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1.  Sex Chromosome Complement Affects Nociception in Tests of Acute and Chronic Exposure to Morphine in Mice 
Hormones and behavior  2007;53(1):124-130.
We tested the role of sex chromosome complement and gonadal hormones in sex differences in several different paradigms measuring nociception and opioid analgesia using “four core genotypes” C57BL/6J mice. The genotypes include XX and XY gonadal males, and XX and XY gonadal females. Adult mice were gonadectomized and tested 3–4 weeks later, so that differences between sexes (mice with testes vs. ovaries) were attributable mainly to organizational effects of gonadal hormones, whereas differences between XX and XY mice were attributable to their complement of sex chromosomes. In experiment 1 (hotplate test of acute morphine analgesia), XX mice of both gonadal sexes had significantly shorter hotplate baseline latencies prior to morphine than XY mice. In experiment 2, (test of development of tolerance to morphine), mice were injected twice daily with 10mg/kg morphine or saline for 6 days. Saline or the competitive NMDA antagonist CPP [3-]2-carboxypiperazin-4yl)propyl-1-phospionic acid] (10mg/kg) was co-injected. On day 7, mice were tested for hotplate latencies before and after administration of a challenge dose of morphine (10mg/kg). XX mice showed shorter hotplate latencies than XY mice at baseline, and the XX-XY difference was greater following morphine. In experiment 3, mice were injected with morphine (10mg/Kg) or saline,15 minutes before intraplantar injection of formalin (5%/25µl). XX mice licked their hindpaw more than XY mice within 5 minutes of formalin injection. The results indicate that X- or Y-linked genes have direct effects, not mediated by gonadal secretions, on sex differences in two different types of acute nociception.
doi:10.1016/j.yhbeh.2007.09.003
PMCID: PMC2713052  PMID: 17956759
X chromosome; Y chromosome; pain; sex difference; hotplate; sex chromosomes
2.  Metabolic impact of sex chromosomes 
Adipocyte  2013;2(2):74-79.
Obesity and associated metabolic diseases are sexually dimorphic. To provide better diagnosis and treatment for both sexes, it is of interest to identify the factors that underlie male/female differences in obesity. Traditionally, sexual dimorphism has been attributed to effects of gonadal hormones, which influence numerous metabolic processes. However, the XX/XY sex chromosome complement is an additional factor that may play a role. Recent data using the four core genotypes mouse model have revealed that sex chromosome complement—independently from gonadal sex—plays a role in adiposity, feeding behavior, fatty liver and glucose homeostasis. Potential mechanisms for the effects of sex chromosome complement include differential gene dosage from X chromosome genes that escape inactivation, and distinct genomic imprints on X chromosomes inherited from maternal or paternal parents. Here we review recent data in mice and humans concerning the potential impact of sex chromosome complement on obesity and metabolic disease.
doi:10.4161/adip.23320
PMCID: PMC3661109  PMID: 23805402
metabolic disease; sex differences; obesity; food intake; fatty liver; circadian rhythm
3.  Dissociation of genetic and hormonal influences on sex differences in alcoholism-related behaviors 
Differences between men and women in alcohol abuse prevalence have long been attributed to social and hormonal factors. It is, however, becoming apparent that sex differences in substance dependence are also influenced by genetic factors. Using a four core genotype mouse model that enables dissociation of chromosomal and gonadal sex, we show that habitual responding for alcohol reinforcement is mediated by sex chromosome complement independent of gonadal phenotype. After moderate instrumental training, chromosomal male (XY) mice became insensitive to outcome devaluation, indicating habitual responding. Chromosomal female (XX) mice remained sensitive to outcome devaluation, signifying goal-directed behavior. There was no effect of gonadal phenotype on habitual responding. Conversely, alcohol drinking was predicted by gonadal phenotype independent of sex chromosome complement. These results indicate that different alcoholism-related behaviors are determined independently by gonadal and chromosomal sex.
doi:10.1523/JNEUROSCI.0548-10.2010
PMCID: PMC2921163  PMID: 20610747
Habit; sex differences; alcohol use and dependence
4.  Cell-autonomous sex determination outside of the gonad 
The classic model of sex determination in mammals states that the sex of the individual is determined by the type of gonad that develops, which in turn determines the gonadal hormonal milieu that creates sex differences outside of the gonads. However, XX and XY cells are intrinsically different because of the cell-autonomous sex-biasing action of X and Y genes. Recent studies of mice, in which sex chromosome complement is independent of gonadal sex, reveal that sex chromosome complement has strong effects contributing to sex differences in phenotypes such as metabolism. Adult mice with two X chromosomes (relative to mice with one X chromosome) show dramatically greater increases in body weight and adiposity after gonadectomy, irrespective of their gonadal sex. When fed a high fat diet, XX mice develop striking hyperinsulinemia and fatty liver, relative to XY mice. The sex chromosome effects are modulated by the presence of gonadal hormones, indicating an interaction of the sex-biasing effects of gonadal hormones and sex chromosome genes. Other cell-autonomous sex chromosome effects are detected in mice in many phenotypes. Birds (relative to eutherian mammals) are expected to show more widespread cell-autonomous sex determination in non-gonadal tissues, because of ineffective sex chromosome dosage compensation mechanisms.
doi:10.1002/dvdy.23936
PMCID: PMC3672066  PMID: 23361913
sex chromosome; sex determination; X chromosome; Y chromosome; Z chromosome; W chromosome; sexual differentiation; androgens; estrogens
5.  Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis 
Background
Both coxsackievirus B3 (CVB3) and influenza A virus (IAV; H1N1) produce sexually dimorphic infections in C57BL/6 mice. Gonadal steroids can modulate sex differences in response to both viruses. Here, the effect of sex chromosomal complement in response to viral infection was evaluated using four core genotypes (FCG) mice, where the Sry gene is deleted from the Y chromosome, and in some mice is inserted into an autosomal chromosome. This results in four genotypes: XX or XY gonadal females (XXF and XYF), and XX or XY gonadal males (XXM and XYM). The FCG model permits evaluation of the impact of the sex chromosome complement independent of the gonadal phenotype.
Methods
Wild-type (WT) male and female C57BL/6 mice were assigned to remain intact or be gonadectomized (Gdx) and all FCG mice on a C57BL/6 background were Gdx. Mice were infected with either CVB3 or mouse-adapted IAV, A/Puerto Rico/8/1934 (PR8), and monitored for changes in immunity, virus titers, morbidity, or mortality.
Results
In CVB3 infection, mortality was increased in WT males compared to females and males developed more severe cardiac inflammation. Gonadectomy suppressed male, but increased female, susceptibility to CVB3. Infection with IAV resulted in greater morbidity and mortality in WT females compared with males and this sex difference was significantly reduced by gonadectomy of male and female mice. In Gdx FCG mice infected with CVB3, XY mice were less susceptible than XX mice. Protection correlated with increased CD4+ forkhead box P3 (FoxP3)+ T regulatory (Treg) cell activation in these animals. Neither CD4+ interferon (IFN)γ (T helper 1 (Th1)) nor CD4+ interleukin (IL)-4+ (Th2) responses differed among the FCG mice during CVB3 infection. Infection of Gdx FCG mice revealed no effect of sex chromosome complement on morbidity or mortality following IAV infection.
Conclusions
These studies indicate that sex chromosome complement can influence pathogenicity of some, but not all, viruses.
doi:10.1186/2042-6410-2-8
PMCID: PMC3162877  PMID: 21806829
6.  What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? 
The “four core genotypes” (FCG) model comprises mice in which sex chromosome complement (XX vs. XY) is unrelated to the animal's gonadal sex. The four genotypes are XX gonadal males or females, and XY gonadal males or females. The model allows one to measure (1) the differences in phenotypes caused by sex chromosome complement (XX vs. XY), (2) the differential effects of ovarian and testicular secretions, and (3) the interactive effects of (1) and (2). Thus, the FCG model provides new information regarding the origins of sex differences in phenotype that has not been available from studies that manipulate gonadal hormone levels in normal XY males and XX females. Studies of the FCG model have uncovered XX vs. XY differences in behaviors (aggression, parenting, habit formation, nociception, social interactions), gene expression (septal vasopressin), and susceptibility to disease (neural tube closure and autoimmune disease) not mediated by gonadal hormones. Some sex chromosome effects are mediated by sex differences in dose of X genes or their parental imprint. Future studies will identify the genes involved and their mechanisms of action.
doi:10.1016/j.yfrne.2008.11.001
PMCID: PMC3282561  PMID: 19028515
Sex chromosome; X chromosome; Y chromosome; Sex differences; Sexual differentiation; Nociception; Neural tube closure; Autoimmune disease; Addiction
7.  Sex chromosome effects unmasked in angiotensin II-induced hypertension 
Hypertension  2010;55(5):1275-1282.
Sex differences in mean arterial pressure (MAP) are reported in many experimental models of hypertension and are ascribed to gonadal sex based of studies showing gonadectomy and gonadal hormone replacement affect MAP. The interpretation of these studies, however, has been confounded by differences in the sex chromosome complement (XX vs. XY). To investigate the sex chromosome complement independently of gonadal sex, we used the four core genotype (FCG) mouse model in which gonadal sex is separated from the sex chromosome complement enabling comparisons among XX and XY females and XX and XY males. We found that in the gonadectomized (GDX) FCG, MAP after 2 weeks of angiotensin II (Ang II) infusion (200 ng/kg/min) was greater in XX than XY [MAP (mm Hg): GDX-XX-Female, 148±4.5; GDX-XY-Female, 133±4.4; GDX-XX-Male, 149±9.4; GDX-XY-Male, 138±5.5; p<0.03, XX vs XY; n=8-9/grp]. In contrast, no sex chromosome effects (SCE) were found on heart rate (HR) body weight (BW) or plasma Ang II 2 weeks after Ang II infusion. This study suggests that in addition to effects of gonadal hormones on blood pressure, X- or Y-linked genes, parental imprinting or X mosaicism contribute to sex differences in hypertension. Furthermore, the finding that MAP was greater in XX mice compared to XY mice in the GDX state suggests adverse SCE encoded within the XX sex chromosome complement could contribute to hypertension in women with ovarian hormone deficiency such as postmenopausal women and women with premature ovarian failure.
doi:10.1161/HYPERTENSIONAHA.109.144949
PMCID: PMC2905778  PMID: 20231528
hypertension; angiotensin II; sex differences; sex chromosomes; four core genotype
8.  Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues 
Journal of neuroendocrinology  2009;21(4):377-386.
XX and XY cells have a different number of X and Y genes. These differences in their genomes cause sex differences in the functions of cells, both in the gonads and in non-gonadal tissues. This review discusses mouse models that have shed light on these direct genetic effects of sex chromosomes that cause sex differences in physiology. Because many sex differences in tissues are caused by different effects of male and female gonadal hormones, it is important to attempt to discriminate between direct genetic and hormonal effects. Numerous mouse models exist in which the number of X or Y genes is manipulated, to observe the effects on phenotype. In two models, the Afour core genotypes@ model and SF1 knockout gonadless mice, it has been possible to detect sex chromosome effects that are not explained by group differences in gonadal hormones. Moreover, mouse models are available to determine whether the sex chromosome effects are caused by X or Y genes.
doi:10.1111/j.1365-2826.2009.01831.x
PMCID: PMC2669494  PMID: 19207816
9.  X-chromosome dosage affects male sexual behavior 
Hormones and Behavior  2012;61(4):565-572.
Sex differences in the brain and behavior are primarily attributed to dichotomous androgen exposure between males and females during neonatal development, as well as adult responses to gonadal hormones. Here we tested an alternative hypothesis and asked if sex chromosome complement influences male copulatory behavior, a standard behavior for studies of sexual differentiation. We used two mouse models with non-canonical associations between chromosomal and gonadal sex. In both models, we found evidence for sex chromosome complement as an important factor regulating sex differences in the expression of masculine sexual behavior. Counter intuitively, males with two X-chromosomes were faster to ejaculate and display more ejaculations than males with a single X. Moreover, mice of both sexes with two X-chromosomes displayed increased frequencies of mounts and thrusts. We speculate that expression levels of a yet to be discovered gene(s) on the X-chromosome may affect sexual behavior in mice and perhaps in other mammals.
doi:10.1016/j.yhbeh.2012.02.003
PMCID: PMC3319230  PMID: 22349083
Sexual differentiation; Klinefelter’s; Turner Syndrome; Aneuploidy; sex difference; Xinactivation
10.  Dissociable Effects of Sry and Sex Chromosome Complement on Activity, Feeding and Anxiety-Related Behaviours in Mice 
PLoS ONE  2013;8(8):e73699.
Whilst gonadal hormones can substantially influence sexual differentiation of the brain, recent findings have suggested that sex-linked genes may also directly influence neurodevelopment. Here we used the well-established murine ‘four core genotype’ (FCG) model on a gonadally-intact, outbred genetic background to characterise the contribution of Sry-dependent effects (i.e. those arising from the expression of the Y-linked Sry gene in the brain, or from hormonal sequelae of gonadal Sry expression) and direct effects of sex-linked genes other than Sry (‘sex chromosome complement’ effects) to sexually dimorphic mouse behavioural phenotypes. Over a 24 hour period, XX and XY gonadally female mice (lacking Sry) exhibited greater horizontal locomotor activity and reduced food consumption per unit bodyweight than XX and XY gonadally male mice (possessing Sry); in two behavioural tests (the elevated plus and zero mazes) XX and XY gonadally female mice showed evidence for increased anxiety-related behaviours relative to XX and XY gonadally male mice. Exploratory correlational analyses indicated that these Sry-dependent effects could not be simply explained by brain expression of the gene, nor by circulating testosterone levels. We also noted a sex chromosome complement effect on food (but not water) consumption whereby XY mice consumed more over a 24hr period than XX mice, and a sex chromosome complement effect in a third test of anxiety-related behaviour, the light-dark box. The present data suggest that: i) the male-specific factor Sry may influence activity and feeding behaviours in mice, and ii) dissociable feeding and anxiety-related murine phenotypes may be differentially modulated by Sry and by other sex-linked genes. Our results may have relevance for understanding the molecular underpinnings of sexually dimorphic behavioural phenotypes in healthy men and women, and in individuals with abnormal sex chromosome constitutions.
doi:10.1371/journal.pone.0073699
PMCID: PMC3751882  PMID: 24009762
11.  Sex chromosome complement affects social interactions in mice 
Hormones and behavior  2008;54(4):565-570.
Sex differences in behavior can be attributed to differences in steroid hormones. Sex chromosome complement can also influence behavior, independent of gonadal differentiation. The mice used for this work combined a spontaneous mutation of the Sry gene with a transgene for Sry that is incorporated into an autosome thus disassociating gonad differentiation from sex chromosome complement. The resulting genotypes are XX and XY− females (ovary-bearing) along with XXSry and XY−Sry males (testes-bearing). Here we report results of basic behavioral phenotyping conducted with these mice. Motor coordination, use of olfactory cues to find a food item, general activity, foot shock threshold, and behavior in an elevated plus maze were not affected by gonadal sex or sex chromosome complement. In a one-way active avoidance learning task females were faster to escape an electric shock than males. In addition, sex chromosome complement differences were noted during social interactions with submissive intruders. Female XY− mice were faster to follow an intruder than XX female mice. All XY− mice spent more time sniffing and grooming the intruder than the XX mice, with XY− females spending the most amount of time in this activity. Finally, XX females were faster to display an asocial behavior, digging, and engaged in more digging than XXSry male mice. All of these behaviors were tested in gonadectomized adults, thus, differences in circulating levels of gonadal steroids cannot account for these effects. Taken together, these data show that sex chromosome complement affects social interaction style in mice.
doi:10.1016/j.yhbeh.2008.05.016
PMCID: PMC2561329  PMID: 18590732
Affective disorders; Autism; Depression; Anxiety; Sexual differentiation; X inactivation; Cognition; Pain
12.  X-Chromosome Dosage and the Response to Cerebral Ischemia 
Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and EdaTa). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes, nor the parent of origin of the remaining X chromosome, had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice.
doi:10.1523/JNEUROSCI.0621-11.2011
PMCID: PMC3179179  PMID: 21917808
13.  The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance 
Background
Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement.
Methods
In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured.
Results
Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups.
Conclusions
We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions.
doi:10.1186/2042-6410-4-15
PMCID: PMC3751353  PMID: 23926958
Klinefelter; Sex chromosome trisomy; XXY; XYY; Mouse; X chromosome; Y chromosome; Body weight; Obesity
14.  Sex Chromosome Complement Affects Nociception and Analgesia in Newborn Mice 
In animal studies of nociception, females are often more sensitive to painful stimuli, whereas males are often more sensitive to analgesia induced by μ agonists. Sex differences are found even at birth, and in adulthood are likely caused, at least in part, by differences in levels of gonadal hormones. Here we investigate nociception and analgesia in neonatal mice, and assess the contribution of the direct action of sex chromosome genes in hotplate and tail withdrawal tests. We used the four core genotypes mouse model, in which gonadal sex is independent of the complement of sex chromosomes (XX vs. XY). Mice were tested at baseline and then injected with μ-opioid agonist morphine (10mg/kg), or with the κ-opioid agonist U50,488H (U50, 12.5mg/Kg) with or without the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.1mg/kg). On the day of birth, XX mice showed faster baseline latencies than XY in tail withdrawal, irrespective of their gonadal type. Gonadal males showed greater effects of morphine than gonadal females in the hotplate test, irrespective of their sex chromosome complement. U50 and morphine were both effective analgesics in both tests, but MK-801 did not block the U50 effect. The results suggest that sex chromosome complement and gonadal secretions both contribute to sex differences in nociception and analgesia by the day of birth.
Perspective: Sex differences in pain may stem not only from the action of gonadal hormones on pain circuits, but from the sex-specific action of X and Y genes. Identification of sex chromosome genes causing sex differences could contribute to better pain therapy in females and males.
doi:10.1016/j.jpain.2008.06.001
PMCID: PMC2575001  PMID: 18635401
pain; sex difference; hotplate; tail withdrawal; sex chromosomes; neonate
15.  The ability of stress to alter sleep in mice is sensitive to reproductive hormones 
Brain research  2009;1305:74-85.
Though stress causes complex sleep disruptions that are different in females and males, little is known about how sex influences the ability of stress to alter sleep. To date there have been no comprehensive examinations of whether effects of stress on sleep are sensitive to determinants of sex, such as reproductive hormones. Since restraint stress produces a sexually dimorphic increase in rapid eye movement sleep (REMS) amount in mice that is greater in males than females, in the current study we sought to determine whether estrogens and androgens influence the ability of restraint stress to alter sleep states. We removed the gonads from adult female and male C57BL/6J mice and implanted the mice with recording electrodes to monitor sleep-wake states. Gonadectomized females and males exhibited similar amounts of REMS in response to restraint stress. Mice were then implanted with continuous release hormone pellets. Females received 17β-estradiol and males received testosterone. Hormone replacement (HR) in females decreased the REMS response to restraint stress while HR in males increased the REMS response to restraint stress. The combined effects of HR in females and males restored the sex difference in the ability of restraint stress to alter REMS. These results demonstrate that sex differences in the effects of stress on REMS are dependent on reproductive hormones and support the view that endogenous or exogenous changes in the reproductive hormone environment influence sleep responses to stress.
doi:10.1016/j.brainres.2009.09.055
PMCID: PMC2787829  PMID: 19769952
gender; sex; restraint; estrogen; androgen
16.  The Maestro (Mro) Gene Is Dispensable for Normal Sexual Development and Fertility in Mice 
PLoS ONE  2008;3(12):e4091.
The mammalian gonad arises as a bipotential primordium from which a testis or ovary develops depending on the chromosomal sex of the individual. We have previously used DNA microarrays to screen for novel genes controlling the developmental fate of the indifferent embryonic mouse gonad. Maestro (Mro), which encodes a HEAT-repeat protein, was originally identified as a gene exhibiting sexually dimorphic expression during mouse gonad development. Wholemount in situ hybridisation analysis revealed Mro to be expressed in the embryonic male gonad from approximately 11.5 days post coitum, prior to overt sexual differentiation. No significant expression was detected in female gonads at the same developmental stage. In order to address its physiological function, we have generated mice lacking Maestro using gene targeting. Male and female mice homozygous for a Mro null allele are viable and fertile. We examined gonad development in homozygous male embryos in detail and observed no differences when compared to wild-type controls. Immunohistochemical analysis of homozygous mutant testes of adult mice revealed no overt abnormalities. Expression profiling using DNA microarrays also indicated no significant differences between homozygote embryonic male gonads and controls. We conclude that Maestro is dispensable for normal male sexual development and fertility in laboratory mice; however, the Mro locus itself does have utility as a site for insertion of transgenes for future studies in the fields of sexual development and Sertoli cell function.
doi:10.1371/journal.pone.0004091
PMCID: PMC2605558  PMID: 19116663
17.  The Role of the Y Chromosome in Brain Function 
In mammals, sex differences are evident in many aspects of brain development, brain function and behaviour. Ultimately, such differences must arise from the differential sex chromosome complements in males and females: males inherit a single X chromosome and a Y chromosome, whilst females inherit two X chromosomes. One possible mechanism for sexual differentiation of the brain is via male-limited expression of genes on the small Y chromosome. Many Y-linked genes have been implicated in the development of the testes, and therefore could theoretically contribute to sexual differentiation of the brain indirectly, through influencing gonadal hormone production. Alternatively, Y-linked genes that are expressed in the brain could directly influence neural masculinisation. The present paper reviews evidence from human genetic studies and animal models for Y-linked effects (both direct and indirect) on neurodevelopment, brain function and behaviour. Besides enhancing our knowledge of the mechanisms underlying mammalian neural sexual differentiation, studies geared towards understanding the role of the Y chromosome in brain function will help to elucidate the molecular basis of sex-biased neuropsychiatric disorders, allowing for more selective sex-specific therapies.
doi:10.2174/1876528900902010020
PMCID: PMC2854822  PMID: 20396406
18.  The end of gonad-centric sex determination in mammals 
Trends in Genetics  2011;28(2):55-61.
The 20th century theory of mammalian sex determination states that the embryo is sexually indifferent until the differentiation of gonads, after which sex differences in phenotype are caused by differential effects of gonadal hormones. That theory is inadequate because some sex differences precede differentiation of the gonads and/or are determined by non-gonadal effects of the sexual inequality in number and type of sex chromosomes. A general theory of sex determination is proposed, which recognizes multiple parallel primary sex-determining pathways initiated by genes or factors encoded by the sex chromosomes. The separate sex-specific pathways interact to synergize with or antagonize each other, enhancing or reducing sex differences in phenotype.
doi:10.1016/j.tig.2011.10.004
PMCID: PMC3268825  PMID: 22078126
19.  Differential Effects of Male and Female Gonadal Hormones on the Intrathymic T cell Maturation 
Developmental Immunology  2001;8(3-4):305-317.
The study was undertaken to further elucidate a role of gonadal hormones in maintenance of normal thymocyte maturation and sexual dimorphism in the intrathymic T-cell development. Rats of both sexes were gonadectomized or sham-gonadectomized (controls) at age of 2 and 6 months, and 30 days later the thymus size, cellularity and thymocyte composition were evaluated. In both control and gonadectomized rats, in spite of age, sexual dimorphism in the thymus size and cellularity was found. Gonadectomy in 2-month-old rats of both sexes increased the thymus cellularity, volumes of both cortex and medulla and thymus size (to a less extent in males), while in 6-month-old rats, in this respect, it was effective only in females. In ovariectomized (OVX) rats the increase in volume of cortex was more marked in younger rats, while that of medulla did not differ between rats of different age. It seems obvious that in both groups of OVX rats the volume of medullary non-lymphoid component was enlarged (the increase in medullary volume was more pronounced than that in its cellularity). Unlikely, in rats orchidectomized (ORX) at age of 2 months the volume of this component was either decreased or unaltered (the increase in the volume of medulla was less conspicuous than that in the number of medullary thymocytes). In control and gonadectomized rats of both ages, sexual dimorphism in the composition of thymocyte subsets was also observed. Gonadectomy in 2-month-old rats affected distinct stages of thymocyte maturation in male (increased the relative proportions of CD4+8+TCRαβlow cells and their CD4–8+TCRαβlow precursors and decreased those of the most mature CD4+8-TCRαβhigh and CD4–8+TCRαβhigh cells) and female rats (decreased only the percentage of the least mature CD4–8-TCRαβ-cells). In older rats only ovariectomy had impact on the relative proportion of thymocytes decreasing, besides the relative proportion of CD4–8-TCRαβ- cells, those of CD4–8+TCRαβ-, CD4–8+TCRαβlow, positively selected CD4+8+TCRαβhigh and the most mature CD4+8-TCRαβhigh, CD4–8+TCRαβhigh cells and exerting an opposite effect on the percentages of CD4+8+TCRαβ- and CD4+8+TCRαβlow cells. Thus, results showed sex- and age-dependent changes in sensitivity of both the developing thymocytes and non-lymphoid cells to long-lasting gonadal deprivation.
doi:10.1155/2001/52789
PMCID: PMC2276083  PMID: 11785679
adult rats; thymus size; thymus cellularity; thymocyte maturation; gonadectomy; sexual dimorphism
20.  Aggressive Behaviors in Adult SF-1 Knockout Mice That Are Not Exposed to Gonadal Steroids During Development 
Behavioral neuroscience  2008;122(4):876-884.
Sex hormones are a major factor responsible for the development of sex differences. Steroidogenic factor 1 (SF-1) is a key regulator of gonadal and adrenal development, and SF-1 knockout mice (SF-1 KO) are born without gonads and adrenal glands. Consequently, these mice are not exposed to gonadal sex steroids. SF-1 KO pups die shortly after birth due to adrenal deficiency. In the present study, SF-1 KO mice were rescued by neonatal corticosteroid injections followed by adrenal transplantations on day 7–8 postnatally. Control mice received corticosteroid injections and were gonadectomized prior to puberty. Mice were observed interacting with ovariectomized hormone primed females and gonad-intact males. In the absence of sex steroid replacement, adult SF-1 KO mice were significantly more aggressive than control mice in tests with stimulus females. After testosterone treatment, control males displayed significantly more aggression towards male intruders than control female mice, or male and female SF-1 KO mice, suggesting a developmental role of gonadal hormones in the expression of aggressive behavior and affirming SF-1 KO mice as a behavioral model to investigate affects of fetal gonad deficiency.
doi:10.1037/0735-7044.122.4.876
PMCID: PMC2562550  PMID: 18729641
sexual differentiation; VMH; steroidogenic factor 1; sex steroids; aggression
21.  Genetic-gonadal-genitals sex (3G-sex) and the misconception of brain and gender, or, why 3G-males and 3G-females have intersex brain and intersex gender 
The categorization of individuals as “male” or “female” is based on chromosome complement and gonadal and genital phenotype. This combined genetic-gonadal-genitals sex, here referred to as 3G-sex, is internally consistent in ~99% of humans (i.e., one has either the “female” form at all levels, or the “male” form at all levels). About 1% of the human population is identified as “intersex” because of either having an intermediate form at one or more levels, or having the “male” form at some levels and the “female” form at other levels. These two types of “intersex” reflect the facts, respectively, that the different levels of 3G-sex are not completely dimorphic nor perfectly consistent. Using 3G-sex as a model to understand sex differences in other domains (e.g., brain, behavior) leads to the erroneous assumption that sex differences in these other domains are also highly dimorphic and highly consistent. But parallel lines of research have led to the conclusion that sex differences in the brain and in behavior, cognition, personality, and other gender characteristics are for the most part not dimorphic and not internally consistent (i.e., having one brain/gender characteristic with the “male” form is not a reliable predictor for the form of other brain/gender characteristics). Therefore although only ~1% percent of humans are 3G-“intersex”, when it comes to brain and gender, we all have an intersex gender (i.e., an array of masculine and feminine traits) and an intersex brain (a mosaic of “male” and “female” brain characteristics).
doi:10.1186/2042-6410-3-27
PMCID: PMC3584732  PMID: 23244600
Sex differences; Gender differences; Male brain; Female brain; Intersex
22.  Enhanced urinary odor discrimination in female aromatase knockout (ArKO) mice 
Hormones and behavior  2006;49(5):580-586.
We asked whether odor discrimination abilities are sexually dimorphic in mice and, if so, whether the perinatal actions of estradiol contribute to these sex differences. The ability to discriminate different types of urinary odors was compared in male and female wild-type (WT) subjects and in mice with a homozygous-null mutation of the estrogen synthetic enzyme, aromatase (aromatase knockout; ArKO). Olfactory discrimination was assessed in WT and ArKO male and female mice after they were gonadectomized in adulthood and subsequently treated with estradiol benzoate. A liquid olfactometer was used to assess food-motivated olfactory discrimination capacity. All animals eventually learned to distinguish between urinary odors collected from gonadally intact males and estrous females; however, WT males as well as ArKO mice of both sexes learned this discrimination significantly more rapidly than WT females. Similar group differences were obtained when mice discriminated between urinary odors collected from gonadally intact vs. castrated males or between two non-social odorants, amyl and butyl acetate. When subjects had to discriminate volatile urinary odors from ovariectomized female mice treated with estradiol sequenced with progesterone versus estradiol alone, ArKO females quickly acquired the task whereas WT males and females as well as ArKO males failed to do so. These results demonstrated a strong sex dimorphism in olfactory discrimination ability, with WT males performing better than females. Furthermore, female ArKO mice showed an enhanced ability to discriminate very similar urinary odorants, perhaps due to an increased sensitivity of the main olfactory nervous system to adult estradiol treatment as a result of perinatal estrogen deprivation.
doi:10.1016/j.yhbeh.2005.12.013
PMCID: PMC2263132  PMID: 16448653
Estrogens; Sex differences; Olfaction; Odor discrimination; Learning
23.  SEX DIFFERENCES IN MOTOR BEHAVIOR IN THE MPTP MOUSE MODEL OF PARKINSON'S DISEASE 
Sex differences in Parkinson's disease (PD) have been reported in humans and rodent models, with a higher incidence in men and increased severity in male rodents. The current study examined sex differences and the effects of gonadal steroid hormones in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of PD. Male (n=51) and female (n=50) mice were gonadectomized and received physiologic replacement with testosterone or estrogen (Experiment 1), or no hormones (Experiment 2). Two weeks later, mice received either MPTP (10mg/kg per day for 5 days) or saline. Higher doses killed female mice. Mice were tested one week after MPTP for motor performance using rotarod, pole and gait tests. In hormone-treated mice, males significantly outperformed females in all three tests (p<0.05). Compared with females, males had a greater overall rotarod performance (ORP: 1317.1±98.3 vs. 988.1±95.6), descended a pole faster (7.1±0.6 vs. 9.6±0.7 sec), and had longer stride lengths (hindlimb 7.3±0.1 vs. 6.8±0.1 cm). By contrast, ovariectomized female mice receiving saline outperformed castrated males on the rotarod (1296.6±83.3 vs. 811.2±113.7, p<0.05) and descended a pole faster (9.7±2.0 vs. 15.6±1.9 sec, p<0.05). MPTP significantly impaired ORP (p<0.05) in hormone-treated males (703.7±65.5) and females (432.8±88.6, p<0.05). After MPTP, stride length was selectively decreased in males (hindlimb 6.6±0.1 cm, p<0.05), and pole test performance was unimpaired in either sex. After gonadectomy, MPTP did not decrease motor performance in males (p>0.05) but significantly reduced ORP in females (975.9±110.3 vs. saline females, p<0.05). Our results show that small, chronic doses of MPTP produce subtle, sexually-dimorphic impairments in motor performance, but without a loss of tyrosine hydroxylase-positive neurons in the substantia nigra. In gonadectomized mice, this sex difference is reversed.
doi:10.1016/j.pbb.2010.03.009
PMCID: PMC2866026  PMID: 20347863
Parkinson's disease; striatum; substantia nigra; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; motor behavior; sex characteristics testosterone, estrogen
24.  Sex-dependent gene expression in early brain development of chicken embryos 
BMC Neuroscience  2006;7:12.
Background
Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms.
Results
Using cDNA microarrays and real-time PCR we found gene expression differences between the male and female embryonic brain (or whole head) that may be independent of morphological differentiation of the gonads. Genes located on the sex chromosomes (ZZ in males and ZW in females) were common among the differentially expressed genes, several of which (WPKCI-8, HINT, MHM non-coding RNA) have previously been implicated in avian sex determination. A majority of the identified genes were more highly expressed in males. Three of these genes (CDK7, CCNH and BTF2-P44) encode subunits of the transcription factor IIH complex, indicating a role for this complex in neuronal differentiation.
Conclusion
In conclusion, this study provides novel insights into sexually dimorphic gene expression in the embryonic chicken brain and its possible involvement in sex differentiation of the nervous system in birds.
doi:10.1186/1471-2202-7-12
PMCID: PMC1386693  PMID: 16480516
25.  A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice 
Objective
A sexual dimorphism exists in body fat distribution; females deposit relatively more fat in subcutaneous/inguinal depots whereas males deposit more fat in the intra-abdominal/gonadal depot. Our objective was to systematically document depot- and sex-related differences in the accumulation of adipose tissue and gene expression, comparing differentially expressed genes in diet-induced obese mice with mice maintained on a chow diet.
Research Design and Methods
We used a microarray approach to determine whether there are sexual dimorphisms in gene expression in age-matched male, female or ovariectomized female (OVX) C57/BL6 mice maintained on a high-fat (HF) diet. We then compared expression of validated genes between the sexes on a chow diet.
Results
After exposure to a high fat diet for 12 weeks, females gained less weight than males. The microarray analyses indicate in intra-abdominal/gonadal adipose tissue in females 1642 genes differ by at least twofold between the depots, whereas 706 genes differ in subcutaneous/inguinal adipose tissue when compared with males. Only 138 genes are commonly regulated in both sexes and adipose tissue depots. Inflammatory genes (cytokine–cytokine receptor interactions and acute-phase protein synthesis) are upregulated in males when compared with females, and there is a partial reversal after OVX, where OVX adipose tissue gene expression is more ′male-like′. This pattern is not observed in mice maintained on chow. Histology of male gonadal white adipose tissue (GWAT) shows more crown-like structures than females, indicative of inflammation and adipose tissue remodeling. In addition, genes related to insulin signaling and lipid synthesis are higher in females than males, regardless of dietary exposure.
Conclusions
These data suggest that male and female adipose tissue differ between the sexes regardless of diet. Moreover, HF diet exposure elicits a much greater inflammatory response in males when compared with females. This data set underscores the importance of analyzing depot-, sex- and steroid-dependent regulation of adipose tissue distribution and function.
doi:10.1038/ijo.2010.12
PMCID: PMC3667412  PMID: 20157318
high-fat diet; inflammation; fat partitioning; gender dimorphism; mouse; microarray

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