Male Regulation Research Articles

Poor sleep and shift work associate with increased blood pressure and inflammation in UK Biobank participants

Disrupted circadian rhythms have been linked to an increased risk of hypertension and cardiovascular disease. However, many studies show inconsistent findings and are not sufficiently powered for targeted subgroup analyses. Using the UK Biobank cohort, we evaluate the association between circadian rhythm-disrupting behaviours, blood pressure (SBP, DBP) and inflammatory markers in >350,000 adults with European white British ancestry. The independent U-shaped relationship between sleep length and SBP/DBP is most prominent with a low inflammatory status. Poor sleep quality and permanent night shift work are also positively associated with SBP/DBP. Although fully adjusting for BMI in the linear regression model attenuated effect sizes, these associations remain significant. Two-sample Mendelian Randomisation (MR) analyses support a potential causal effect of long sleep, short sleep, chronotype, daytime napping and sleep duration on SBP/DBP. Thus, in the current study, we present a positive association between circadian rhythm-disrupting behaviours and SBP/DBP regulation in males and females that is largely independent of age.

The metabolic interplay between dietary carbohydrate and exercise and its role in acute appetite regulation in males: a randomized controlled study.

An understanding of the metabolic determinants of postexercise appetite regulation would facilitate development of adjunctive therapeutics to suppress compensatory eating behaviours and improve the efficacy of exercise as a weight-loss treatment. Metabolic responses to acute exercise are, however, dependent on pre-exercise nutritional practices, including carbohydrate intake. We therefore aimed to determine the interactive effects of dietary carbohydrate and exercise on plasma hormonal and metabolite responses and explore mediators of exercise-induced changes in appetite regulation across nutritional states. In this randomized crossover study, participants completed four 120 min visits: (i) control (water) followed by rest; (ii) control followed by exercise (30 min at ∼75% of maximal oxygen uptake); (iii) carbohydrate (75 g maltodextrin) followed by rest; and (iv) carbohydrate followed by exercise. An ad libitum meal was provided at the end of each 120 min visit, with blood sample collection and appetite assessment performed at predefined intervals. We found that dietary carbohydrate and exercise exerted independent effects on the hormones glucagon-like peptide 1 (carbohydrate, 16.8 pmol/L; exercise, 7.4 pmol/L), ghrelin (carbohydrate, -48.8 pmol/L; exercise: -22.7 pmol/L) and glucagon (carbohydrate, 9.8 ng/L; exercise, 8.2 ng/L) that were linked to the generation of distinct plasma 1 H nuclear magnetic resonance metabolic phenotypes. These metabolic responses were associated with changes in appetite and energy intake, and plasma acetate and succinate were subsequently identified as potential novel mediators of exercise-induced appetite and energy intake responses. In summary, dietary carbohydrate and exercise independently influence gastrointestinal hormones associated with appetite regulation. Future work is warranted to probe the mechanistic importance of plasma acetate and succinate in postexercise appetite regulation. KEY POINTS: Carbohydrate and exercise independently influence key appetite-regulating hormones. Temporal changes in postexercise appetite are linked to acetate, lactate and peptide YY. Postexercise energy intake is associated with glucagon-like peptide 1 and succinate levels.

Differences in phytohormone and flavonoid metabolism explain the sex differences in responses of Salix rehderiana to drought and nitrogen deposition.

Due to global warming and the increase in nitrogen oxide emissions, plants experience drought and nitrogen (N) deposition. However, little is known about the acclimation to drought and N deposition of Salix species, which are dioecious woody plants. Here, an investigation into foliar N deposition combined with drought was conducted by assessing integrated phenotypes, phytohormones, transcriptomics, and metabolomics of male and female Salix rehderiana. The results indicated that there was greater transcriptional regulation in males than in females. Foliar N deposition induced an increase in foliar abscisic acid (ABA) levels in males, resulting in the inhibition of stomatal conductance, photosynthesis, carbon (C) and N accumulation, and growth, whereas more N was assimilated in females. Growth as well as C and N accumulation in drought-stressed S. rehderiana females increased after N deposition. Interestingly, drought decreased flavonoid biosynthesis whereas N deposition increased it in females. Both drought and N deposition increased flavonoid methylation in males and glycosylation in females. However, in drought-exposed S. rehderiana, N deposition increased the biosynthesis and glycosylation of flavonoids in females but decreased glycosylation in males. Therefore, foliar N deposition affects the growth and drought tolerance of S. rehderiana by altering the foliar ABA levels and the biosynthesis and modification of flavonoids. This work provides a basis for understanding how S. rehderiana may acclimate to N deposition and drought in the future.

What about males? Exploring sex differences in the relationship between emotion difficulties and eating disorders

ObjectiveWhile eating disorders (EDs) are more commonly diagnosed in females, there is growing awareness that men also experience EDs and may do so in a different way. Difficulties with emotion processing and emotion regulation are believed to be important in EDs, but as studies have involved predominantly female samples, it is unclear whether this is also true for males.MethodsIn a sample of 1604 participants (n = 631 males), we assessed emotion processing and emotion regulation in males with EDs (n = 109) and compared results to both females with EDs (n = 220) and males from the general population (n = 522). We also looked at whether emotion processing and emotion regulation difficulties predicted various aspects of eating psychopathology and whether this was moderated by sex. We assessed emotion processing with the Toronto Alexithymia Scale, emotion regulation with the Difficulties in Emotion Regulation Scale and the Emotion Regulation Questionnaire, and eating psychopathology with the Eating Disorder Examination Questionnaire.ResultsWe found that males with ED, like their female counterparts, suffered from emotion processing and emotion regulation deficits. We did find some sex differences, in that males with EDs tended to report more difficulties with their emotions as well as a more externally oriented thinking style compared to females with EDs. Difficulties with emotion processing and emotion regulation were strongly predictive of various aspects of eating psychopathology in both sexes. Importantly, we found that sex moderated the relationship between cognitive reappraisal and eating restraint. As such, low use of reappraisal was found to be associated with higher levels of restraint in females but not in males.DiscussionDifficulties with emotion processing and emotion regulation are associated with eating psychopathology in both males and females. Reappraisal was not found to be associated with reduced eating psychopathology in males, suggesting a cautious approach to interventions targeting this strategy. Research around explanatory mechanisms and interventions must adopt a broader viewpoint including those that are traditionally overlooked in EDs.

TMET-13. SEX DIFFERENCES IN GLUCOSE METABOLISM AND MITOCHONDRIAL FUNCTION IN GLIOBLASTOMA IMPLICATE HYPOXIA-INDUCIBLE FACTOR 1 ALPHA (HIF1A) ACTIVITY

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is more prevalent in males and female patients have better survival. Investigating the molecular mechanisms underlying this disparity is imperative for understanding its development and progression as well as developing novel treatment paradigms. Carbohydrate (namely glucose) metabolism is a critical GBM nutrient source for biosynthesis, energetics, and reducing equivalents. Previously, our group discovered that elevated glycolytic activity uniquely predicted the outcomes of male, but not female, lower grade glioma patients. Our goal was to characterize sex differences in GBM carbohydrate metabolism and their effects on cellular phenotype. First, we discovered that male transformed murine astrocytes were more susceptible to glucose deprivation than females. We confirmed this phenotype with irreversible inhibition of hexokinase with 2-deoxyglucose as well as a GLUT1-selective inhibitor. Time-resolved stable isotope tracing of cell metabolism with carbon-13 glucose in transformed astrocytes further supported these findings; male cells had significantly higher rates of glucose uptake and metabolism than female cells. These results were validated with stable isotope metabolomics datasets from human cancer cell lines. Using additional assays of cellular metabolism, we discovered that male transformed astrocytes had a higher glycolytic rate, higher pyruvate kinase activity, higher mitochondrial respiration, and higher mitochondrial mass compared to females. This was validated by a TCGA pancancer analysis that revealed significantly higher expression of nuclear genes involved in mitochondrial regulation in males than in females. This prompted us to identify possible regulators of this metabolic phenotype. We discovered that HIF1A had robust hypoxia-inducible expression that was significantly higher in male transformed astrocytes. Moreover, HIF1A expression as well as its target transcripts were significantly higher in TCGA pancancer tumor datasets. Together, our data underscore the potential for developing sex-specific metabolic targeting approaches for patients with GBM.

Abstract P003: Chemerin Supports Basal Blood Pressure In Both Male And Female Dahl SS Rats

Evidence supports that Antisense oligonucleotides (ASO) against the adipokine chemerin reduce the blood pressure of the normal male Sprague Dawley rat and, to a greater magnitude, the hypertensive Dahl SS rat fed a high fat diet. In the Dahl SS rat, chemerin protein concentration in white adipose tissue [mesenteric perivascular adipose tissue (Mes PVAT)] was significantly higher in females vs males. We hypothesized that female Dahl SS rats would be more dependent on chemerin for blood pressure maintenance than males because of the Mes PVAT’s proximity to blood vessels that control total peripheral resistance. Age-matched male and female Dahl SS rats on a standard chow (0.2% NaCl, 6.2% fat) diet were used. Radiotelemeters were implanted to measure blood pressure (MAP) and heart rate (bpm). Following a two-week recovery period after implantation, one week of baseline measures were collected. Knockdown of whole body chemerin was achieved by subcutaneous injections of scrambled control ASO or whole-body ASO against chemerin (both 25 mg/kg) on days 0, 7, 14, and 21. On day 23, the rats were euthanized, and samples were collected for western blot and qPCR of the chemerin gene Rarres2 . Plasma chemerin was abolished in both male and female rats given the ASO against chemerin vs that of rats receiving the control ASO. In males and females, respectively, chemerin mRNA expression (2 -ΔCT ) was reduced from 0.53 to 0.001 ± 0.002 and 0.23 to 0.001 ± 0.02 in liver, 0.05 to 0.01 ± 0.005 and 0.07 to 0.005 ± 0.02 in RP fat, and 0.09 to 0.01 ± 0.003 and 0.05 to 0.001 ± 0.02 in epididymal/uterine fat. MAP in control ASO rats showed no significant change from baseline measurements (M:137.4 ± 3.0 /F: 130.6 ± 1.5 mmHg), while males and females treated with whole-body ASO dropped by 10.7 ± 1.6 and 10.9 ± 2.1 mmHg respectively after four injections, with no significant change in heart rate. Pulse pressure also decreased by 5.6 ± 1.3 and 6.8 ± 1.3 mmHg in whole-body ASO males and females, respectively, with no significant changes from baseline in the control animals. These data suggest, contrary to our hypothesis, that chemerin plays a similar role in basal blood pressure regulation in males and females. This indicates that males and females may be equally dependent on chemerin for high fat diet-induced hypertension.

A Review on Birth control: Natural source as Anti-fertility agents

The population is increasing at a steady rate worldwide and it is now identified as one of the main threats to our planet in the 21st century. Since ancient times herbal medicines have been used for fertility regulation in males and females. Antifertility agents and contraceptive agents are the drugs that hinder the process of fertilization through barrier as well as the anti-fertility effects. Contraception involves the methodology of preventing the normal process of ovulation by affecting the menstrual cycle, fertilization, and ovulation. One example of birth control pills is progesterone and estrogen in combination. Anti-fertility component noticed as an active agent in females for prevention of fertilization and in case of males, prevention of spermatogenesis by inhibiting testosterone or action on the gonadotropin of organs or mortality of sperms. Numerous plants have phytoestrogens as novel agents which have noxious effects by making changes in the normal gestation procedure and lead to impaired fertility in domestic animals. Various experimental models have been developed and evidenced for evaluating the efficacy of antifertility agents. The review provides a comprehensive summary of contraceptive methods used in males and females, various plants, parts of plants and extracts are been used for the facilitation of anti-fertility have used as anti-fertility agents. Moreover highlighted old and presently used experimental models for the evaluating the anti-fertility agents.

PTBP2 – a gene with relevance for both Anorexia nervosa and body weight regulation

Genetic factors are relevant for both eating disorders and body weight regulation. A recent genome-wide association study (GWAS) for anorexia nervosa (AN) detected eight genome-wide significant chromosomal loci. One of these loci, rs10747478, was also genome-wide and significantly associated with body mass index (BMI). The nearest coding gene is the Polypyrimidine Tract Binding Protein 2 gene (PTBP2). To detect mutations in PTBP2, Sanger sequencing of the coding region was performed in 192 female patients with AN (acute or recovered) and 191 children or adolescents with (extreme) obesity. Twenty-five variants were identified. Twenty-three of these were predicted to be pathogenic or functionally relevant in at least one in silico tool. Two novel synonymous variants (p.Ala77Ala and p.Asp195Asp), one intronic SNP (rs188987764), and the intronic deletion (rs561340981) located in the highly conserved region of PTBP2 may have functional consequences. Ten of 20 genes interacting with PTBP2 were studied for their impact on body weight regulation based on either previous functional studies or GWAS hits for body weight or BMI. In a GWAS for BMI (Pulit et al. 2018), the number of genome-wide significant associations at the PTBP2 locus was different between males (60 variants) and females (two variants, one of these also significant in males). More than 65% of these 61 variants showed differences in the effect size pertaining to BMI between sexes (absolute value of Z-score >2, two-sided p < 0.05). One LD block overlapping 5′UTR and all coding regions of PTBP2 comprises 56 significant variants in males. The analysis based on sex-stratified BMI GWAS summary statistics implies that PTBP2 may have a more pronounced effect on body weight regulation in males than in females.

The Role of Reproductive Hormones in Sex Differences in Sleep Homeostasis and Arousal Response in Mice.

There are various sex differences in sleep/wake behaviors in mice. However, it is unclear whether there are sex differences in sleep homeostasis and arousal responses and whether gonadal hormones are involved in these sex differences. Here, we examined sleep/wake behaviors under baseline condition, after sleep deprivation by gentle handling, and arousal responses to repeated cage changes in male and female C57BL/6 mice that are hormonally intact, gonadectomized, or gonadectomized with hormone supplementation. Compared to males, females had longer wake time, shorter non-rapid eye movement sleep (NREMS) time, and longer rapid eye movement sleep (REMS) episodes. After sleep deprivation, males showed an increase in NREMS delta power, NREMS time, and REMS time, but females showed a smaller increase. Females and males showed similar arousal responses. Gonadectomy had only a modest effect on homeostatic sleep regulation in males but enhanced it in females. Gonadectomy weakened arousal response in males and females. With hormone replacement, baseline sleep in gonadectomized females was similar to that of intact females, and baseline sleep in gonadectomized males was close to that of intact males. Gonadal hormone supplementation restored arousal response in males but not in females. These results indicate that male and female mice differ in their baseline sleep–wake behavior, homeostatic sleep regulation, and arousal responses to external stimuli, which are differentially affected by reproductive hormones.

1950-P: Fat Mass Affects Metabolic Response to Erythropoietin in Mice

Erythropoietin (EPO) is required for erythrocyte production. However, EPO receptor (EpoR) expression extends beyond erythroid tissue. To assess EPO activity on glucose homeostasis and fat mass accumulation, wild type (WT, C57BL/6) mice, ΔEpoRE mice with EpoR restricted to hematopoietic tissue and ΔEpoRWAT mice with targeted EpoR deletion in fat tissue were fed a high fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at age 3, 4, and 6 months. EPO increased hematocrit in all mice and improved glucose tolerance when fat mass was less than 35% which included all female mice. In male WT mice EPO improved glucose tolerance and reduced fat mass which at 6 months was 40% on HFD and below 35% with HFD/EPO treatment. In female mice, estrogen interferes with EPO fat mass regulation. EPO treatment did not affect fat mass in ΔEpoRE mice, indicating that EPO regulation of fat mass is a non-hematopoietic response. EPO improved glucose tolerance in female and only age 3 month male ΔEpoRE mice when fat mass was less than 35%. In male ΔEpoRWAT mice, EPO minimally reduced fat mass indicating that EPO fat mass regulation in males is largely a direct fat tissue response. EPO treatment improved glucose tolerance in male ΔEpoRWAT mice when fat mass was below 35% but not at 6 months when fat mass exceeded 40%. These data demonstrate that EPO improved glucose tolerance when fat mass was below 35%, that the sex-dimorphic EPO regulation of fat mass is primarily mediated by EpoR in fat, and that EPO activity in glucose metabolism and fat mass is differentially regulated and does not follow EPO stimulated erythropoiesis. Disclosure H. Rogers: None. C.T. Noguchi: None. Funding National Institutes of Health

Aromatase deficiency in hematopoietic cells improves glucose tolerance in male mice through skeletal muscle-specific effects.

Estrogens are important for maintaining metabolic health in males. However, the key sources of local estrogen production for regulating energy metabolism have not been fully defined. Immune cells exhibit aromatase activity and are resident in metabolic tissues. To determine the relative contribution of immune cell-derived estrogens for metabolic health in males, C57BL6/J mice underwent bone marrow transplant with marrow from either wild-type (WT(WT)) or aromatase-deficient (WT(ArKO)) donors. Body weight, body composition, and glucose and insulin tolerance were assessed over 24 weeks with mice maintained on a regular chow diet. No differences were found in insulin sensitivity between groups, but WT(ArKO) mice were more glucose tolerant than WT(WT) mice 20 weeks after transplant, suggestive of enhanced glucose disposal (AUCglucose 6061±3349 in WT(WT) mice versus 3406±1367 in WT(ArKO) mice, p = 0.01). Consistent with this, skeletal muscle from WT(ArKO) mice showed higher expression of the mitochondrial genes Ppargc1a (p = 0.03) and Nrf1 (p = 0.01), as well as glucose transporter type 4 (GLUT4, Scl2a4; p = 0.02). Skeletal muscle from WT(ArKO) mice had a lower concentration of 17β-estradiol (5489±2189 pg/gm in WT(WT) mice versus 3836±2160 pg/gm in WT(ArKO) mice, p = 0.08) but higher expression of estrogen receptor-α (ERα, Esr1), raising the possibility that aromatase deficiency in immune cells led to a compensatory increase in ERα signaling. No differences between groups were found with regard to body weight, adiposity, or gene expression within adipose tissue or liver. Immune cells are a key source of local 17β-estradiol production and contribute to metabolic regulation in males, particularly within skeletal muscle. The respective intracrine and paracrine roles of immune cell-derived estrogens require further delineation, as do the pathways that regulate aromatase activity in immune cells specifically within metabolic tissues.

Disadaptive reactions of the cardiovascular system in relation to sleep and coping behavior in students of northern medical institute

The aimof the study is to assess the relation between hemodynamic parameters and coping behavior and sleep in order to maintain health of students of the northern university.Design and methods. We examined 96 students of the northern medical university (61 females). During academic days, we performed ambulatory monitoring of blood pressure (ABPM) 24 h + 10–120 minutes. We analyzed following parameters: mezors of heart rate (HR), systolic (SBP), diastolic (DBP), and pulse blood pressure (BP), mean BP, Kerdo autonomic index (KI), functional change index (FCI); hypertension time indices of SBP (TI SBP) and DBD (TI DBP) (%), variability of SBP (Var. SBD) and DBD (Var. DBP); night dipping of SBP and DBP (%). We assessed coping behavior. The sleep was assessed using the subjective characteristics of sleep questionnaire and the Epworth sleepiness scale. Statistical analysis was performed using Statistica 10.0 and Excel 2013 software.Results. We found optimal/normal values of mean BP and intersexual differences among students. Female students in all periods showed higher rates of HR and sympathetic influences; males had higher SBD, higher TI SBP during day and night, higher SBP variability at night, and tended to develop isolated systolic hypertension. Parameters and dynamics of the vascular component of BP are in normal ranges. We did not find significant intersexual differences in mechanisms of the vascular regulation. Cardiovascular system regulation in males depended on the sleep and coping, and it was more autonomous from behavior in girls.Conclusions. One of the most effective and affordable ways to prevent cardiovascular diseases during the university education is the consistent training of students in adaptive behavior in a situation of psycho-emotional stress and recommendations on sleep hygiene. Greater efficiency of the learning adaptive coping behavior can be expected in males, and male gender is one of the non-modifiable risk factors for cardiovascular pathology.

Sex Differences in the Production of SLC5A5, Thyroid Peroxidase, and Thyroid Hormones in Pubertal Rats Exposed to Endocrine Disruptor Dichlorodiphenyltrichloroethane (DDT) during Postnatal Ontogeny.

Sex differences in the expression of iodide transporter SLC5A5 and thyroid peroxidase in thyroid follicular epithelium and thyroid serum profile were assessed in pubertal rats exposed to endocrine disruptor DDT starting from the first postnatal day. It was found that exposure to DDT reduced expression of SLC5A5 in peripheral regions of thyroid lobes in males and in central regions in females. The most pronounced sex differences were observed in thyroid peroxidase expression that remained sensitive to thyroid stimulating hormone regulation in males and lost sensitivity to pituitary stimulation in females after exposure to disruptor, which determines more pronounced hypothyroidism in females.

AB294. SPR-21 Sex differences in bladder dysfunction in response to enteric neuronal NFκB overactivation and experimentally induced colitis in mice

ObjectiveIn experimental models, animals with induced colitis have increased urinary frequency and abnormalities in bladder contraction to cholinergic and electric field stimulation (EFS). Nuclear factor kappa B (NFκB) is a major mediator of the inflammatory response in inflammatory bowel disease and syndrome. The aim of the present study was to determine the effect of increased NFκB signalling in enteric neurons on bladder contraction with and without experimentally induced colitis.MethodsCalretinin-Cre-ERT2-IKK2CA/tdTomato transgenic (TG) mice were generated and compared to littermate wild-type (WT) controls. At two months of age, the mice were treated for three days with tamoxifen causing continuous NFκB activation in enteric neuronal cells. One month later, the mice were treated with vehicle or 2.5% dextran sulfate sodium (DSS) for 7 days to induce colitis. Full thickness urinary bladder strips were stimulated with potassium and then EFS to induce nerve mediated contraction. The effect of atropine to inhibit muscarinic receptors and alpha, beta methylene ATP (ATP) to desensitize purinergic receptors was determined.ResultsEven though the bladder contractile response to high potassium stimulation was similar between sexes in both WT and TG mice, the EFS induced maximal contraction was greater in WT males than in WT females. Bladder strips from WT female mice had a significantly greater atropine resistant (purinergic) component of EFS induced contraction, compared to WT male mice, but this was not found in TG mice. The cholinergic component of EFS induced contraction was not different between male and female mice (WT or TG). Acute colitis significantly reduced KCl stimulated and nerve mediated contraction in bladder strips from WT female and male mice, and from TG female mice. Constitutive activation of neuronal NFκB preserved the nerve mediated and KCL induced contractile response in male mice. Acute colitis increased the purinergic component of nerve mediated contractions in male WT mice only.ConclusionsExperimentally induced colitis causes decreased bladder contraction. Neuronal NFκB signalling rescued the decreased bladder contraction due to colitis, perhaps through purinergic regulation in males. Neurogenic inflammation in the bladder may cause a larger degree of bladder dysfunction in female than in male mice perhaps because females have a greater purinergic component of nerve mediated bladder contraction that does not further increase due to colitisFunding Source(s)RO1DK075684; P2ODK097819

Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design.

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body’s principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems. Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission. Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males. In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR). These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases. Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%). These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission.

A Multiscale, Mechanism-Driven, Dynamic Model for the Effects of 5α-Reductase Inhibition on Prostate Maintenance

A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound binding properties, dosing regimens, and target validation.

Thermal tolerance of the crab Pachygrapsus marmoratus: intraspecific differences at a physiological (CTMax) and molecular level (Hsp70)

Temperature is one of the most important variables influencing organisms, especially in the intertidal zone. This work aimed to test physiological and molecular intraspecific differences in thermal tolerance of the crab Pachygrapsus marmoratus (Fabricius, 1787). The comparisons made focused on sex, size, and habitat (estuary and coast) differences. The physiological parameter was upper thermal limit, tested via the critical thermal maximum (CTMax) and the molecular parameter was total heat shock protein 70 (Hsp70 and Hsp70 plus Hsc70) production, quantified via an enzyme-linked imunosorbent assay. Results showed that CTMax values and Hsp70 production are higher in females probably due to different microhabitat use and potentially due to different hormonal regulation in males and females. Among females, non-reproducing ones showed a higher CTMax value, but no differences were found in Hsp70, even though reproducing females showed higher variability in Hsp70 amounts. As reproduction takes up a lot of energy, its allocation for other activities, including stress responses, is lower. Juveniles also showed higher CTMax and Hsp70 expression because they occur in greater shore heights and ageing leads to alterations in protein synthesis. Comparing estuarine and coastal crabs, no differences were found in CTMax but coastal crabs produce more Hsp70 than estuarine crabs because they occur in drier and hotter areas than estuarine ones, which occur in moister environments. This work shows the importance of addressing intraspecific differences in the stress response at different organizational levels. This study shows that these differences are key factors in stress research, climate research, and environmental monitoring.

Reduced body weight in male Tspan8-deficient mice

The gene TSPAN8 was recently identified in a genome-wide association study as the most likely causal gene in a locus that was correlated with the risk of type 2 diabetes (T2D) in northern European individuals. To assess whether Tspan8 is the actual T2D-causal gene in this locus, we ablated its expression in mice and determined the consequences of this ablation on a multitude of metabolic traits. We found that genetic ablation of Tspan8 in mice results in a reduction (-15.6%) in the body weight of males fed a normal chow diet and that this deficiency results in a resistance to body weight gain (-13.7%) upon feeding a high fat and high carbohydrate diet. The differences in body weight could only be detected in male mice and were the consequence of both a decrease in fat deposition, and a decrease in lean body mass (16.9 and 11%, respectively). In spite of the significant body weight difference, no changes in fasting insulin and glucose levels could be detected in Tspan8 knockout mice, nor could we identify changes in the clearance of glucose or sensitivity to insulin in oral glucose tolerance test and intraperitoneal insulin sensitivity test studies, respectively. In addition, male Tspan8 knockout mice showed significantly lower bone mineral density and phosphorus levels (6.2 and 16.6%, respectively). Expression of Tspan8 in mouse was highest in digestive tissues, but virtually absent from the pancreas. In contrast, expression of human TSPAN8 was substantial in digestive tissues, as well as pancreatic cells. Our results argue for a role for Tspan8 in body-weight regulation in males, but do not show differences in T2D-associated traits that were anticipated from previous human genome-wide association studies. Differences in Tspan8 expression levels in mouse and human tissues suggest that Tspan8 could fulfill different or additional physiological functions in these organisms.

Genetics: Male regulator switched

Genetics: Male regulator switched

Cardiac action potential duration and calcium regulation in males and females

Adult women have longer QT intervals compared with men of a similar age, indicating differences in the speed of repolarisation of the ventricles. We investigate the influences of gender on ventricular electrophysiology and intracellular Ca2+ regulation of the guinea pig heart. Comparing sexually mature animals, females exhibited a significantly longer APD. Peak L-type Ca2+ current (ICaL) was larger in females and when this current was inhibited with nifedipine the gender differences in APD were removed. APD differences also disappeared when the SR was depleted of Ca2+. Inactivation of ICaL during a clamp step is faster in females but slower during an action potential and SR Ca2+ content is larger. We suggest that gender differences in APD result from variation in the kinetics of ICaL stemming from alterations to Ca2+ release.