RESUMEN
Neurological and neuropsychiatric disorders affect men and women differently. Multiple sclerosis, Alzheimer's disease, anxiety disorders, depression, meningiomas and late-onset schizophrenia affect women more frequently than men. By contrast, Parkinson's disease, autism spectrum condition, attention-deficit hyperactivity disorder, Tourette's syndrome, amyotrophic lateral sclerosis and early-onset schizophrenia are more prevalent in men. Women have been historically under-recruited or excluded from clinical trials, and most basic research uses male rodent cells or animals as disease models, rarely studying both sexes and factoring sex as a potential source of variation, resulting in a poor understanding of the underlying biological reasons for sex and gender differences in the development of such diseases. Putative pathophysiological contributors include hormones and epigenetics regulators but additional biological and non-biological influences may be at play. We review here the evidence for the underpinning role of the sex chromosome complement, X chromosome inactivation, and environmental and epigenetic regulators in sex differences in the vulnerability to brain disease. We conclude that there is a pressing need for a better understanding of the genetic, epigenetic and environmental mechanisms sustaining sex differences in such diseases, which is critical for developing a precision medicine approach based on sex-tailored prevention and treatment.
Asunto(s)
Trastorno del Espectro Autista , Encefalopatías , Esquizofrenia , Animales , Femenino , Masculino , Factores Sexuales , Caracteres SexualesRESUMEN
There are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed using ovariectomized females, brain masculinized females and orchiectomized males. These results suggest genomic reasons, possibly related to sex chromosome complement, for sex differences in AT2 expression in microglia, as the AT2 receptor gene is located in the X chromosome. Furthermore, sex differences in expression of AT2 receptors were associated to sex differences in microglial expression of key anti-inflammatory cytokines such as interleukin-10 and pro-inflammatory cytokines such as interleukin-1ß and interleukin-6. In conclusion, sex differences in microglial AT2 receptor expression appear as a major factor contributing to sex differences in the neuroinflammatory responses beyond the effects of circulating steroids.
Asunto(s)
Microglía , Receptor de Angiotensina Tipo 2 , Angiotensinas/metabolismo , Angiotensinas/farmacología , Animales , Antiinflamatorios/farmacología , Citocinas/metabolismo , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , Microglía/metabolismo , ARN/metabolismo , ARN Mensajero/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismoRESUMEN
The past decade has produced a plethora of studies examining sex differences in the transcriptional profiles of stress and mood disorders. As we move forward from accepting the existence of extensive molecular sex differences in the brain to exploring the purpose of these sex differences, our approach must become more systemic and less reductionist. Earlier studies have examined specific brain regions and/or cell types. To use this knowledge to develop the next generation of personalized medicine, we need to comprehend how transcriptional changes across the brain and/or the body relate to each other. We provide an overview of the relationships between baseline and depression/stress-related transcriptional sex differences and explore contributions of preclinically identified mechanisms and their impacts on behavior.
Asunto(s)
Caracteres Sexuales , Transcriptoma , Encéfalo , Depresión/genética , Femenino , Humanos , Masculino , Trastornos del HumorRESUMEN
Sex differences in multiple sclerosis (MS) incidence and severity have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive disease remain poorly defined. Using a T cell adoptive transfer model of chronic experimental autoimmune encephalomyelitis (EAE), we find that male Th17 cells induce disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produce IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, XY chromosomal complement increases the pathogenicity of male Th17 cells. An X-linked immune regulator, Jarid1c, is downregulated in pathogenic male murine Th17 cells, and functional experiments reveal that it represses the severity of Th17-mediated EAE. Furthermore, Jarid1c expression is downregulated in CD4+ T cells from MS-affected individuals. Our data indicate that male sex chromosomal complement critically regulates Th17 cell pathogenicity.
Asunto(s)
Encefalomielitis Autoinmune Experimental/patología , Cromosomas Sexuales/genética , Células Th17/inmunología , Animales , Autoinmunidad , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Índice de Severidad de la Enfermedad , Células Th17/citología , Células Th17/metabolismoRESUMEN
Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted whole genome bisulfite sequencing (WGBS) as well as RNA-seq on liver samples from mice with different combinations of sex phenotype and sex-chromosome complement. We compared groups of animals with different sex phenotypes, but the same genetic sexes, and vice versa, same sex phenotypes, but different sex-chromosome complements. We also compared sex-biased DNA methylation in mouse and human livers. Our data show that sex phenotype, X-chromosome dosage, and the presence of Y chromosome shape the differences in DNA methylation between males and females. We also demonstrate that sex bias in autosomal methylation is associated with sex bias in gene expression, whereas X-chromosome dosage-dependent methylation differences are not, as expected for a dosage-compensation mechanism. Furthermore, we find partial conservation between the repertoires of mouse and human genes that are associated with sex-biased methylation, an indication that gene function is likely to be an important factor in this phenomenon.
Asunto(s)
Metilación de ADN/genética , Expresión Génica/genética , Hígado/fisiopatología , Cromosomas Sexuales/genética , Animales , Femenino , Humanos , Masculino , FenotipoRESUMEN
Brain expression of the enzyme P450-aromatase has been studied extensively. Subsequent to the aromatisation hypothesis having established brain aromatase as a key factor to convert gonadal testosterone to oestradiol, several studies have investigated the regulation of aromatase during the critical period of brain sexual differentiation. We review previous and recent findings concerning regulation of aromatase. The role of gonadal hormones, sex chromosome genes and neurosteroids is analysed in terms of their contribution to aromatase expression, as well as implications for the organisational effect of steroids during development.
Asunto(s)
Aromatasa/metabolismo , Encéfalo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Hormonas Esteroides Gonadales/metabolismo , Diferenciación Sexual/fisiología , Animales , Aromatasa/genética , Encéfalo/embriología , Femenino , MasculinoRESUMEN
Men and women exhibit significant differences in obesity, cardiovascular disease, and diabetes. To provide better diagnosis and treatment for both sexes, it is important to identify factors that underlie the observed sex differences. Traditionally, sex differences have been attributed to the differential effects of male and female gonadal secretions (commonly referred to as sex hormones), which substantially influence many aspects of metabolism and related diseases. Less appreciated as a contributor to sex differences are the fundamental genetic differences between males and females, which are ultimately determined by the presence of an XX or XY sex chromosome complement. Here, we review the mechanisms by which gonadal hormones and sex chromosome complement each contribute to lipid metabolism and associated diseases, and the current approaches that are used to study them. We focus particularly on genetic approaches including genome-wide association studies in humans and mice, -omics and systems genetics approaches, and unique experimental mouse models that allow distinction between gonadal and sex chromosome effects.
Asunto(s)
Hormonas Gonadales , Metabolismo de los Lípidos/genética , Obesidad/genética , Cromosomas Sexuales , Animales , Femenino , Humanos , Masculino , Ratones , Caracteres Sexuales , Factores SexualesRESUMEN
Autoimmune diseases affect up to 10% of the world's population, and approximately 80% of those affected are female. The majority of autoimmune diseases occur more commonly in females, although some are more frequent in males, while others show no bias by sex. The mechanisms leading to sex biased disease prevalence are not well understood. However, for adult-onset autoimmune disease, at least some of the cause is usually ascribed to sex hormones. This is because levels of sex hormones are one of the most obvious physiological differences between adult males and females, and their impact on immune system function is well recognised. While for paediatric-onset autoimmune diseases a sex bias is not as common, there are several such diseases for which one sex predominates. For example, the oligoarticular subtype of juvenile idiopathic arthritis (JIA) occurs in approximately three times more girls than boys, with a peak age of onset well before the onset of puberty, and at a time when levels of androgen and oestrogen are low and not strikingly different between the sexes. Here, we review potential explanations for autoimmune disease sex bias with a particular focus on paediatric autoimmune disease, and biological mechanisms outside of sex hormone differences.
Asunto(s)
Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Factores de Edad , Epigenómica , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Factores de Riesgo , Caracteres Sexuales , Cromosomas Sexuales , Factores SexualesRESUMEN
Clinical and basic findings indicate that angiotensin II (ANG II) differentially modulates hydroelectrolyte and cardiovascular responses in male and female. But are only the activational and organizational hormonal effects to blame for such differences? Males and females not only differ in their sex (males are born with testes and females with ovaries) but also carry different sex chromosome complements and are thus influenced throughout life by different genomes. In this review, we discuss our recent studies in order to evaluate whether sex chromosome complement is in part responsible for gender differences previously observed in ANG II bradycardic-baroreflex response and sodium depletion-induced sodium appetite and neural activity. To test the hypothesis that XX or XY contributes to the dimorphic ANG II bradycardic-baroreflex response, we used the four core genotype mouse model, in which the effects of gonadal sex (testes or ovaries) and sex chromosome complement (XX or XY) are dissociated. The results indicate that ANG II bradycardic-baroreflex sexual dimorphic response may be ascribed to differences in sex chromosomes, indicating an XX-sex chromosome complement facilitatory bradycardic-baroreflex control of heart rate. Furthermore, we evaluated whether genetic differences within the sex chromosome complement may differentially modulate the known sexually dimorphic sodium appetite as well as basal or induced brain activity due to physiological stimulation of the renin-angiotensin system by furosemide and low-sodium treatment. Our studies demonstrate an organizational hormonal effect on sexually dimorphic induced sodium intake in mice, while at the brain level (subfornical organ and area postrema) we showed a sex chromosome complement effect in sodium-depleted mice, suggesting a sex chromosome gene participation in the modulation of neural pathways underlying regulatory response to renin-angiotensin stimulation.
Asunto(s)
Barorreflejo/fisiología , Líquidos Corporales/fisiología , Bradicardia/fisiopatología , Homeostasis/fisiología , Caracteres Sexuales , Sodio en la Dieta , Angiotensina II/farmacología , Animales , Apetito/efectos de los fármacos , Apetito/genética , Apetito/fisiología , Barorreflejo/efectos de los fármacos , Barorreflejo/genética , Líquidos Corporales/efectos de los fármacos , Bradicardia/genética , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/genética , Frecuencia Cardíaca/fisiología , Homeostasis/efectos de los fármacos , Homeostasis/genética , Masculino , Ratones , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiología , Cromosomas SexualesRESUMEN
Previous studies indicate a sex chromosome complement (SCC) effect on the angiotensin II-sexually dimorphic hypertensive and bradycardic baroreflex responses. We sought to evaluate whether SCC may differentially modulate sexually dimorphic-induced sodium appetite and specific brain activity due to physiological stimulation of the rennin angiotensin system. For this purpose, we used the "four core genotype" mouse model, in which the effect of gonadal sex and SCC is dissociated, allowing comparisons of sexually dimorphic traits between XX and XY females as well as in XX and XY males. Gonadectomized mice were sodium depleted by furosemide (50 mg/kg) and low-sodium diet treatment; control groups were administered with vehicle and maintained on normal sodium diet. Twenty-one hours later, the mice were divided into two groups: one group was submitted to the water-2% NaCl choice intake test, while the other group was perfused and their brains subjected to the Fos-immunoreactivity (FOS-ir) procedure. Sodium depletion, regardless of SCC (XX or XY), induced a significantly lower sodium and water intake in females than in males, confirming the existence in mice of sexual dimorphism in sodium appetite and the organizational involvement of gonadal steroids. Moreover, our results demonstrate a SCC effect on induced brain FOS-ir, showing increased brain activity in XX-SCC mice at the paraventricular nucleus, nucleus of the solitary tract, and lateral parabrachial nucleus, as well as an XX-SCC augmented effect on sodium depletion-induced brain activity at two circumventricular organs, the subfornical organ and area postrema, nuclei closely involved in fluid and blood pressure homeostasis.