrous consequences for cells. Similar oxidative radical damage can occur to proteins (especially in a lipid environment) and nucleic acids. 

An exception is vitamin E, but not for the reasons proposed by W.E. Shute (1972) (43) in his best-seller book. High intake of polyenic acids can cause a vitamin E deficiency in experimental animals and man, mainly if the vitamin E content of food is marginal. 

A proportion of the vitamin Be in foods may be biologically unavailable after heating, as a result of the formation of (phospho)pyridoxyllysine by reduction of the alditnine (Schiff base) by which pyridoxal and the phosphate are bound to the e-amino groups of lysine residues in proteins. A proportion of this pyridoxyUysine may be useable, because it is a substrate for pyridoxamine phosphate oxidase to form pyridoxal and pyridoxal phosphate. However, it is also a vitamin Be antimetaboUte, and even at relatively low concentrations can accelerate the development of deficiency in experimental animals maintained on vitamin Be-deficient diets (Gregory, 1980a, 1980b). 

Selenium deficiency in experimental animal studies is exacerbated by vitamin E depletion. The antioxidant properties of tocopherol and glutathione peroxidase are similar and can to some extent overlap, although this is highly species dependent. °... 

Using dogs as their experimental animals, Sheffy and Schultz (1978) found that the humoral response could be influenced by selenium and Vitamin E, Vaccination with a canine distemper, infectious hepatitis virus vaccine resulted in lower antibody titers in animals deficient in selenium and Vitamin E than in control animals. The appearance of measurable antibody titers following immunization was also delayed in the Vitamin E, selenium-deficient dogs. The primary immune response to SRBC was unaffected in these dogs, whereas it was the secondary response the (IgG) antl-SRBC antibody levels that were reduced in the deficient animals. 

Vitamin E was discovered as the antisterility factor of the female rat. Deficiency in experimental animals results mainly in atrophy of the testes and dystrophy of muscles. In man, a deficiency disease is not knoiMi some authors, however, suspect that muscular dystrophy may be connected with vitamin E deficiency. 

Pure selenium deficiency, without concurrent vitamin E deficiency, is not generally seen except in animals on experimental diets (113). In China, selenium deficiency in humans has been associated with Keshan disease, a cardiomyopathy seen in children and in women of child-bearing ages, and Kashin-Beck disease, an endemic osteoarthritis in adolescents (113). 

In experimental animals, vitamin E deficiency results in resorption of femses and testicular atrophy. Dietary deficiency of vitamin E in humans is unknown, though patients with severe fat malabsorption, cystic fibrosis, and some forms of chronic fiver disease suffer deficiency because they are unable to absorb the vitamin or transport it, exhibiting nerve and muscle membrane damage. Premamre infants are born with inadequate reserves of the vitamin. Their erythrocyte membranes are abnormally fragile as a result of peroxidation, which leads to hemolytic anemia. 

In experimental animals, vitamin E deficiency depresses immune system function, with reduced mitogenesis of B and T lymphocytes, reduced phagocytosis and chemotaxis, and reduced production of antibodies and interleukin-2. This suggests a signaling role in the immune system (Moriguchi and Muraga, 2000). 

Table 4.2 Responses of Signs of Vitamin E or Selenium Deficiency to Vitamin E, Selenium, and Synthetic Antioxidants in Experimental Animals...

Although vitamin E deficiency causes infertility in experimental animals (Section 4.4.1), there is no evidence that deficiency has any similar effects on human fertility. It is a considerable leap of logic from the effects of gross depletion in experimental animals to the popular, and unfounded, claims for vitamin E in enhancing human fertility and virility. 

Selenium is an amphoteric element whose chemistry and biochemistry has mnch in common with snlfur. The essentiality of selenium in experimental animals was demonstrated in 1957. It was necessary that the animals be vitamin E deficient to manifest selenium deficiency. Selenium manifests antioxidant activity by its incorporation into selenocysteine and its subseqnent participation at the... 

The signs of a vitamin E deficiency may be quite different in animals and humans. The signs occurring in experimental animals indude impaired reproduction and muscle weakness (muscular dystrophy). Reproductive defects in female animals involve a failure of the fetus to thrive. In males, the deficiency results in an inhibition of sperm production. One feature common to humans and animals is the formation of lesions (pathological structures) in nerves and muscles. The deficiency can cause the degeneration of nerves and the accumulation of a compound called lipofuscin in various tissues, such as muscle. Lipofuscin has an amorphous structure and is thought to be composed of lipid degradation products and croSS linked proteins. 

Studies with animals have revealed an interesting pattern of relahorLships involving Se and vitamin E nutrition. In chicks, experimentally induced deficiencies in both S5e and vitamin E result in exudative diathesis, muscular dystrophy, and pancreatic atrophy. The first two problems can be prevented by vitamin E... 

In experimental animals, deficiency of pantothenic acid (needed for CoASH and, hence, succinyl-CoA synthesis), lack of vitamin Be, or the presence of compounds that block the functioning of pyridoxal phosphate (e.g.. 

In experimental animals, many injuries caused by vitamin E deficiency can be corrected completely or in part by selenium, coenzyme Q, or some sulfur amino acids. 

Pure fatty acid hydroperoxides are very toxic to experimental animals when administered intravenously (i.v.) but not oraUy (Horgan et al., 1957 Olcott and Dolev, 1963 Findlay et al., 1970). Cortesi and Privett (1972) have shown that the 24-h lethal i.v. dose of a high purity preparation of methyl linoleate hydroperoxides in adult male rats was approximately 0.07 mmol/100 g body weight, and that the major effect of injected linoleate hydroperoxides was on the lungs. Also, vitamin E deficiency symptoms such as encephalomalacia in chicks (Nishida et al., 1960), and creatinuria and erythrocyte hemolysis in rabbits (Kokatnur et al., 1966) have been observed in animals infused with methyl linoleate hydroperoxides. 

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