Male-specific Effects Research Articles

Short-term oral exposure to low doses of nano-sized TiO2 and potential modulatory effects on intestinal cells

The present study investigated potential modulatory effects of low doses of nano-sized titanium dioxide (TiO2) on intestinal cells in vivo and in vitro. After short-term exposure to TiO2 nanoparticles in rats, histopathological analysis of intestinal tissues indicated a gender-specific effect with increased length of intestinal villi in male rats only. Moreover the intestinal tissue showed nanoparticle deposition as revealed by ICP-MS determination of titanium. Increased serum testosterone levels were also detected. Considering the male-specific effects detected in vivo, the TiO2 nanoparticle interaction with intestinal cells was further characterized in vitro and the modulating effect of testosterone and a hormone-induced growth factor, namely Insulin-like Growth Factor 1 (IGF-1), was also assessed. Cytotoxicity assays and analysis of Reactive Oxygen Species (ROS) production showed neither cellular alteration nor oxidative stress for nanoparticles at low concentrations, even though they were able to penetrate intestinal cells, as revealed by electron microscopy. Cell treatments with nanoparticles in association with testosterone or IGF-1 showed increased cell proliferation, compared to nanoparticles or testosterone/IGF-1 alone. Since long-term intake of TiO2 nanoparticles at low doses is a relevant scenario for human exposure, attention should be given to the potential modulating activity of this nanomaterial on cell proliferation.

A general theory of sexual differentiation.

A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male-specific effects of the Y chromosome, including expression of the testis-determining gene Sry that causes differentiation of testes. Thus, Sry sets up lifelong sex differences in effects of gonadal hormones. Y genes also act outside of the gonads to cause male-specific effects. Differences in the number of X chromosomes between XX and XY cells cause sex differences in expression (1) of Xist, (2) of X genes that escape inactivation, and (3) of parentally imprinted X genes. Sex differences in phenotype are ultimately the result of multiple, independent sex-biasing factors, hormonal and sex chromosomal. These factors act in parallel and in combination to induce sex differences. They also can offset each other to reduce sex differences. Other mechanisms, operating at the level of populations, cause groups of males to differ on average from groups of females. The theory frames questions for further study, and directs attention to inherent sex-biasing factors that operate in many tissues to cause sex differences, and to cause sex-biased protection from disease. © 2016 Wiley Periodicals, Inc.

Male-specific effects of lipopolysaccharide on glucocorticoid receptor nuclear translocation in the prefrontal cortex of depressive rats

Inflammation plays a key role in the pathogenesis of major depressive disorder (MDD) for a subset of depressed individuals. One of the possible routes by which cytokines can induce depressive symptoms is by promoting the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis via altering glucocorticoid receptor (GR) function. We investigated the mechanisms that finely tune the GR functioning upon lipopolysaccharide (LPS), i.e., subcellular localization of the GR, the levels of its co-chaperones FK506 binding protein 52 (FKBP4) and FK506 binding protein 51 (FKBP5), the receptor phosphorylation status along with its upstream kinases, as well as mRNA levels of GR-regulated genes in the prefrontal cortex (PFC) of male and female Wistar rats. We found that upon LPS treatment, animals of both sexes exhibited depressive-like behavior and elevated serum corticosterone. However, the nuclear translocation of the GR and both FKBPs was found only in males, together with elevated phosphorylation of the GR at serine 232 and 246 and the activation and nuclear translocation of all analyzed kinases. This activation of the GR in males was paralleled with altered expression of GR-related genes, particularly PTGS2 and BDNF. Our data suggest that LPS treatment produced alterations in the mechanisms that control the GR nuclear translocation in the PFC of males, and that these mechanisms may contribute to the sex-specific dysfunction of GR-related neurotrophic and neuroinflammatory processes in inflammation-associated depression.

Reproductive toxicity of low level bisphenol A exposures in a two-generation zebrafish assay: Evidence of male-specific effects

Bisphenol A (BPA), a high-volume chemical used to make polycarbonate plastic and epoxy resins, is a ubiquitous contaminant in environment and human body. To investigate the reproductive effects of long-term exposure to low concentrations of BPA, a two-generation study was conducted using the aquatic model species of zebrafish. Our findings revealed that exposure to 1nM (0.228μg/L) BPA for continuous two generations resulted in female-biased sex ratio in both F1 and F2 adult population, decreased sperm density, and decreased sperm quality as measured by motility, velocity, ATP content and lipid peroxidation in F1 and F2 males. Females were less sensitive to BPA exposures than males as no adverse effects were found in female gonads or gametes. Delayed hatching at 48hpf and increased malformation and mortality were found in the offspring from BPA exposed F2, but not F1 parents. Most importantly, the adverse effect on larval development and survival from BPA exposed F2 parents was paternal-specific, resulting mainly from BPA exposed males. Subsequent transcription analysis of F2 male gonads revealed dysregulated mitochondrial biogenesis and significant activation of non-canonical Wnt/planar cell polarity and Wnt/Calcium signaling pathways. Gene expression analysis of larvae from BPA exposed F2 parents showed significant reduced expression of DNA methyltransferases such as dnmt1, dnmt3, and dnmt5. In conclusion, low level BPA exposures for continuous two generations not only affects sex ratio and sperm quantity/quality in F1 and F2 adults, reproductive success in offspring from F2 parents, but also perturbs various molecular pathways potentially contributing to these BPA induced male-specific reproductive defects.

Sex-specific trans-regulatory variation on the Drosophila melanogaster X chromosome.

The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change.

PM-10 * CDCA7L FUNCTIONS AS A MALE-SPECIFIC ONCOGENE IN ASTROCYTOMA

The most common types of primary brain tumors, astrocytoma and glioblastoma multiforme (GBM), are currently incurable. Both astrocytoma and GBM show male predominance, with a male to female ratio of 1.42:1 and 1.58:1, respectively. We performed linkage analysis in the Nf1-/ + ;Trp53-/ + cis (NPcis) mouse model of astrocytoma/GBM to identify a male-specific gliomagenesis modifier and further used combinatorial bioinformatics approaches as well as cross-species comparisons to prioritize male-specific candidate gene(s). Here, we showed that Cell division cycle-associated 7-like (CDCA7L), a myc cotranscription factor, is a male-specific oncogene in astrocytoma/GBM. CDCA7L expression is up-regulated in astrocytoma cells compared to normal brain, with males showing higher levels than females in both human and mouse. shRNA-mediated CDCA7L knockdown led to the decreased cell growth and viability of male-derived astrocytoma cells, but not female tumor cells in both human and mouse. Further mechanistic studies showed that CDCA7L depletion in male-derived astrocytoma cells led to the induction of cleaved Caspase-3 and p27 expression and reduction of Cyclin D1 expression. Furthermore, Cdca7l overexpression promotes the growth of WT mouse primary astrocytes only in males by inducing Cyclin D1 expression, but not in female astrocytes, suggesting a male-specific oncogenic role for CDCA7L in astrocytoma/GBM. Strikingly, CDCA7L depletion in human female U87MG GBM cells caused the increase of both growth and viability opposite to what is seen in male cells. Because male-female differences in CDCA7L action are hormone-independent, we examined whether the male-specific histone demethylase KDM5D regulates the effects of CDCA7L. We found that knockdown of KDM5D inhibits male-specific effects of CDCA7L on p27 and Cyclin D1 expression. Our data highlight the sex-specificity of CDCA7L in astrocytoma/GBM tumorigenesis and show that CDCA7L signaling pathways can be oncogenic in males, while being neutral or tumor suppressive in females. This has important implications for the application of therapies to human GBM patients.

Long-term effects of combined neonatal and adolescent stress on brain-derived neurotrophic factor and dopamine receptor expression in the rat forebrain

Altered brain-derived neurotrophic factor (BDNF) signalling and dopaminergic neurotransmission have been shown in the forebrain in schizophrenia. The ‘two hit’ hypothesis proposes that two major disruptions during development are involved in the pathophysiology of this illness. We therefore used a ‘two hit’ rat model of combined neonatal and young-adult stress to assess effects on BDNF signalling and dopamine receptor expression. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. At adulthood the medial prefrontal cortex (mPFC), caudate putamen (CPu) and nucleus accumbens (NAc) were analysed by qPCR and Western blot. The ‘two hit’ combination of MS and CORT treatment caused significant increases in BDNF mRNA and protein levels in the mPFC of male, but not female rats. BDNF mRNA expression was unchanged in the CPu but was significantly reduced by CORT in the NAc. DR3 and DR2 mRNA were significantly up-regulated in the mPFC of two-hit rats and a positive correlation was found between BDNF and DR3 expression in male, but not female rats. DR2 and DR3 expression were significantly increased following CORT treatment in the NAc and a significant negative correlation between BDNF and DR3 and DR2 mRNA levels was found. Our data demonstrate male-specific two-hit effects of developmental stress on BDNF and DR3 expression in the mPFC. Furthermore, following chronic adolescent CORT treatment, the relationship between BDNF and dopamine receptor expression was significantly altered in the NAc. These results elucidate the long-term effects of ‘two hit’ developmental stress on behaviour.

What cost mitochondria? The maintenance of functional mitochondrial DNA within and across generations.

The peculiar biology of mitochondrial DNA (mtDNA) potentially has detrimental consequences for organismal health and lifespan. Typically, eukaryotic cells contain multiple mitochondria, each with multiple mtDNA genomes. The high copy number of mtDNA implies that selection on mtDNA functionality is relaxed. Furthermore, because mtDNA replication is not strictly regulated, within-cell selection may favour mtDNA variants with a replication advantage, but a deleterious effect on cell fitness. The opportunities for selfish mtDNA mutations to spread are restricted by various organism-level adaptations, such as uniparental transmission, germline mtDNA bottlenecks, germline selection and, during somatic growth, regular alternation between fusion and fission of mitochondria. These mechanisms are all hypothesized to maintain functional mtDNA. However, the strength of selection for maintenance of functional mtDNA progressively declines with age, resulting in age-related diseases. Furthermore, organismal adaptations that most probably evolved to restrict the opportunities for selfish mtDNA create secondary problems. Owing to predominantly maternal mtDNA transmission, recombination among mtDNA from different individuals is highly restricted or absent, reducing the scope for repair. Moreover, maternal inheritance precludes selection against mtDNA variants with male-specific effects. We finish by discussing the consequences of life-history differences among taxa with respect to mtDNA evolution and make a case for the use of microorganisms to experimentally manipulate levels of selection.

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD. In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository. We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp22.33/Yp11.31 in the MO families of predominantly paternal origin (rs2535443, p = 3.8 × 10(-8) ). Five markers that reside within a 550 kb intergenic region on chromosome 13q33.3, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p = 3.3 × 10(-5) to 5.3 × 10(-7) ). In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females. Our results suggest that the pseudoautosomal boundary on Xp22.33/Yp11.31 may harbor male-specific genetic variants for ASD.

Early-Life Lead Exposure Results in Dose- and Sex-Specific Effects on Weight and Epigenetic Gene Regulation in Weanling Mice

Epidemiological and animal data suggest that the development of adult chronic conditions is influenced by early-life exposure-induced changes to the epigenome. This study investigates the effects of perinatal lead (Pb) exposure on DNA methylation and bodyweight in weanling mice. Viable yellow agouti (A(vy)) mouse dams were exposed to 0, 2.1, 16 and 32 ppm Pb acetate before conception through weaning. Epigenetic effects were evaluated by scoring coat color of A(vy)/a offspring and quantitative bisulfite sequencing of two retrotransposon-driven (A(vy) and CDK5 activator-binding protein intracisternal A particle element) and two imprinted (Igf2 and Igf2r) loci in tail DNA. Maternal blood Pb levels were below the limit of detection in controls, and 4.1, 25.1 and 32.1 µg/dl for each dose, respectively. Pb exposure was associated with a trend of increased wean bodyweight in males (p = 0.03) and altered coat color in A(vy)/a offspring. DNA methylation at A(vy) and the CDK5 activator-binding protein intracisternal A-particle element was significantly different from controls following a cubic trend (p = 0.04; p = 0.01), with male-specific effects at the A(vy) locus. Imprinted genes did not shift in methylation across exposures. Dose- and sex-specific responses in bodyweight and DNA methylation indicate that Pb acts on the epigenome in a locus-specific fashion, dependent on the genomic feature hosting the CpG site of interest, and that sex is a factor in epigenetic response.

The role of androgen receptor in transcriptional modulation of cannabinoid receptor type 1 gene in rat trigeminal ganglia

We have previously shown that anti-hyperalgesic effects of cannabinoid agonists under inflammatory condition are much greater in male than female, and that inflammatory cytokines upregulate cannabinoid receptor type 1 (CB1) expression in male, but not female, trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we investigated the mechanisms underlying the testosterone-mediated regulation of peripheral CB1 expression. We hypothesized that testosterone upregulates CB1 through transcriptional modulation by androgen receptor (AR). Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, upregulated CB1 mRNA expression in TG of male rats. The cytokine-induced upregulation was prevented by the pretreatment with flutamide, a specific antagonist for AR, but not by ICI 182,780, a specific antagonist for estrogen receptor, suggesting that the effects of testosterone are not mediated by estradiol, a testosterone metabolite. The expression levels of AR and IL-1β receptors were comparable between male and female TG, suggesting that the male specific IL-1β effects on CB1 upregulation occurs downstream to these receptors. The chromatin immunoprecipitation assay showed AR binding to the CB1 promoter in the rat TG. Furthermore, luciferase reporter assay revealed that AR activated the CB1 gene in response to testosterone or dihydrotestosterone treatment. These experiments provided compelling evidence that testosterone regulates CB1 gene transcription in TG through AR following cytokine stimulation. These results should provide mechanistic bases for understanding cytokine–hormone–neuron interactions in peripheral cannabinoid systems, and have important clinical implications for pain patients in whom testosterone level is naturally low, gradually declining or pharmacologically compromised.

666 Corticotropin Releasing Hormone Receptor 1 (CRH-R1) and Progestoerone Receptor (PGR) Polymorphisms Interact With Early Life Trauma in Healthy Controls (HC) and Patients With Irritable Bowel Syndrome (IBS)

BACKGROUND: Although studies have suggested genetic and environmental influences interact to contribute substantially to vulnerability to illness, the search for direct genetic x environmental influences contributing to the risk for IBS have been inconclusive so far. Genes regulating the effects of stress via the HPA axis have been implicated in the physiological and pathological regulation of stress reactivity as being mediated by release of hypothalamic corticotrophin releasing hormone (CRH). HPA activity is modulated by sex hormones progesterone and estrogen. HPA axis hyperactivity may be a function of psychosocial stressors such as early adverse life events (EALs) and may show sex-specific effects on emotional arousal circuitry in the brain. The hippocampus is a major component of the emotional arousal system and expresses CRH-R1, PGR and estrogen receptors (ESR1). AIMS: To examine gene-environment interactions on hippocampal volumes in male and female IBS patients and HCs. CRH-R1, PGR, and ESR1 polymorphisms were examined for effects on hippocampal volumes and interactions with early life trauma, sex, and diagnosis. METHODS: In a racially diverse community population of IBS and HCs, three SNPs of the CRH-R1 gene (rs7209436, rs110402, and rs242924), 2 SNPs of the PGR gene (rs1042838, rs10895068) and 1 SNP of the ESR1 gene (rs9340799) were genotyped. Subjects completed structural MRI scans and the volumes of the right and left hippocampus were computed. Haplotypes were created using Mendel software for each gene of interest and were analyzed in a linear regression model controlling for age, race, and total brain volume. We tested for main effects of genotype, sex, diagnosis, early life trauma index (ETI) as well as interactions between genotype and ETI with sex and diagnosis. RESULTS: 122 IBS patients (91 female) and 205 HCs (female 164) were studied. Significant Sex x Gene x ETI interactions were seen for PGR and CRH-R1 in the right hippocampus and for PGR in the left hippocampus. For males with PGR minor alleles, higher ETI was associated with smaller right and left hippocampal volumes, while no effect was seen in females. For males with CRH-R1 major alleles, higher ETI was associated with smaller right hippocampal volume. CONCLUSION: Sex differences in interactions between EALs and polymorphisms in genes directly involved or modulating the stress reactivity CRH system were demonstrated for volume of the hippocampus, a region involved in emotional arousal. Specifically, PGR and CRH-R1 demonstrated male-specific effects of ETI on hippocampal volume. Both PGR and CRH-R1 are expressed in the hippocampus. Progesterone is involved in neurogenesis and modulates HPA activity. The results highlight the importance of considering sex in examining gene-environment effects in IBS.

667 Corticotropin Releasing Hormone Receptor 1 (CRH-R1) Polymorphisms Are Predictive of Irritable Bowel Syndrome (IBS) Status

BACKGROUND: Although studies have suggested genetic and environmental influences interact to contribute substantially to vulnerability to illness, the search for direct genetic x environmental influences contributing to the risk for IBS have been inconclusive so far. Genes regulating the effects of stress via the HPA axis have been implicated in the physiological and pathological regulation of stress reactivity as being mediated by release of hypothalamic corticotrophin releasing hormone (CRH). HPA activity is modulated by sex hormones progesterone and estrogen. HPA axis hyperactivity may be a function of psychosocial stressors such as early adverse life events (EALs) and may show sex-specific effects on emotional arousal circuitry in the brain. The hippocampus is a major component of the emotional arousal system and expresses CRH-R1, PGR and estrogen receptors (ESR1). AIMS: To examine gene-environment interactions on hippocampal volumes in male and female IBS patients and HCs. CRH-R1, PGR, and ESR1 polymorphisms were examined for effects on hippocampal volumes and interactions with early life trauma, sex, and diagnosis. METHODS: In a racially diverse community population of IBS and HCs, three SNPs of the CRH-R1 gene (rs7209436, rs110402, and rs242924), 2 SNPs of the PGR gene (rs1042838, rs10895068) and 1 SNP of the ESR1 gene (rs9340799) were genotyped. Subjects completed structural MRI scans and the volumes of the right and left hippocampus were computed. Haplotypes were created using Mendel software for each gene of interest and were analyzed in a linear regression model controlling for age, race, and total brain volume. We tested for main effects of genotype, sex, diagnosis, early life trauma index (ETI) as well as interactions between genotype and ETI with sex and diagnosis. RESULTS: 122 IBS patients (91 female) and 205 HCs (female 164) were studied. Significant Sex x Gene x ETI interactions were seen for PGR and CRH-R1 in the right hippocampus and for PGR in the left hippocampus. For males with PGR minor alleles, higher ETI was associated with smaller right and left hippocampal volumes, while no effect was seen in females. For males with CRH-R1 major alleles, higher ETI was associated with smaller right hippocampal volume. CONCLUSION: Sex differences in interactions between EALs and polymorphisms in genes directly involved or modulating the stress reactivity CRH system were demonstrated for volume of the hippocampus, a region involved in emotional arousal. Specifically, PGR and CRH-R1 demonstrated male-specific effects of ETI on hippocampal volume. Both PGR and CRH-R1 are expressed in the hippocampus. Progesterone is involved in neurogenesis and modulates HPA activity. The results highlight the importance of considering sex in examining gene-environment effects in IBS.

Male-Specific Differences in Proliferation, Neurogenesis, and Sensitivity to Oxidative Stress in Neural Progenitor Cells Derived from a Rat Model of ALS

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor dysfunction and the loss of large motor neurons in the spinal cord and brain stem. A clear genetic link to point mutations in the superoxide dismutase 1 (SOD1) gene has been shown in a small group of familial ALS patients. The exact etiology of ALS is still uncertain, but males have consistently been shown to be at a higher risk for the disease than females. Here we present male-specific effects of the mutant SOD1 transgene on proliferation, neurogenesis, and sensitivity to oxidative stress in rat neural progenitor cells (rNPCs). E14 pups were bred using SOD1G93A transgenic male rats and wild-type female rats. The spinal cord and cortex tissues were collected, genotyped by PCR using primers for the SOD1G93A transgene or the male-specific Sry gene, and cultured as neurospheres. The number of dividing cells was higher in male rNPCs compared to female rNPCs. However, SOD1G93A over-expression significantly reduced cell proliferation in male cells but not female cells. Similarly, male rNPCs produced more neurons compared to female rNPCs, but SOD1G93A over-expression significantly reduced the number of neurons produced in male cells. Finally we asked whether sex and SOD1G93A transgenes affected sensitivity to oxidative stress. There was no sex-based difference in cell viability after treatment with hydrogen peroxide or 3-morpholinosydnonimine, a free radical-generating agent. However, increased cytotoxicity by SOD1G93A over-expression occurred, especially in male rNPCs. These results provide essential information on how the mutant SOD1 gene and sexual dimorphism are involved in ALS disease progression.

Sex-Specific Perinatal Nicotine-Induced Asthma in Rat Offspring

Recently, we have suggested that down-regulation of homeostatic mesenchymal peroxisome proliferator-activated receptor γ signaling after in utero nicotine exposure might contribute to asthma. Here, we have exploited an in vivo rat model of asthma to determine if the effects of perinatal nicotine exposure on offspring pulmonary function and mesenchymal markers of airway contractility in both tracheal and lung parenchymal tissue are sex specific, and whether the protection afforded by the peroxisome proliferator-activated receptor γ agonist, rosiglitazone (RGZ), against the perinatal nicotine-induced effect on offspring lung is also sex specific. Pregnant rat dams received placebo, nicotine, or nicotine plus RGZ daily from Embryonic Day 6 until Postnatal Day 21, at which time lung resistance, compliance, tracheal contractility, and the expression of structural and functional mesenchymal markers of pulmonary contractility were determined. Compared with control animals, perinatal nicotine exposure caused a significant increase in airway resistance and a decrease in airway compliance after a methacholine challenge in both male and female offspring, with more pronounced changes in the males. In contrast to this, the effects of perinatal nicotine exposure on acetylcholine-induced tracheal constriction, along with the expression of its mesenchymal markers, were observed exclusively in the male offspring. Concomitant treatment with RGZ normalized the nicotine-induced alterations in pulmonary function in both sexes, as well as the male-specific effects on acetylcholine-induced tracheal constriction, along with the affected mesenchymal markers. These data suggest that perinatal nicotine exposure causes sex-specific perinatal cigarette smoke exposure-induced asthma, providing a powerful phenotypic model for unequivocally determining the underlying nature of the cell molecular mechanism for this disease.

Sex determines which section of the SLC6A4 gene is linked to obsessive–compulsive symptoms in normal Chinese college students

Previous case–control and family-based association studies have implicated the SLC6A4 gene in obsessive–compulsive disorder (OCD). Little research, however, has examined this gene's role in obsessive–compulsive symptoms (OCS) in community samples. The present study genotyped seven tag SNPs and two common functional tandem repeat polymorphisms (5-HTTLPR and STin2), which together cover the whole SLC6A4 gene, and investigated their associations with OCS in normal Chinese college students (N = 572). The results revealed a significant gender main effect and gender-specific genetic effects of the SLC6A4 gene on OCS. Males scored significantly higher on total OCS and its three dimensions than did females (ps < .01). The 5-HTTLPR in the promoter region showed a female-specific genetic effect, with the l/l and l/s genotypes linked to higher OCS scores than the s/s genotype (ps < .05). In contrast, a conserved haplotype polymorphism (rs1042173| rs4325622| rs3794808| rs140701| rs4583306| rs2020942) covering from intron 3 to the 3′ UTR of the SLC6A4 gene showed male-specific genetic effects, with the CGAAGG/CGAAGG genotype associated with lower OCS scores than the other genotypes (ps < .05). These effects remained significant after controlling for OCS-related factors including participants' depressive and anxiety symptoms as well as stressful life events, and correction for multiple tests. These results are discussed in terms of their implications for our understanding of the sex-specific role of the different sections of the SLC6A4 gene in OCD.

Maternal deprivation in the middle of a stress hyporesponsive period decreases hippocampal calcineurin expression and causes abnormal social and cognitive behaviours in adult male Wistar rats: Relevance to negative symptoms of schizophrenia

Adverse experiences in early life profoundly influence the developing nervous, endocrine, and immune systems, and also affect human behaviour during adult life and are considered in the pathogenesis of psychiatric disorders. Numerous studies have provided evidence that maternal deprivation in the middle of a stress hyporesponsive period (SHRP) causes multiple behavioural and physiological abnormalities that mimic positive symptoms of schizophrenia in humans. To investigate the neurochemical characteristics of maternal deprivation in the middle of the SHRP in the context of a possible animal model of the symptoms of schizophrenia, we examined calcineurin expression in the hippocampus of maternally deprived rats. To investigate other behavioural characteristics, we behaviourally phenotyped the rats by applying a comprehensive behavioural test battery. The results indicate that maternal deprivation in the middle of the SHRP has no effects on general health, neurological reflexes, sensory function, or motor function, but does have sex-specific effects on a type of anxiety-related behaviour in the open field test and male-specific effects on hippocampal calcineurin expression, social behaviour, and objective memory function. An interpretation of our results and previous studies in the context of the neurodevelopmental hypothesis of schizophrenia suggests that maternal deprivation in the middle of the SHRP in rats models some positive and negative aspects of schizophrenia. The findings regarding the sex-specific effects of maternal deprivation in the middle of the SHRP may become a strong tool for investigating sex differences in the pathogenesis and pathology of schizophrenia in humans.

INBREEDING AND HAPLOID CHROMOSOMES: A RESPONSE TO HEDRICK (2011)

We have shown that inbreeding allows maternally transmitted organelles to respond to selection on male-specific fitness effects (Wade and Brandvain 2009, see also Unckless and Herren 2009). Hedrick (2011) confirms our results, but takes issue with our characterization of "inbreeding" at mitochondrial loci. The reason for this disagreement is straightforward-we define inbreeding as the process of mating between relatives, whereas Hedrick (2011) defines inbreeding as increased homozygosity at autosomal loci genome-wide, which occurs because of mating between relatives. Here, we insist that our definition is not incorrect, and highlight some benefits of our view.

Australian Athletes' Knowledge of Performance Enhancing Substances

PURPOSE: To examine Australian athletes' knowledge of the banned status of four commonly known performance enhancing substances (PES) from the WADA Prohibited Substances List and the desired and adverse effects of these PES METHODS: As part of a comprehensive questionnaire, 30 substances including amphetamines, anabolic steroids (AAS), growth hormone (GH) and erythropoietin (EPO) were required to be identified as banned at all times, banned in-competition only or don't know. Open questions probed knowledge of the desired and adverse effects of these four PES. RESULTS: We recruited 1990 elite athletes (mean age 21 yr, 60% male). On average, 58% of athletes correctly identified the banned status of the four PES and 10% did not know. Amphetamines were incorrectly believed by 91% of athletes to be banned at all times and 28% did not know the status of EPO. The correct desired effects of the PES were provided by 49% of athletes, but 35% could not answer. The majority of athletes (74%) correctly identified increased arousal/competitiveness as a reason for stimulant use. The desired effects of AAS and GH were well known where 93% and 81% of athletes respectively correctly named increased muscle mass and strength as benefits. EPO was least well answered whereby 58% of athletes could not name a desired effect. By contrast, overall athlete knowledge of the side effects of the four PES was merely fair. Only 29% of athletes correctly named a side effect for the four PES whereas 59% of athletes could not provide answers. Heart and psychiatric problems were the most commonly identified side effects of Stimulants. With respect to AAS, male specific and psychological adverse effects were mostly named. Knowledge of the side effects of Growth Hormone was poor in athletes where a range of effects (18%) and bone growth (12%) were listed as the favoured adverse effects. Over half of athletes provided incorrect answers and 61% could not offer an answer. Although a range of side effects and clots were the most common side effects of EPO given, EPO was the most poorly understood substance where 78% of athletes could not provide an answer. CONCLUSIONS: Athlete knowledge of well known PES is limited. Development of specific drug education targeting PES is warranted. Supported by Department Health and Ageing Anti-Doping Research Program Grant

Chromosomal mapping of pancreatic islet morphological features and regulatory hormones in the spontaneously diabetic (Type 2) Goto-Kakizaki rat

Insulin resistance and altered endocrine pancreas function are central pathophysiological features of type 2 diabetes mellitus (T2DM). The Goto-Kakizaki (GK) rat is a model of spontaneous T2DM characterised by reduced beta cell mass and genetically determined glucose intolerance and altered insulin secretion. To identify genetic determinants of endocrine pancreas histopathology, we carried out quantitative trait locus (QTL) mapping of histological phenotypes (beta cell mass -BCM and insulin-positive cell area -IPCA) and plasma concentration of hormones and growth factors in a F2 cohort derived from GK and normoglycemic Brown Norway rats. Although IPCA and BCM in the duodenal region of the pancreas were highly positively correlated (P < 10−6), and similarly in the splenic region, both measures were poorly correlated when comparing duodenal and splenic phenotypes. Strongest evidence of linkage to pancreas morphological traits was obtained between BCM and chromosome 10 (LOD 3.2). Evidence of significant linkage (LOD 4.2) to plasma corticosterone was detected in a region of chromosome 1 distal to other QTLs previously identified in the GK. Male-specific genetic effects were detected, including linkages (LOD > 4) to growth hormome (GH) on chromosome 6 and prolactin on chromosome 17. These data suggest independent genetic control of the structure and function of ontologically different regions of the endocrine pancreas. Novel QTLs for corticosterone, prolactin and GH may contribute to diabetes in the GK. The QTLs that we have identified in this, and previous genetic studies collectively underline the complex and multiple mechanisms involved in diabetes in the GK strain.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-010-9285-3) contains supplementary material, which is available to authorized users.