Female-specific target sites for both oestrogen and androgen in the teleost brain

To dissect the molecular and cellular basis of sexual differentiation of the teleost brain, which maintains marked sexual plasticity throughout life, we examined sex differences in neural expression of all subtypes of nuclear oestrogen and androgen receptors (ER and AR) in medaka. All receptors were differentially expressed between the sexes in specific nuclei in the forebrain. The most pronounced sex differences were found in several nuclei in the ventral telencephalic and preoptic areas, where ER and AR expression were prominent in females but almost completely absent in males, indicating that these nuclei represent female-specific target sites for both oestrogen and androgen in the brain. Subsequent analyses revealed that the female-specific expression of ER and AR is not under the direct control of sex-linked genes but is instead regulated positively by oestrogen and negatively by androgen in a transient and reversible manner. Taken together, the present study demonstrates that sex-specific target sites for both oestrogen and androgen occur in the brain as a result of the activational effects of gonadal steroids. The consequent sex-specific but reversible steroid sensitivity of the adult brain probably contributes substantially to the process of sexual differentiation and the persistent sexual plasticity of the teleost brain.     

Tuning breadth and sex-specific sensitivity in chemosensory neurons of male and female Uca pugnax

Chemosensory neurons of female fiddler crabs (genus Uca) display greater sensitivity to mixtures of food-related stimuli than do neurons in males. This phenomenon represents an interesting contrast to other sex-specific systems, which tend to be in response to cues associated with mating and parental care. This study examined the responses of chemosensory neurons in males and females to ten individual stimuli to determine if sex-specific responses were restricted to a few key compounds, or if the heightened sensitivity of females was broadly distributed. Neurons in males and females responded well to all stimuli, and although fiddler crabs are primarily herbivorous, highly efficacious physiological stimulants included amino acids and amines as well as carbohydrates most closely associated with plant material. The chemosensory neurons are characterized by broad tuning and relatively high response thresholds, when compared to other crustaceans. Most importantly, the investigations revealed a robust pattern in which female neurons displayed elevated responses to all stimuli. Tuning breadth was not shown to be sex-specific, nor were there detectable differences in over-all response profiles. The most likely explanation for these patterns is that the broad sex-specificity in Uca is produced via fundamental alterations in cellular properties associated with chemosensory transduction. Accepted: 29 June 1999     

Regulation of the expression of the sex-specific isoforms of cytochrome P-450 in rat liver

The hepatic metabolism of steroid hormones and of xenobiotics frequently depends on the expression of the sex-specific isoforms of cytochrome P-450 and on differences in sex hormones. Following biochemical, immunological and molecular biological investigations, it was shown that in adult rat liver there exist at least four male-specific and one female-specific isoforms of cytochrome P-450. The designation of these sex-specific genes is IIC11, IIIA2, IIC13 and IIA2 in males, and IIC12 in females. The irreversible programming of the expression of these isoforms of cytochrome P-450 in adulthood occurs during the perinatal period of life, and is named enzyme imprinting. One of the main factors that regulates the expression of the sex-specific isoforms of cytochrome P-450 is the level of androgens in the blood. Castration of adult rats decreased the level of the male isoforms of cytochrome P-450 and the activity of the monooxygenase enzyme system that remained higher than in intact females. The mechanism of enzyme imprinting can be explained as follows: neonatal androgens program the secretion of hypothalamic hormones, somatostatin and growth-hormone-releasing factor. These factors determine the type of growth hormone secretion in adult rats, and this controls the type of sex-specific isoforms of cytochrome P-450 expressed in adulthood. Metabolic regulation similar to that outlined above was shown to occur for several metabolism-dependent chemical carcinogens. Such a pathway may explain the different sensitivity displayed by male and female rats to treatment with these carcinogenic agents. One possible way of modulating the expression of some isoforms of cytochrome P-450 in adult rats is by treating neonates with specific xenobiotics that change the constitutive expression of neonatal androgens. It appears that this enzyme imprinting plays an important role in determining the individual sensitivity to the carcinogenic effects of chemicals.     

Sex differences in telomeres and lifespan

Males and females often age at different rates resulting in longevity 'gender gaps', where one sex outlives the other. Why the sexes have different lifespans is an age-old question, still fiercely debated today. One cellular process related to lifespan, which is known to differ according to sex, is the rate at which the protective telomere chromosome caps are lost. In humans, men have shorter lifespans and greater telomere shortening. This has led to speculation in the medical literature that sex-specific telomere shortening is one cause of sex-specific mortality. However, telomere shortening may be a cause for and/or a consequence of the processes that govern survival, and to infer general principles from single-taxon studies may be misleading. Here, we review recent work on telomeres in a variety of animal taxa, including those with reverse sexual lifespan dimorphism (i.e., where males live longer), to establish whether sex-specific survival is generally associated with sex differences in telomere dynamics. By doing this, we attempt to tease apart the potential underlying causes for sex differences in telomere lengths in humans and highlight targets for future research across all taxa.     

Sex differences and estrogen modulation of the cellular immune response after injury

Cell-mediated immunity is extremely important for resolution of infection and for proper healing from injury. However, the cellular immune response is dysregulated following injuries such as burn and hemorrhage. Sex hormones are known to regulate immunity, and a well-documented dichotomy exists in the immune response to injury between the sexes. This disparity is caused by differences in immune cell activation, infiltration, and cytokine production during and after injury. Estrogen and testosterone can positively or negatively regulate the cellular immune response either by aiding in resolution or by compounding the morbidity and mortality. It is apparent that the hormonal dysregulation is dependent not only on the type of injury sustained but also the amount of circulating hormones. Therefore, it may be possible to design sex-specific therapies to improve immunological function and patient outcome.     

Tetrahydrobiopterin Availability in Parkinson’s and Alzheimer’s Disease; Potential Pathogenic Mechanisms

Within the central nervous system, tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis. In addition, BH4 is now established to be an essential cofactor for all isoforms of nitric oxide synthase (NOS). Inborn errors of metabolism affecting BH4 availability are well documented and the clinical presentation can be attributed to a paucity of dopamine, serotonin, and nitric oxide (NO) generation. In this article, we have focussed upon the sensitivity of BH4 to oxidative catabolism and the observation that when BH4 is limiting some cellular sources of NOS may generate superoxide whilst other BH4 saturated NOS enzymes may be generating NO. Such a scenario could favor peroxynitrite generation. If peroxynitrite is not scavenged, e.g., by antioxidants such as reduced glutathione, irreversible damage to critical cellular enzymes could ensue. Such targets include components of the mitochondrial electron transport chain, alpha ketoglutarate dehydrogenase and possibly pyruvate dehydrogenase. Such a cascade of events is hypothesized, in this article, to occur in neurodegerative conditions such as Parkinson’s and Alzheimer’s disease.     

Sexual dimorphism from birth to age 60 in relation to the type of body shape

Sexual dimorphism depends on age. It can be analysed within a population by a comparison of sex-specific body measurements based on cross-sectional samples. We analysed four length measurements, three circumferences, and one skinfold diameter of a representative cross-sectional sample of healthy German subjects aged 0 to 65 years. We here report that sexual dimorphism of these body measurements already is present in newborns. The percentages of anthropometric differences between female and male subjects behave in a specific pattern during growth age from birth up to adolescence. Girls are born smaller on an average, but they have a more accelerated growth than boys. Girls reach the peak of their adolescent growth spurt earlier in their chronological age. This means that their biological age at this time is at least 2 years older than that of boys of the same chronological age. This sex-specifically differential onset of the adolescent growth spurt, and its peak, as well as the differential decrease of growth velocity cause a dramatic change in sexual dimorphism. This change is clearly shown in this cross-sectional study. Except for the subcutaneous fat layer, there is a clear male growth advantage in all of the measurements investigated after the peak of the adolescent growth spurt. The largest differences between the measurements of both sexes in favour of the male sex are reached at young adult age. In the further course of life, the anthropometrical differences between the sexes decrease again. Sexual dimorphism within a population at a defined chronological age is therefore not only the result of a developing sex-specific physique, but also the result of a sex-specific growth velocity during the successive stages of biological development. Interestingly, we found that the sex-specific velocity of physical development, and by this the development of sexual dimorphism, proceeds differently in the tall and slim leptomorphic individuals in comparison to the smaller and more corpulent pyknomorphic individuals.     

Linkage mapping of sex-specific differences

Most current linkage analyses assume identical fractions of meiotic recombination between homologous marker loci of the two sexes. This assumption is not realistic, because considerable sex-related differences have been observed in recombination fraction. In this paper, a general EM-based algorithm is presented to estimate sex-specific recombination fractions for a mixed set of molecular markers segregating differently in a full-sib family derived from two heterozygous parents. The asymptotic variances of the estimates of linkage specifically for each of the parents are evaluated using a numerical analysis based on information functions. This approach will have important implications for precise gene mapping based on sex-specific linkage maps.     

Sex-specific differences in chromosome-dependent regulation of vascular reactivity in female consomic rat strains from a SSxBN cross

High-throughput studies in the Medical College of Wisconsin Program for Genomic Applications (Physgen) were designed to link chromosomes with physiological function in consomic strains derived from a cross between Dahl salt-sensitive SS/JrHsdMcwi (SS) and Brown Norway normotensive BN/NHsdMcwi (BN) rats. The specific goal of the vascular protocol was to characterize the responses of aortic rings from these strains to vasoconstrictor and vasodilator stimuli (phenylephrine, acetylcholine, sodium nitroprusside, and bath hypoxia) to identify chromosomes that either increase or decrease vascular reactivity to these vasoactive stimuli. Because previous studies demonstrated sex-specific quantitative trait loci (QTLs) related to regulation of cardiovascular phenotypes in an F2 cross between the parental strains, males and females of each consomic strain were included in all experiments. As there were significant sex-specific differences in aortic sensitivity to vasoconstrictor and vasodilator stimuli compared with the parental SS strain, we report the results of the females separately from the males. There were also sex-specific differences in aortic ring sensitivity to these vasoactive stimuli in consomic strains that were fed a high-salt diet (4% NaCl) for 3 wk to evaluate salt-induced changes in vascular reactivity. Differences in genetic architecture could contribute to sex-specific differences in the development and expression of cardiovascular diseases via differential regulation and expression of genes. Our findings are the first to link physiological traits with specific chromosomes in female SS rats and support the idea that sex is an important environmental variable that plays a role in the expression and regulation of genes.     

Stress-induced reductions of sensory reactivity in female rats depend on ovarian hormones and the application of a painful stressor

The current experiments occurred in the context of disputes in the literature concerning whether inescapable stress causes differential changes in sensory reactivity, which could lead to differences in many learning procedures. We tested rats for differences in sensitivity and responsivity to acoustic stimuli through the use of the acoustic startle response (ASR) 2 h after stressor exposure and ambulatory activity 24 h later in the open field. Stressed females showed reduced responsivity to acoustic stimuli with no apparent shift in stimulus sensitivity. Males did not show differences in either reactivity index following stressor exposure. Reduced responsivity did not occur if females had been OVX (OVX alone did not effect stimulus responsivity or sensitivity). All groups that experienced tailshock stress also had reduced open field activity 24 h later. Restraint for 2 h did not reduce stimulus responsivity in the ASR or open field activity in female rats. Acute reductions in ASRs after a painful stressor appear to be a feature specific to females, with an apparent role of ovarian hormones as a modulator of the effect. Possible hormone and/or immunological mechanisms of these sex-specific effects are discussed. Understanding the mechanisms of this stressor-induced reduction in sensory reactivity could advance our knowledge of how individual differences in ovarian hormone levels influence the physical and psychological processes by which females acutely respond and later recover from traumatic events.     

Microsatellite (GATA)n reveals sex-specific differences in Papaya

Papaya, an economically important fruit plant, is polygamous in nature. The sex of dioecious papaya plants can be deduced only after they attain reproductive maturity (6–8 months). Normally, 50% of the population in a field is composed of unfruitful male plants and almost 45% of these have to be uprooted at the flowering stage. This unnecessary cultivation of unwanted males leads to wastage of resources, which can be avoided if the sex of the plant is determined at juvenile stage. Morphological and cytological studies conducted so far have failed to differentiate between the various sex forms of papaya. Its dioecious nature, occasional sex-reversal of male flowers and the absence of a heteromorphic pair of sex chromosomes make papaya an interesting system to study sex determination at the molecular level. In the present study, highly informative microsatellite and minisatellite probes were employed to identify sex-specific differences in papaya. Among these, only the microsatellite probe (GATA)₄ demonstrated sex-specific differences in all the cultivars analysed. The diagnostic potential of this microsatellite marker was exploited to sex papaya plants at the seedling stage. This study also indicates that the genetic material of the X and Y chromosomes of papaya is diverging in a sex-specific manner and hence they are in the process of differentiation. Received: 26 February 1999 / Accepted: 25 March 1999     

Distinct Molecular Phenotypes in Male and Female Schizophrenia Patients

Background

In schizophrenia, sex specific dimorphisms related to age of onset, course of illness and response to antipsychotic treatment may be mirrored by sex-related differences in the underlying molecular pathways.

Methodology/Principal Findings

Here, we have carried out multiplex immunoassay profiling of sera from 4 independent cohorts of first episode antipsychotic naive schizophrenia patients (n = 133) and controls (n = 133) to identify such sex-specific illness processes in the periphery. The concentrations of 16 molecules associated with hormonal, inflammation and growth factor pathways showed significant sex differences in schizophrenia patients compared with controls. In female patients, the inflammation-related analytes alpha-1-antitrypsin, B lymphocyte chemoattractant BLC and interleukin-15 showed negative associations with positive and negative syndrome scale (PANSS) scores. In male patients, the hormones prolactin and testosterone were negatively associated with PANSS ratings. In addition, we investigated molecular changes in a subset of 33 patients before and after 6 weeks of treatment with antipsychotics and found that treatment induced sex-specific changes in the levels of testosterone, serum glutamic oxaloacetic transaminase, follicle stimulating hormone, interleukin-13 and macrophage-derived chemokine. Finally, we evaluated overlapping and distinct biomarkers in the sex-specific molecular signatures in schizophrenia, major depressive disorder and bipolar disorder.

Conclusions/Significance

We propose that future studies should investigate the common and sex-specific aetiologies of schizophrenia, as the current findings suggest that different therapeutic strategies may be required for male and female patients.     

A sex-specific metabolite identified in a marine invertebrate utilizing phosphorus-31 nuclear magnetic resonance

Hormone level differences are generally accepted as the primary cause for sexual dimorphism in animal and human development. Levels of low molecular weight metabolites also differ between men and women in circulating amino acids, lipids and carbohydrates and within brain tissue. While investigating the metabolism of blue crab tissues using Phosphorus-31 Nuclear Magnetic Resonance, we discovered that only the male blue crab (Callinectes sapidus) contained a phosphorus compound with a chemical shift well separated from the expected phosphate compounds. Spectra obtained from male gills were readily differentiated from female gill spectra. Analysis from six years of data from male and female crabs documented that the sex-specificity of this metabolite was normal for this species. Microscopic analysis of male and female gills found no differences in their gill anatomy or the presence of parasites or bacteria that might produce this phosphorus compound. Analysis of a rare gynandromorph blue crab (laterally, half male and half female) proved that this sex-specificity was an intrinsic biochemical process and was not caused by any variations in the diet or habitat of male versus female crabs. The existence of a sex-specific metabolite is a previously unrecognized, but potentially significant biochemical phenomenon. An entire enzyme system has been synthesized and activated only in one sex. Unless blue crabs are a unique species, sex-specific metabolites are likely to be present in other animals. Would the presence or absence of a sex-specific metabolite affect an animal's development, anatomy and biochemistry?     

Sex-specific genetic differentiation and coalescence times: estimating sex-biased dispersal rates

I derive the equilibrium values of sex-specific FST parameters, in an island model for a dioecious species with sex-biased dispersal and binomial distribution of family size before dispersal (as assumed in a Wright-Fisher population). I show that FST may take different values among males and among females whenever dispersal is a trait conditioned on gender. This has not always been recognized, because some models assumed that genes are sampled before dispersal. In particular, the ratios of sex-specific FST parameters evaluated after dispersal over FST evaluated before dispersal are simple functions of sex-specific dispersal rates. Therefore, a simple moment-based estimator of sex-specific dispersal rate is proposed. This method is based on the comparison of FST estimated before and after dispersal and assumes equilibrium between migration and drift. I evaluate this method through stochastic simulations for a range of sex-specific dispersal rates and sampling effort (sample size, number of loci scored).     

Sex differences in phenotypic plasticity of a mechanism that controls body size: implications for sexual size dimorphism

The degree and/or direction of sexual size dimorphism (SSD) varies considerably among species and among populations within species. Although this variation is in part genetically based, much of it is probably due to the sexes exhibiting differences in body size plasticity. Here, we use the hawkmoth, Manduca sexta, to test the hypothesis that moths reared on different diet qualities and at different temperatures will exhibit sex-specific body size plasticity. In addition, we explore the proximate mechanisms that potentially create sex-specific plasticity by examining three physiological variables known to regulate body size in this insect: the growth rate, the critical weight (which measures the cessation of juvenile hormone secretion from the corpora allata) and the interval to cessation of growth (ICG; which measures the time interval between the critical weight and the secretion of the ecdysteroids that regulate pupation and metamorphosis). We found that peak larval mass of males and females did not exhibit sex-specific plasticity in response to diet or temperature. However, the sexes did exhibit sex-specific plasticity in the mechanism that controls size; males and females exhibited sex-specific plasticity in the growth rate and the critical weight in response to both diet and temperature, whereas the ICG only exhibited sex-specific plasticity in response to diet. Our results suggest it is important for the sexes to maintain the same degree of SSD across environments and that this is accomplished by the sexes exhibiting differential sensitivity of the physiological factors that determine body size to environmental variation.     

The integrative role of cryo electron microscopy in molecular and cellular structural biology

After gradually moving away from preparation methods prone to artefacts such as plastic embedding and negative staining for cell sections and single particles, the field of cryo electron microscopy (cryo‐EM) is now heading off at unprecedented speed towards high‐resolution analysis of biological objects of various sizes. This ‘revolution in resolution’ is happening largely thanks to new developments of new‐generation cameras used for recording the images in the cryo electron microscope which have much increased sensitivity being based on complementary metal oxide semiconductor devices. Combined with advanced image processing and 3D reconstruction, the cryo‐EM analysis of nucleoprotein complexes can provide unprecedented insights at molecular and atomic levels and address regulatory mechanisms in the cell. These advances reinforce the integrative role of cryo‐EM in synergy with other methods such as X‐ray crystallography, fluorescence imaging or focussed‐ion beam milling as exemplified here by some recent studies from our laboratory on ribosomes, viruses, chromatin and nuclear receptors. Such multi‐scale and multi‐resolution approaches allow integrating molecular and cellular levels when applied to purified or in situ macromolecular complexes, thus illustrating the trend of the field towards cellular structural biology.     

Sex Differences in Liver Toxicity—Do Female and Male Human Primary Hepatocytes React Differently to Toxicants In Vitro?

There is increasing amount of evidence for sex variation in drug efficiency and toxicity profiles. Women are more susceptible than men to acute liver injury from xenobiotics. In general, this is attributed to sex differences at a physiological level as well as differences in pharmacokinetics and pharmacodynamics, but neither of these can give a sufficient explanation for the diverse responses to xenobiotics. Existing data are mainly based on animal models and limited data exist on in vitro sex differences relevant to humans. To date, male and female human hepatocytes have not yet been compared in terms of their responses to hepatotoxic drugs. We investigated whether sex-specific differences in acute hepatotoxicity can be observed in vitro by comparing hepatotoxic drug effects in male and female primary human hepatocytes. Significant sex-related differences were found for certain parameters and individual drugs, showing an overall higher sensitivity of female primary hepatocytes to hepatotoxicants. Moreover, our work demonstrated that high content screening is feasible with pooled primary human hepatocytes in suspension.     

Distinct regulatory programs establish widespread sex-specific alternative splicing in Drosophila melanogaster

In Drosophila melanogaster, female-specific expression of Sex-lethal (SXL) and Transformer (TRA) proteins controls sex-specific alternative splicing and/or translation of a handful of regulatory genes responsible for sexual differentiation and behavior. Recent findings in 2009 by Telonis-Scott et al. document widespread sex-biased alternative splicing in fruitflies, including instances of tissue-restricted sex-specific splicing. Here we report results arguing that some of these novel sex-specific splicing events are regulated by mechanisms distinct from those established by female-specific expression of SXL and TRA. Bioinformatic analysis of SXL/TRA binding sites, experimental analysis of sex-specific splicing in S2 and Kc cells lines and of the effects of SXL knockdown in Kc cells indicate that SXL-dependent and SXL-independent regulatory mechanisms coexist within the same cell. Additional determinants of sex-specific splicing can be provided by sex-specific differences in the expression of RNA binding proteins, including Hrp40/Squid. We report that sex-specific alternative splicing of the gene hrp40/squid leads to sex-specific differences in the levels of this hnRNP protein. The significant overlap between sex-regulated alternative splicing changes and those induced by knockdown of hrp40/squid and the presence of related sequence motifs enriched near subsets of Hrp40/Squid-regulated and sex-regulated splice sites indicate that this protein contributes to sex-specific splicing regulation. A significant fraction of sex-specific splicing differences are absent in germline-less tudor mutant flies. Intriguingly, these include alternative splicing events that are differentially spliced in tissues distant from the germline. Collectively, our results reveal that distinct genetic programs control widespread sex-specific splicing in Drosophila melanogaster.