Effects of selenomethionine supplementation on selenium status and thyroid hormone concentrations in healthy adults.

BACKGROUND: Selenium, a potential cancer prevention agent currently being tested against prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), plays an integral role in thyroid metabolism. The effects of long-term selenium supplementation on thyroid hormone concentrations are unknown. OBJECTIVE: The objective was to investigate the effects of long-term selenium supplementation on thyroid hormone concentrations. DESIGN: Twenty-eight healthy adults took 200 microg selenomethionine/d for 28 mo. The thyroid hormones triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) were measured in plasma for 4 mo before supplementation and quarterly during supplementation. The assay methods were changed midstudy; the results of the 2 methods were not comparable. Therefore, one analysis was conducted based on the results of the first method, and a second analysis was based on all of the data, adjusted for the change. Serial data collection permitted a test for trends rather than simply a difference between initial and final values. RESULTS: By 9 mo, mean (+/-SEM) plasma selenium concentrations had increased from 1.78 +/- 0.07 micromol/L at baseline to 2.85 +/- 0.11 micromol/L for men and from 1.64 +/- 0.04 to 3.32 +/- 0.1.2 micromol/L for women. T3 concentrations in men increased 5% per year (P = 0.01). T4 and TSH concentrations were unchanged. CONCLUSIONS: Selenium supplementation produced no clinically significant changes in thyroid hormone concentrations. A small but statistically significant increase in T3 concentrations was noted in men, with no corresponding decreases in TSH. A subset of SELECT subjects might be monitored periodically for changes during long-term selenium supplementation.

Decreased beta-adrenoceptor chronotropic response in selenium-deficient mice: negative crosstalk between iNOS activity and cAMP accumulation.

With the aim to study if selenium (Se) deficiency affects the basal frequency and cardiac response to isoproterenol (ISO), mice were fed a Se-deficient diet (Se-) or the same diet supplemented with 0.2 ppm Se as sodium selenite (Se+) for 4 wk. Atria frequency, cyclic AMP (cAMP) accumulation, nitric oxide synthase (NOS) activity, and beta-adrenoceptor-binding assay were then examined. Results showed that Se-mice have both a reduction in atria frequency as well as in cAMP content but higher NOS activity levels either at basal or after ISO stimulation. These differences were suppressed by feeding Se-mice with a Se-supplemented diet for 1 wk or by inhibition of inducible nitric oxide synthase (iNOS). Alterations observed after ISO stimulation in atria of Se-mice were not related to a beta-adrenoceptor expression modification because specific radioligand-binding parameters in cardiac membranes from Se-mice and Se+ mice were similar. The reduced response on rate and cAMP in atria from Se-mice to direct adenylate cyclase (AC) stimulation by forskolin and the shifted upward levels present in 2-amino-4-methylpyridine-treated Se-mice is in agreement with a negative crosstalk between iNOS activity and AC activity in Se-mice.

Host nutritional status: the neglected virulence factor.

The emergence of new infectious diseases and old diseases with new pathogenic properties is a burgeoning worldwide problem. Severe acute respiratory syndrome (SARS) and acquired immune deficiency syndrome (AIDS) are just two of the most widely reported recent emerging infectious diseases. What are the factors that contribute to the rapid evolution of viral species? Various hypotheses have been proposed, all involving opportunities for virus spread (for example, agricultural practices, climate changes, rainforest clearing or air travel). However, the nutritional status of the host, until recently, has not been considered a contributing factor to the emergence of infectious disease. In this review, we show that host nutritional status can influence not only the host response to the pathogen, but can also influence the genetic make-up of the viral genome. This latter finding markedly changes our concept of host-pathogen interactions and creates a new paradigm for the study of such phenomena.

Selenium deficiency and viral infection.

The discovery that the juvenile cardiomyopathy known as Keshan disease likely has a dual etiology that involves both a nutritional deficiency of the essential trace mineral selenium (Se) as well as an infection with an enterovirus provided the impetus for additional studies of relationships between nutrition and viral infection. An amyocarditic strain of coxsackievirus B3, CVB3/0, converted to virulence when it was inoculated into Se-deficient mice. This conversion was accompanied by changes in the genetic structure of the virus so that its genome closely resembled that of other known virulent CVB3 strains. Similar alterations in virulence and genomic composition of CVB3/0 could be observed in mice fed normal diets but genetically deprived of the antioxidant selenoenzyme glutathione peroxidase (knockout mice). More recent research has shown that a mild strain of influenza virus, influenza A/Bangkok/1/79, also exhibits increased virulence when given to Se-deficient mice. This increased virulence is accompanied by multiple changes in the viral genome in a segment previously thought to be relatively stable. Epidemic neuropathy in Cuba has features that suggest a combined nutritional/viral etiology. Further research, both basic and applied, is needed to assess properly the possible role of malnutrition in contributing to the emergence of novel viral diseases.

Coxsackievirus B3-resistant mice become susceptible in Se/vitamin E deficiency.

The severity of the heart damage caused by a coxsackievirus infection in mice is determined by several factors, including the genotype of the infecting virus as well as the genetic background of the infected host. Earlier work by us showed that the cardiovirulence of a given coxsackievirus genotype could be increased substantially by feeding the host a diet nutritionally deficient in either selenium or vitamin E. Here we report that host genetic background as a determinant of viral infection outcome is superseded by feeding the host a diet nutritionally deficient in both selenium and vitamin E. Mice of the C57Bl/6 strain, normally resistant to coxsackievirus B3-induced myocarditis, become susceptible when fed such a doubly deficient diet. Our results demonstrate the powerful influence of host nutritional status on the course of viral infection compared to other variables traditionally considered to play major roles in determining the extent of virally induced inflammatory heart disease.

Reduced inotropic heart response in selenium-deficient mice relates with inducible nitric oxide synthase.

Atria from mice fed a selenium-deficient (Se(-)) diet have a diminished beta-adrenoceptor-inotropic cardiac response to isoproterenol or norepinephrine compared with atria from mice fed the same diet supplemented with 0.2 mg/kg Se as sodium selenite (Se(+)). This diminished response could be reversed by feeding Se(-) mice the Se(+) diet for 1 wk or by pretreatment with nitric oxide synthase (NOS) inhibitors such as N(G)-monomethyl-l-arginine or aminopyridine. Elevated serum concentrations of nitrite/nitrate as well as a threefold increase in the atrial NOS activity were seen in the Se(-) versus Se(+) mice. Western blotting and indirect immunofluorescence indicated an enhanced expression of inducible NOS in hearts from Se(-) mice. Increased expression and activity of NOS and increased nitrite/nitrate levels from Se(-) mice correlated with an impaired response to beta-adrenoceptor inotropic cardiac stimulation. Elevated nitric oxide levels may account for some of the pathophysiological effects of Se deficiency on the heart.

Host selenium deficiency increases the severity of chronic inflammatory myopathy in Trypanosoma cruzi-inoculated mice.

Weanling C3H/HeN mice were fed either a torula yeast-based diet deficient in selenium (Se) or the same diet supplemented with 0.2 ppm Se as sodium selenite. After 4 wk of feeding, the mice were inoculated intraperitoneally with the CA-I strain (clone K98) of Trypanosoma cruzi (TC). Before inoculation, mean serum Se levels were 430 versus 61 ng/ml in adequate and deficient mice, respectively. During the ascending phase of parasitemia, the Se-deficient mice exhibited significantly higher levels of parasites at 22-34 days postinfection (PI). However, no difference was found in the subsequent descending phase. As judged by visual examination at 2-mo-PI, some Se-deficient infected mice presented clinical signs of motor dysfunction. At 3-mo-PI, the end of the observation period, this chronic disease developed into a hind limb flaccid paralysis affecting 5 of 8 infected deficient mice. No signs of paralysis were seen in noninfected mice fed either diet or in infected mice fed the Se-adequate diet. At the histological level, both Se-adequate and Se-deficient infected mice showed mild myocarditis and moderate to severe myositis, with increasing intensity from 1- to 3-mo-PI in both groups. However, the severity of myositis was always more intense in the Se-deficient mice so that prominent areas of skeletal muscle replaced by fibrotic tissue were frequently observed. Thus, it can be concluded that Se deficiency in the murine host increases the severity of TC-induced myositis.