Boar taint in entire male pigs: a genomewide association study for direct and indirect genetic effects on androstenone.

Androstenone is one of the compounds causing boar taint of pork and is highly heritable (approximately 0.6). Recently, indirect genetic effects (IGE; also known as associative effects or social genetic effects) were found for androstenone, meaning that pen mates (boars) affect each other's androstenone level genetically. Similar to estimating variance components with a direct-indirect animal model, direct and indirect genetic SNP effects can be estimated for androstenone. This study aims to detect SNP with significant direct genetic effects and IGE on androstenone. The dataset consisted of 1,282 noncastrated boars (993 boars genotyped) from 184 groups of pen members. After quality control, 46,421 SNP were included in the analysis. One model for single-SNP regression was fitted, where both the direct SNP effect of the individual itself and the indirect SNP effects of its pen mates were included. None of the SNP (direct or indirect) were found genomewide significant. One QTL on SSC6 was chromosome-wide significant for the direct effect. A single SNP on SSC9 and 2 regions and a single SNP on SSC14 were found for the indirect effect. A backwards elimination method and haplotype analysis were used to quantify the variance explained by the SNP. The backwards elimination method identified 4 independent regions affecting androstenone. The QTL on SSC6 explained 2.1 and 2.6% of the phenotypic variance using the backwards elimination method or the haplotype analysis. The QTL on SSC14 explained 3.4 and 2.7% of the phenotypic variance using the backwards elimination method or the haplotype analysis. The single association on SSC9 explained 2.2% of the phenotypic variance. All significant QTL together explained 7 to 8% of phenotypic variance and 40 to 44% of the total genetic variance available for response to selection. Besides the newly discovered QTL and the confirmation of known QTL, this study also presents a methodology to model SNP for IGE.

[Sex steroids and monoamines in the system of neuroendocrine regulation of amygdala functions].

The aim of this review is a review of literature data, which characterize participation of monoamines brain systems and sex steroids in regulation (modulation) of the amygdalas' functions. Shown were characteristic noradrenergic, dopaminergic and serotoninergic systems and their representation in amygdala. Effect ofnoradrenaline, dopamine and serotonine on neurons of Amygdala was shown realized from appropriate cell receptors under modulated influence of sex steroids. Combined participation of monoamines and sex steroids occur in regulation of activity in cyclic centre of secretion and releasing of gonadotropins, constituted a base of forming adaptive (sexual, food and aggressive-defensive) behaviour, including stress reaction. The presented data could be used for understanding influence of gender factor on personality characteristics of humans, cognitive abilities and behavioural reactions, and also in application to development of optimal medicinal treatment of psychoneurological diseases.

The secret codes of mammalian scents.

The scents of mammals are complex blends of natural products that reveal a wealth of individual information. Many mammals can decipher these scent codes to discern the gender, age, endocrine status, social status, and genotype of conspecifics using dedicated sensory receptors in their olfactory system. Among these social odors are pheromones, chemicals that trigger innate behaviors and physiological responses. Here, we review classes of mammal-derived natural products that influence behavior through activation of the olfactory system.

Molecular mechanisms of epithelial cell-specific expression and regulation of the human anion exchanger (pendrin) gene.

Pendrin, a Cl(-)/anion exchanger encoded by the gene PDS, is highly expressed in the kidney, thyroid, and inner ear epithelia and is essential for bicarbonate secretion, iodide accumulation, and endolymph ion balance, respectively. This study aimed to define promoter regulatory elements essential for renal, thyroid, and inner ear epithelial cell-specific expression of human PDS (hPDS) and to explore the effect of ambient pH and aldosterone on hPDS promoter activity. Endogenous pendrin mRNA and protein were detected in renal HEK293, thyroid LA2, and inner ear VOT36 epithelial cell lines, but not in the fibroblast cell line, NIH3T3. A 4.2-kb hPDS 5'-flanking DNA sequence and consecutive 5'-deletion products were cloned into luciferase reporter vectors and transiently transfected into the above cell lines. Distinct differences in expression/activity of deduced positive/negative regulatory elements within the hPDS promoter between HEK293, LA2, and VOT36 cells were demonstrated, with only basal activity in NIH3T3 cells. Acidic pH (7.0-7.1) decreased and alkaline pH (7.6-7.7) increased hPDS promoter activity in transfected HEK293 and VOT36, but not in LA2 cells. Aldosterone (10(-8) M) reduced hPDS promoter activity in HEK293 but had no effect in LA2 and VOT36 cells. These pH and aldosterone-induced effects on the hPDS promoter occurred within 96-bp and 89-bp regions, respectively, which likely contain distinct response elements to these modulators. Acidic pH and aldosterone decreased, and alkaline pH increased, endogenous pendrin mRNA level in HEK293 cells. In conclusion, pendrin-mediated HCO3(-) secretion in the renal tubule and anion transport in the endolymph may be regulated transcriptionally by systemic pH and aldosterone.

Relationship between the expression of hepatic but not testicular 3beta-hydroxysteroid dehydrogenase with androstenone deposition in pig adipose tissue.

This study investigated the relationship between expression of hepatic and testicular 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and accumulation of androstenone in adipose tissue because of its relation to boar taint. The experiments were performed on 13 Large White (50%) x Landrace (50%) and Meishan (25%) x Large White (25%) x Landrace (50%), pigs, which differed in the level of backfat androstenone. Our previous work showed that the major product of the hepatic androstenone metabolism is 3beta-androstenol. In this study, the formation of 3beta-androstenol was inhibited by the specific 3beta-HSD inhibitor trilostane. These results are the first direct confirmation that 3beta-HSD is the enzyme responsible for androstenone metabolism in the pig. The expression of the hepatic but not testicular 3beta-HSD protein showed a negative relationship with the level of backfat androstenone (r2 = 0.64; P < 0.001) and was accompanied by a reduced rate of the hepatic androstenone clearance. Low expression of 3beta-HSD protein in the liver of high androstenone pigs was also accompanied by a reduced level of 3beta-HSD mRNA (P < 0.001), which suggests a defective regulation of the hepatic 3beta-HSD expression at the level of transcription. In contrast, expression of the testicular 3beta-HSD protein did not differ between animals with high and low androstenone levels (P > 0.05) and was lower compared with the hepatic 3beta-HSD expression. Cloning and sequencing of the 3beta-HSD coding regions established that the hepatic and testicular 3beta-HSD cDNA have identical sequences, which were 98% similar to the human 3beta-HSD isoform I. It is suggested that expression of a single 3beta-HSD gene is regulated by different mechanisms in pig liver and testis. The liver-specific regulation of 3beta-HSD expression contributes to the low rate of hepatic androstenone metabolism and therefore can be considered as one of the factors regulating deposition of androstenone in pig adipose tissue and subsequent development of boar taint.

Monoamines and neurosteroids in sexual function during induced hypogonadism in healthy men.

CONTEXT: Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans. OBJECTIVE: To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism. DESIGN: Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design. SETTING: National Institutes of Health, Bethesda, Md. PARTICIPANTS: Twelve healthy male volunteers. INTERVENTIONS: We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month. MAIN OUTCOME MEASURES: Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites. RESULTS: The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = -0.76 and -0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = -0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure. CONCLUSION: These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.

Androgens induce relaxation of contractile activity in pregnant human myometrium at term: a nongenomic action on L-type calcium channels.

It has long been accepted that progesterone regulates uterine contractile activity. However, little is known about the role of androgens in female physiology, and their importance and biological function on myometrial contractility so far have received limited attention. In this work, we examined the direct effect of androgens on the contractile activity of the isolated human myometrium. Myometrial biopsies were obtained, with consent, from pregnant women undergoing elective cesarean section at term. Each androgen tested (dehydroepiandrosterone, testosterone, 5alpha- and 5beta-dihydrotestosterone, androsterone, or androstanediol) caused a concentration-dependent inhibition of spontaneous contractile activity; a relaxing effect of these androgens was also observed on the contractions induced by high potassium (KCl) solution. Interestingly, nonpregnant myometrium was also sensitive to androgen-induced relaxation. 5beta-Dihydrotestosterone (5beta-DHT) was dramatically more potent than the other androgens in inducing myometrial relaxation in all preparations. Relaxation response to androgens had very rapid time courses and was affected by neither the specific antiandrogen (flutamide) nor inhibitors of protein synthesis (cycloheximide) and transcription (actinomycin D), implying that androgens act through a nongenomic mechanism. Importantly, 5beta-DHT significantly reduced the increase in intracellular calcium concentration associated with exposure to KCl in human myometrial smooth-muscle cells loaded with Fura-2-AM. The blockade of l-type calcium channels seems to be involved in the nongenomic relaxing action of androgens. These observations demonstrate that androgens may play a crucial role in maintaining pregnancy.

Assessment of olfactory function and androstenone odor thresholds in humans with or without functional occlusion of the vomeronasal duct.

To obtain information on the possible role of the vomeronasal duct (VND) in odor perception and human pheromone detection, the present study investigated different aspects of olfactory function, including thresholds for androstenone in adults with or without detectable VNDs. The study also examined correlations between detection thresholds of androstenone odor and general olfactory function. Subjects' olfaction was assessed with tests for odor identification, odor discrimination, and phenyl ethyl alcohol odor threshold. Measurements were performed on 1 side only, with and without covering the VND. Subjects with or without detectable VNDs did not differ in olfactory sensitivity or androstenone odor thresholds. A small but significant correlation was found between detection thresholds of androstenone and general olfactory function. Finally, covering of the VND did not affect olfactory function or androstenone sensitivity. Results suggest that the human VND does not play a major role in sensitivity toward odorants or the perception of androstenone.

Epiandrosterone, a metabolite of testosterone precursor, blocks L-type calcium channels of ventricular myocytes and inhibits myocardial contractility.

The dehydroepiandrosterone metabolite epiandrosterone (EPI) inhibits the pentose phosphate pathway (PPP) and dilates isolated blood vessels pre-contracted by partial depolarization. We found that EPI (10-100 microM) also dose-dependently decreases left-ventricular developed pressure (LVDP), the rate of myocardial contraction (+d p /d t), and the pressure rate product (PRP); at 100 microM EPI, LVDP (131+/-9 vs 34+/-7 mmHg), +d p /dt (1515+/-94 vs 542+/-185 mmHg/s), and PRP (37870+/-2471 vs 9498+/-2375 HR x mmHg/min) were all significantly (P<0.05) reduced. EPI also elevated CPP in isolated hearts, decreased levels of myocardial NADPH and nitrite, and dose-dependently relaxed rat aortic rings pre-contracted with KCl. Electrophysiological analysis of single ventricular myocytes using whole cell clamp showed EPI to dose-dependently (100 n M-100 microM) and reversibly inhibit L-type channel currents carried by Ba2+ (IBa) (IC50=42+/-6 microM) by as much as 50%. At 30 microM, EPI shifted the steady-state inactivation curve to more negative potentials (V50=-26.6 mV vs -38.0 mV), thereby accelerating the decay of IBa during depolarization. These results suggest that EPI may act as a L-type Ca2+ channel antagonist with properties similar to those of 1,4-dihydropyridine (DHP) Ca2+ channel blockers.

Androsterone sulfate: physiology and clinical significance in hirsute women.

Androsterone sulfate (Andros-S) is the most abundant 5 alpha-reduced androgen metabolite in serum. To determine whether this steroid could serve as a marker of 5 alpha-reductase activity, we developed a specific RIA, using tritiated Andros-S to assess procedural losses. Baseline serum Andros-S levels (mumol/L; mean +/- SEM) in 14 hirsute women (3.0 +/- 0.4) were not reduced by ovarian suppression with leuprolide (3.0 +/- 0.3), but were decreased by 79% with combined ovarian and adrenal suppression with leuprolide and dexamethasone. The mean Andros-S level in polycystic ovarian syndrome (3.2 +/- 0.4) and in idiopathic hirsutism (3.5 +/- 0.5) was not significantly different from levels in normal women (3.0 +/- 0.5), but were significantly greater than levels in obese women (1.7 +/- 0.3; P < 0.05). The serum concentrations of Andros-S were about 10-fold greater than those of androsterone glucuronide and 100-fold greater than those of androstanediol glucuronide. Serum Andros-S concentrations correlated strongly with dehydroepiandrosterone sulfate (R = 0.59; P < 0.001) and to a lesser degree with androstanediol glucuronide and androsterone glucuronide (R = 0.28 and 0.49, respectively). There was a weak correlation with androstenedione levels and the androstenedione response to ACTH (R = 0.38 and 0.34, respectively), and no significant correlation with serum testosterone (R = 0.19). The ratio of any of the 5 alpha-reduced products (Andros-S, androstanediol glucuronide, and androsterone glucuronide) to precursors (androstenedione and testosterone) was not increased in hirsute women, suggesting that these women did not have a generalized increase in 5 alpha-reductase activity. In conclusion, these results confirm that Andros-S is the most abundant 5 alpha-reduced androgen metabolite in serum. It is primarily, if not exclusively, of adrenal origin in hirsute women. The fact that its levels were not elevated in hirsutism, although those of other adrenal androgens and androgen metabolites (androstanediol glucuronide and androsterone glucuronide) were, suggests that variations in sulfotransferase activity or metabolic clearance of Andros-S may be important determinants of serum Andros-S levels. Although Andros-S may be a marker of systemic 5 alpha-reductase activity, there was no evidence of a generalized increase in 5 alpha-reductase activity in hirsute women. Andros-S is therefore not recommended as a marker of either adrenal androgen production or of hirsutism.

Ultrastructural-morphometric analysis of the rat prostate (ventral lobe).

A morphometric model, which provides information on the structure of the normal gland (ventral lobe) has been developed for the rat prostate. The model consists of morphologically defined space and membrane compartments, which are used to describe the specific components of the protein and enzyme synthesizing and secreting glandular cells. The results presented are relative to a cubic centimeter of prostatic tissue, a cubic centimeter of acinar parenchyma and glandular cell cytoplasm. Special interest was given to the cell compartments which are involved in protein and enzyme synthesis.