Marten Michaelis

Efficient selenium transfer from mother to offspring in selenoprotein-P-deficient mice enables dose-dependent rescue of phenotypes associated with selenium deficiency

Mice deficient in selenoprotein P exhibit a disturbed selenium distribution and reduced activities of other selenoenzymes and display defects in growth and motor co-ordination. We have normalized selenoenzyme activities and rescued the phenotype of mutant mice by supplementing their nursing mothers with sodium selenite. Our results indicate that selenium from inorganic sources can be transferred efficiently via mothers milk to the developing offspring in a form that is both highly bioavailable by target tissues and yet sufficiently safe to prevent overdosages.

Selenoprotein P in seminal fluid is a novel biomarker of sperm quality.

Hepatically-derived selenoprotein P (SePP) transports selenium (Se) via blood to other tissues including the testes. Male Sepp-knockout mice are infertile. SePP-mediated Se transport to Sertoli cells is needed for supporting biosynthesis of the selenoenzyme glutathione peroxidase-4 (GPX4) in spermatozoa. GPX4 becomes a structural component of sperm midpiece during sperm maturation, and its expression correlates to semen quality. We tested whether SePP is also present in seminal plasma, potentially correlating to fertility parameters. Semen quality was assessed by sperm density, morphology and motility. SePP was measured by an immunoluminometric assay, and trace elements were determined by X-ray fluorescence spectroscopy. SePP levels were considerably lower in seminal plasma as compared to serum (0.4±0.1 mg/l vs. 3.5±1.0 mg/l); Se concentrations showed a similar but less pronounced difference (48.9±20.7 μg/l vs. 106.7±17.3 μg/l). Se and Zn correlated positively in seminal fluid but not in serum. Seminal plasma SePP concentrations were independent of serum SePP concentrations, but correlated positively to sperm density and fraction of vital sperm. SePP concentrations in seminal plasma of vasectomized men were similar to controls indicating that accessory sex glands are a testes-independent source of SePP. This notion was corroborated by histochemical analyses localizing SePP in epithelial cells of seminal vesicles. We conclude that SePP is not only involved in Se transport to testes supporting GPX4 biosynthesis but it also becomes secreted into seminal plasma, likely important to protect sperm during storage, genital tract passage and final journey.

Sex-specific effects of spironolactone on blood pressure in gonadectomized male and female Wistar rats.

A low-salt diet is known to decrease and salt excess to increase blood pressure in humans and rodents. Sex steroids seem to play a role in salt dependent hypertension. However, little is known about sex differences in mineralocorticoid receptor blockade between male and female rats. The objective of the work was at first to investigate the effects of a low-salt vs. a high-salt diet on blood pressure without the influence of gonadal steroids in male and female rats. Second, to determine the sex-specific effects of mineralocorticoid receptor blockade by spironolactone in high-salt and low-salt fed gonadectomized male and female animals. Normotensive male and female Wistar rats were gonadectomized and put on a low (NaCl<0.03%) or high (NaCl=4%) salt diet. On each diet animals received spironolactone or placebo. Blood pressure was measured by tail-cuff-method; 24-h urine samples were collected in metabolic cages and blood was collected for hormonal measurements. High-salt diet significantly increased systolic blood pressure in both sexes. This effect could be blocked effectively by spironolactone only in male rats. Spironolactone treatment significantly increased aldosterone levels in males and females independent of the sodium content of the diet. High sodium diet significantly increased relative kidney weight, which was not altered by spironolactone treatment. Independently of gonadal steroids a high-salt diet increased blood pressure in gonadectomized male and female rats. Spironolactone lowered blood pressure only in male not in female rats on a high-salt diet clearly indicating sex-specific effects of the mineralo-corticoid antagonist spironolactone.

Flutamide increases aldosterone levels in gonadectomized male but not female Wistar rats.

BACKGROUND Sex-specific differences in blood pressure (BP) suggest an important modulating role of testosterone in the kidney. However, little is known about the interaction between androgens and the mineralocorticoid aldosterone. Our objective was to determine the effects of testosterone in gonadectomized male and female rats on a low-salt diet, and to determine the effect of androgen receptor (AR) blockade by flutamide on BP and on aldosterone levels. METHODS Normotensive male and female Wistar rats were gonadectomized and put on a low-salt diet. They were treated for 16 days with testosterone or placebo. In addition, the animals received the AR antagonist flutamide or placebo, respectively. BP was measured by tail-cuff method, 24-h urine samples were collected in metabolic cages and blood was collected for hormonal measurements. RESULTS Testosterone increased BP in males and females, and this effect could be blocked by flutamide. Flutamide treatment itself significantly increased aldosterone levels in male but not in female rats. These elevated aldosterone levels could be lowered by testosterone treatment during AR blockade. Accordingly to aldosterone levels, flutamide increased in males the serum sodium/potassium to urinary sodium/potassium ratio, an in vivo indicator of renal aldosterone action. CONCLUSIONS Testosterone regulates BP in male and female gonadectomized rats via the AR. Flutamide by itself exerts influence over aldosterone in the absence of gonadal steroid replacement suggesting AR involvement in renal sodium handling. These flutamide effects were sex-specific and not seen in female rats.