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1
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Li T, Thoen ZE, Applebaum JM, Khalil RA. Menopause-related changes in vascular signaling by sex hormones. J Pharmacol Exp Ther 2025; 392:103526. [PMID: 40184819 DOI: 10.1016/j.jpet.2025.103526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 02/24/2025] [Indexed: 04/07/2025] Open
Abstract
Cardiovascular disease (CVD), such as hypertension and coronary artery disease, involves pathological changes in vascular signaling, function, and structure. Vascular signaling is regulated by multiple intrinsic and extrinsic factors that influence endothelial cells, vascular smooth muscle, and extracellular matrix. Vascular function is also influenced by environmental factors including diet, exercise, and stress, as well as genetic background, sex differences, and age. CVD is more common in adult men and postmenopausal women than in premenopausal women. Specifically, women during menopausal transition, with declining ovarian function and production of estrogen (E2) and progesterone, show marked increase in the incidence of CVD and associated vascular dysfunction. Mechanistic research suggests that E2 and E2 receptor signaling have beneficial effects on vascular function including vasodilation, decreased blood pressure, and cardiovascular protection. Also, the tangible benefits of E2 supplementation in improving menopausal symptoms have prompted clinical trials of menopausal hormone therapy (MHT) in CVD, but the results have been inconsistent. The inadequate benefits of MHT in CVD could be attributed to the E2 type, dose, formulation, route, timing, and duration as well as menopausal changes in E2/E2 receptor vascular signaling. Other factors that could affect the responsiveness to MHT are the integrated hormonal milieu including gonadotropins, progesterone, and testosterone, vascular health status, preexisting cardiovascular conditions, and menopause-related dysfunction in the renal, gastrointestinal, endocrine, immune, and nervous systems. Further analysis of these factors should enhance our understanding of menopause-related changes in vascular signaling by sex hormones and provide better guidance for management of CVD in postmenopausal women. SIGNIFICANCE STATEMENT: Cardiovascular disease is more common in adult men and postmenopausal women than premenopausal women. Earlier observations of vascular benefits of menopausal hormone therapy did not materialize in randomized clinical trials. Further examination of the cardiovascular effects of sex hormones in different formulations and regimens, and the menopausal changes in vascular signaling would help to adjust the menopausal hormone therapy protocols in order to enhance their effectiveness in reducing the risk and the management of cardiovascular disease in postmenopausal women.
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Affiliation(s)
- Tao Li
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Zachary E Thoen
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Jessica M Applebaum
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Raouf A Khalil
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
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2
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Schaffner SL, Tosefsky KN, Inskter AM, Appel-Cresswell S, Schulze-Hentrich JM. Sex and gender differences in the molecular etiology of Parkinson's disease: considerations for study design and data analysis. Biol Sex Differ 2025; 16:7. [PMID: 39901234 PMCID: PMC11789417 DOI: 10.1186/s13293-025-00692-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 01/25/2025] [Indexed: 02/05/2025] Open
Abstract
Parkinson's disease (PD) is more prevalent in men than women, and presents with different clinical features in each sex. Despite widespread recognition of these differences, females are under-represented in clinical and experimental studies of PD, and much remains to be elucidated regarding the biological underpinnings of sex differences in PD. In this review, we summarize known contributors to sex differences in PD etiology across the life course, with a focus on neurological development and gene regulation. Sex differences that are established at conception and heightened during adolescence and midlife may partially embed future PD risk, due to the complex interactions between gonadal hormones, gene regulation, lifestyle factors, and aging. While the neuroprotective properties of estrogen are strongly implicated in reduced prevalence of PD in women, interactions with genotype and gender-biased lifestyle factors are incompletely understood. Consideration of sex and gender-related factors in study design, data analysis, and interpretation have the power to expedite our knowledge of the etiology of PD in men and in women, and to inform prevention and therapeutic strategies tailored to each sex.
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Affiliation(s)
- Samantha L Schaffner
- Pacific Parkinson's Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Edwin S. H. Leong Centre for Healthy Aging, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Kira N Tosefsky
- Pacific Parkinson's Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Edwin S. H. Leong Centre for Healthy Aging, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- MD Undergraduate Program, University of British Columbia, Vancouver, BC, Canada
| | - Amy M Inskter
- BC Children's Hospital Research Institute, Vancouver, BC, V5Z 4H4, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada
| | - Silke Appel-Cresswell
- Pacific Parkinson's Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Edwin S. H. Leong Centre for Healthy Aging, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Julia M Schulze-Hentrich
- Department of Genetics/Epigenetics, Faculty NT, Saarland University, Campus, Building A2.4, 66123, 66041, Saarbrücken, Germany.
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3
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Bobotis BC, Khakpour M, Braniff O, de Andrade EG, Gargus M, Allen M, Carrier M, Baillargeon J, Rangachari M, Tremblay MÈ. Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus. J Neuroinflammation 2025; 22:18. [PMID: 39856696 PMCID: PMC11762133 DOI: 10.1186/s12974-025-03341-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
The brain presents various structural and functional sex differences, for which multiple factors are attributed: genetic, epigenetic, metabolic, and hormonal. While biological sex is determined by both sex chromosomes and sex hormones, little is known about how these two factors interact to establish this dimorphism. Sex differences in the brain also affect its resident immune cells, microglia, which actively survey the brain parenchyma and interact with sex hormones throughout life. However, microglial differences in density and distribution, morphology and ultrastructural patterns in physiological conditions during adulthood are largely unknown. Here, we investigated these aforementioned properties of microglia using the Four Core Genotypes (FCG) model, which allows for an independent assessment of gonadal hormones and sex chromosomal effects in four conditions: FCG XX and Tg XY- (both ovaries); Tg XXSry and Tg XYSry (both testes). We also compared the FCG results with XX and XY wild-type (WT) mice. In adult mice, we focused our investigation on the ventral hippocampus across different layers: CA1 stratum radiatum (Rad) and CA1 stratum lacunosum-moleculare (LMol), as well as the dentate gyrus polymorphic layer (PoDG). Double immunostaining for Iba1 and TMEM119 revealed that microglial density is influenced by both sex chromosomes and sex hormones. We show in the Rad and LMol that microglia are denser in FCG XX compared to Tg XYSry mice, however, microglia were densest in WT XX mice. In the PoDG, ovarian animals had increased microglial density compared to testes animals. Additionally, microglial morphology was modulated by a complex interaction between hormones and chromosomes, affecting both their cellular soma and arborization across the hippocampal layers. Moreover, ultrastructural analysis showed that microglia in WT animals make overall more contacts with pre- and post-synaptic elements than in FCG animals. Lastly, microglial markers of cellular stress, including mitochondrion elongation, and dilation of the endoplasmic reticulum and Golgi apparatus, were mostly chromosomally driven. Overall, we characterized different aspects of microglial properties during normal physiological conditions that were found to be shaped by sex chromosomes and sex hormones, shading more light onto how sex differences affect the brain immunity at steady-state.
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Affiliation(s)
- Bianca Caroline Bobotis
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Mohammadparsa Khakpour
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Olivia Braniff
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | | | - Makenna Gargus
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Micah Allen
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Micaël Carrier
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval, Québec City, QC, Canada
| | - Joanie Baillargeon
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
| | - Manu Rangachari
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Département de médecine moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada.
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
- Département de médecine moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada.
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada.
- Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
- Institute on Aging and Lifelong Health (IALH), University of Victoria, Victoria, BC, Canada.
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4
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Scheinman SB, Dong H. The impact of sex on memory during aging and Alzheimer's disease progression: Epigenetic mechanisms. J Alzheimers Dis 2024; 102:562-576. [PMID: 39539121 PMCID: PMC11721493 DOI: 10.1177/13872877241288709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Alzheimer's disease (AD) is a leading cause of dementia, disability, and death in the elderly. While the etiology of AD is unknown, there are several established risk factors for the disease including, aging, female sex, and genetics. However, specific genetic mutations only account for a small percentage (1-5%) of AD cases and the much more common sporadic form of the disease has no causative genetic basis, although certain risk factor genes have been identified. While the genetic code remains static throughout the lifetime, the activation and expression levels of genes change dynamically over time via epigenetics. Recent evidence has emerged linking changes in epigenetics to the pathogenesis of AD, and epigenetic alterations also modulate cognitive changes during physiological aging. Aging is the greatest risk factor for the development of AD and two-thirds of all AD patients are women, who experience an increased rate of symptom progression compared to men of the same age. In humans and other mammalian species, males and females experience aging differently, raising the important question of whether sex differences in epigenetic regulation during aging could provide an explanation for sex differences in neurodegenerative diseases such as AD. This review explores distinct epigenetic changes that impact memory function during aging and AD, with a specific focus on sexually divergent epigenetic alterations (in particular, histone modifications) as a potential mechanistic explanation for sex differences in AD.
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Affiliation(s)
- Sarah B Scheinman
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Hongxin Dong
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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5
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Serio B, Hettwer MD, Wiersch L, Bignardi G, Sacher J, Weis S, Eickhoff SB, Valk SL. Sex differences in functional cortical organization reflect differences in network topology rather than cortical morphometry. Nat Commun 2024; 15:7714. [PMID: 39231965 PMCID: PMC11375086 DOI: 10.1038/s41467-024-51942-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 08/21/2024] [Indexed: 09/06/2024] Open
Abstract
Differences in brain size between the sexes are consistently reported. However, the consequences of this anatomical difference on sex differences in intrinsic brain function remain unclear. In the current study, we investigate whether sex differences in intrinsic cortical functional organization may be associated with differences in cortical morphometry, namely different measures of brain size, microstructure, and the geodesic distance of connectivity profiles. For this, we compute a low dimensional representation of functional cortical organization, the sensory-association axis, and identify widespread sex differences. Contrary to our expectations, sex differences in functional organization do not appear to be systematically associated with differences in total surface area, microstructural organization, or geodesic distance, despite these morphometric properties being per se associated with functional organization and differing between sexes. Instead, functional sex differences in the sensory-association axis are associated with differences in functional connectivity profiles and network topology. Collectively, our findings suggest that sex differences in functional cortical organization extend beyond sex differences in cortical morphometry.
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Affiliation(s)
- Bianca Serio
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany.
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
- Max Planck School of Cognition, Leipzig, Germany.
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
| | - Meike D Hettwer
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
- Max Planck School of Cognition, Leipzig, Germany
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Lisa Wiersch
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
- Brain-Based Predictive Modeling Lab, Feinstein Institutes for Medical Research, Glen Oaks, New York, NY, USA
| | - Giacomo Bignardi
- Max Planck School of Cognition, Leipzig, Germany
- Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
| | - Julia Sacher
- Max Planck School of Cognition, Leipzig, Germany
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Leipzig Center for Female Health & Gender Medicine, Medical Faculty, University Clinic Leipzig, Leipzig, Germany
- Clinic for Cognitive Neurology, University Medical Center Leipzig, Leipzig, Germany
| | - Susanne Weis
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Simon B Eickhoff
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
- Max Planck School of Cognition, Leipzig, Germany
| | - Sofie L Valk
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany.
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
- Max Planck School of Cognition, Leipzig, Germany.
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
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6
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Küchenhoff S, Bayrak Ş, Zsido RG, Saberi A, Bernhardt BC, Weis S, Schaare HL, Sacher J, Eickhoff S, Valk SL. Relating sex-bias in human cortical and hippocampal microstructure to sex hormones. Nat Commun 2024; 15:7279. [PMID: 39179555 PMCID: PMC11344136 DOI: 10.1038/s41467-024-51459-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 07/25/2024] [Indexed: 08/26/2024] Open
Abstract
Determining sex-bias in brain structure is of great societal interest to improve diagnostics and treatment of brain-related disorders. So far, studies on sex-bias in brain structure predominantly focus on macro-scale measures, and often ignore factors determining this bias. Here we study sex-bias in cortical and hippocampal microstructure in relation to sex hormones. Investigating quantitative intracortical profiling in-vivo using the T1w/T2w ratio in 1093 healthy females and males of the cross-sectional Human Connectome Project young adult sample, we find that regional cortical and hippocampal microstructure differs between males and females and that the effect size of this sex-bias varies depending on self-reported hormonal status in females. Microstructural sex-bias and expression of sex hormone genes, based on an independent post-mortem sample, are spatially coupled. Lastly, sex-bias is most pronounced in paralimbic areas, with low laminar complexity, which are predicted to be most plastic based on their cytoarchitectural properties. Albeit correlative, our study underscores the importance of incorporating sex hormone variables into the investigation of brain structure and plasticity.
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Affiliation(s)
- Svenja Küchenhoff
- Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany.
- Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
- Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
- Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK.
| | - Şeyma Bayrak
- Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany
- Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Rachel G Zsido
- Cognitive Neuroendocrinology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Amin Saberi
- Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany
- Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | | | - Susanne Weis
- Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - H Lina Schaare
- Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany
- Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Julia Sacher
- Centre for Integrative Women's Health and Gender Medicine, Medical Faculty & University Hospital Leipzig, Leipzig, Germany
| | - Simon Eickhoff
- Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sofie L Valk
- Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany.
- Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
- Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
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7
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Kestering-Ferreira É, Heberle BA, Sindermann Lumertz F, Gobira PH, Orso R, Grassi-Oliveira R, Viola TW. Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence. Neurosci Lett 2024; 837:137898. [PMID: 39013536 DOI: 10.1016/j.neulet.2024.137898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 07/18/2024]
Abstract
PURPOSE Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. MATERIALS AND METHODS Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the μ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. RESULTS Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. CONCLUSIONS The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.
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MESH Headings
- Animals
- Fentanyl/pharmacology
- Male
- Female
- Mice, Inbred C57BL
- Sex Characteristics
- Receptors, Opioid, mu/genetics
- Receptors, Opioid, mu/metabolism
- Mice
- DNA Methylation/drug effects
- Analgesics, Opioid/pharmacology
- Corpus Striatum/metabolism
- Corpus Striatum/drug effects
- Locomotion/drug effects
- Prefrontal Cortex/drug effects
- Prefrontal Cortex/metabolism
- Receptors, Dopamine/genetics
- Receptors, Dopamine/metabolism
- Naloxone/pharmacology
- Behavior, Animal/drug effects
- Substance Withdrawal Syndrome/genetics
- Substance Withdrawal Syndrome/metabolism
- Epigenesis, Genetic/drug effects
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Affiliation(s)
- Érika Kestering-Ferreira
- School of Medicine, Brain Institute of Rio Grande do Sul, Developmental Cognitive Neuroscience Lab, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
| | | | - Francisco Sindermann Lumertz
- School of Medicine, Brain Institute of Rio Grande do Sul, Developmental Cognitive Neuroscience Lab, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - Pedro Henrique Gobira
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rodrigo Orso
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Rodrigo Grassi-Oliveira
- School of Medicine, Brain Institute of Rio Grande do Sul, Developmental Cognitive Neuroscience Lab, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Thiago Wendt Viola
- School of Medicine, Brain Institute of Rio Grande do Sul, Developmental Cognitive Neuroscience Lab, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
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8
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Quintana GR, Pfaus JG. Do Sex and Gender Have Separate Identities? ARCHIVES OF SEXUAL BEHAVIOR 2024; 53:2957-2975. [PMID: 39105983 PMCID: PMC11335805 DOI: 10.1007/s10508-024-02933-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 06/07/2024] [Accepted: 06/09/2024] [Indexed: 08/07/2024]
Abstract
The largely binary nature of biological sex and its conflation with the socially constructed concept of gender has created much strife in the last few years. The notion of gender identity and its differences and similarities with sex have fostered much scientific and legal confusion and disagreement. Settling the debate can have significant repercussions for science, medicine, legislation, and people's lives. The present review addresses this debate though different levels of analysis (i.e., genetic, anatomical, physiological, behavioral, and sociocultural), and their implications and interactions. We propose a rationale where both perspectives coexist, where diversity is the default, establishing a delimitation to the conflation between sex and gender, while acknowledging their interaction. Whereas sex in humans and other mammals is a biological reality that is largely binary and based on genes, chromosomes, anatomy, and physiology, gender is a sociocultural construct that is often, but not always, concordant with a person' sex, and can span a multitude of expressions.
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Affiliation(s)
- Gonzalo R Quintana
- Departamento de Psicología y Filosofía, Facultad de Ciencias Sociales, Universidad de Tarapacá, Arica, Arica y Parinacota, Chile
| | - James G Pfaus
- Department of Psychology and Life Sciences, Charles University, Prague, 18200, Czech Republic.
- Center for Sexual Health and Intervention, Czech National Institute of Mental Health, Klecany, Czech Republic.
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9
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Armani-Tourret M, Bone B, Tan TS, Sun W, Bellefroid M, Struyve T, Louella M, Yu XG, Lichterfeld M. Immune targeting of HIV-1 reservoir cells: a path to elimination strategies and cure. Nat Rev Microbiol 2024; 22:328-344. [PMID: 38337034 PMCID: PMC11131351 DOI: 10.1038/s41579-024-01010-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2024] [Indexed: 02/12/2024]
Abstract
Successful approaches for eradication or cure of HIV-1 infection are likely to include immunological mechanisms, but remarkably little is known about how human immune responses can recognize and interact with the few HIV-1-infected cells that harbour genome-intact viral DNA, persist long term despite antiretroviral therapy and represent the main barrier to a cure. For a long time regarded as being completely shielded from host immune responses due to viral latency, these cells do, on closer examination with single-cell analytic techniques, display discrete footprints of immune selection, implying that human immune responses may be able to effectively engage and target at least some of these cells. The failure to eliminate rebound-competent virally infected cells in the majority of persons likely reflects the evolution of a highly selected pool of reservoir cells that are effectively camouflaged from immune recognition or rely on sophisticated approaches for resisting immune-mediated killing. Understanding the fine-tuned interplay between host immune responses and viral reservoir cells will help to design improved interventions that exploit the immunological vulnerabilities of HIV-1 reservoir cells.
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Affiliation(s)
- Marie Armani-Tourret
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Benjamin Bone
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Toong Seng Tan
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Weiwei Sun
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Maxime Bellefroid
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Tine Struyve
- HIV Cure Research Center, Ghent University, Ghent, Belgium
| | - Michael Louella
- Community Advisory Board, Delaney AIDS Research Enterprise (DARE), San Francisco, CA, USA
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| | - Xu G Yu
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Mathias Lichterfeld
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA.
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
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10
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Ivanescu AC, Dan GA. Sex Differences in Cardiovascular Management: A Call for Better Acknowledgment-Part 1 Pharmacological Differences in Women and Men; How Relevant Are They? Am J Ther 2024; 31:e237-e245. [PMID: 38691663 DOI: 10.1097/mjt.0000000000001753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
BACKGROUND Sex differences (SDs) in pharmacology of cardiovascular (CV) drugs have been described previously; however, paradoxically, there are scarce recommendations in therapy based on these differences. It is of utmost importance to identify whether these SDs determine a modified clinical response and the potential practical implications for this, to provide a base for personalized medicine. AREA OF UNCERTAINTY The aim of this article was to outline the most important pharmacological drivers of cardiovascular drugs that differ between women and men, along with their implications and challenges in clinical practice. DATA SOURCES A detailed assessment of English-written resources reflecting SDs impact in CV drug pharmacology was performed using PubMed and Embase databases. RESULTS Despite large variations in CV drug pharmacokinetics and pharmacodynamics in individuals, correcting for height, weight, surface area, and body composition compensate for most "sex-dependent" differences. In addition, individual, cultural, and social factors significantly impact disease management in women versus men. Gender-biased prescribing patterns and gender-dependent adherence to therapy also influence outcomes. The development of sex-specific guidelines requires that they should reflect the SDs implications for the management of a disease and that the evidence should be carefully evaluated as to whether there is an adequate representation of both sexes and whether sex-disaggregated data are reported. CONCLUSIONS Pharmacological drivers are under the influence of an impressive number of differences between women and men. However, to establish their significance in clinical practice, an adequate representation of women in studies and the reporting of distinct results is mandatory.
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Affiliation(s)
- Andreea-Cristina Ivanescu
- Carol Davila University of Medicine, Bucharest, Romania; and
- Colentina Clinical Hospital, Bucharest, Romania
| | - Gheorghe-Andrei Dan
- Carol Davila University of Medicine, Bucharest, Romania; and
- Colentina Clinical Hospital, Bucharest, Romania
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11
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Castillo-Ordoñez WO, Cajas-Salazar N, Velasco-Reyes MA. Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents. Neural Regen Res 2024; 19:846-854. [PMID: 37843220 PMCID: PMC10664119 DOI: 10.4103/1673-5374.382232] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/15/2023] [Accepted: 07/18/2023] [Indexed: 10/17/2023] Open
Abstract
Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer's disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer's disease, known as familial Alzheimer's disease (onset < 65 years) and late-onset or sporadic Alzheimer's disease (onset ≥ 65 years). Patients with familial Alzheimer's disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer's disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer's disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer's disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer's disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer's disease-related genes.
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Affiliation(s)
- Willian Orlando Castillo-Ordoñez
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
- Departamento de Estudios Psicológicos, Universidad Icesi, Cali, Colombia
| | - Nohelia Cajas-Salazar
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
| | - Mayra Alejandra Velasco-Reyes
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
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12
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Li H, Jiang W, Liu S, Yang M, Chen S, Pan Y, Cui M. Connecting the mechanisms of tumor sex differences with cancer therapy. Mol Cell Biochem 2024; 479:213-231. [PMID: 37027097 DOI: 10.1007/s11010-023-04723-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 03/26/2023] [Indexed: 04/08/2023]
Abstract
Sex differences in cancer incidence and survival are constant and pronounced globally, across all races and all age groups of cancer types. In 2016, after the National Institutes of Health proposed a policy of utilizing sex as a biological variable, researchers started paying more attention to the molecular mechanisms behind gender variations in cancer. Historically, most previous studies investigating sex differences have been centered on gonadal sex hormones. Nevertheless, sex differences also involve genetic and molecular pathways that run throughout the entire process of cancer cell proliferation, metastasis, and treatment response, in addition to sex hormones. In particular, there is significant gender dimorphism in the efficacy and toxicity of oncology treatments, including conventional radiotherapy and chemotherapy, as well as the emerging targeted therapies and immunotherapy. To be clear, not all mechanisms will exhibit gender bias, and not all gender bias will affect cancer risk. Our goal in this review is to discuss some of the significant sex-related changes in fundamental cancer pathways. To this purpose, we summarize the differential impact of gender on cancer development in three dimensions: sex hormones, genetics, and epigenetics, and focus on current hot subjects including tumor suppressor function, immunology, stem cell renewal, and non-coding RNAs. Clarifying the essential mechanisms of gender differences will help guide the clinical treatment of both sexes in tumor radiation and chemotherapy, medication therapy with various targets, immunotherapy, and even drug development. We anticipate that sex-differentiated research will help advance sex-based cancer personalized medicine models and encourage future basic scientific and clinical research to take sex into account.
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Affiliation(s)
- Huan Li
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Weibo Jiang
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Shui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Manshi Yang
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Siyuan Chen
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Yihan Pan
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China.
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13
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Raffaele S, Thougaard E, Laursen CCH, Gao H, Andersen KM, Nielsen PV, Ortí-Casañ N, Blichfeldt-Eckhardt M, Koch S, Deb-Chatterji M, Magnus T, Stubbe J, Madsen K, Meyer M, Degn M, Eisel ULM, Wlodarczyk A, Fumagalli M, Clausen BH, Brambilla R, Lambertsen KL. Microglial TNFR2 signaling regulates the inflammatory response after CNS injury in a sex-specific fashion. Brain Behav Immun 2024; 116:269-285. [PMID: 38142915 PMCID: PMC11500189 DOI: 10.1016/j.bbi.2023.12.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/21/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023] Open
Abstract
Microglia, the resident immune cells of the central nervous system (CNS), play a major role in damage progression and tissue remodeling after acute CNS injury, including ischemic stroke (IS) and spinal cord injury (SCI). Understanding the molecular mechanisms regulating microglial responses to injury may thus reveal novel therapeutic targets to promote CNS repair. Here, we investigated the role of microglial tumor necrosis factor receptor 2 (TNFR2), a transmembrane receptor previously associated with pro-survival and neuroprotective responses, in shaping the neuroinflammatory environment after CNS injury. By inducing experimental IS and SCI in Cx3cr1CreER:Tnfrsf1bfl/fl mice, selectively lacking TNFR2 in microglia, and corresponding Tnfrsf1bfl/fl littermate controls, we found that ablation of microglial TNFR2 significantly reduces lesion size and pro-inflammatory cytokine levels, and favors infiltration of leukocytes after injury. Interestingly, these effects were paralleled by opposite sex-specific modifications of microglial reactivity, which was found to be limited in female TNFR2-ablated mice compared to controls, whereas it was enhanced in males. In addition, we show that TNFR2 protein levels in the cerebrospinal fluid (CSF) of human subjects affected by IS and SCI, as well as healthy donors, significantly correlate with disease stage and severity, representing a valuable tool to monitor the inflammatory response after acute CNS injury. Hence, these results advance our understanding of the mechanisms regulating microglia reactivity after acute CNS injury, aiding the development of sex- and microglia-specific, personalized neuroregenerative strategies.
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Affiliation(s)
- Stefano Raffaele
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark; Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, 20133 Milan, Italy
| | - Estrid Thougaard
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark
| | - Cathrine C H Laursen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark; BRIDGE-Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark
| | - Han Gao
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, 510630 Guangzhou, China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, 510630 Guangzhou, China
| | - Katrine M Andersen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark
| | - Pernille V Nielsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark
| | - Natalia Ortí-Casañ
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen 9713 AV, Netherlands
| | - Morten Blichfeldt-Eckhardt
- Department of Anaesthesiology, Vejle Hospital, 7100 Vejle, Denmark; Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark
| | - Simon Koch
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Milani Deb-Chatterji
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Tim Magnus
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jane Stubbe
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark
| | - Kirsten Madsen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark
| | - Morten Meyer
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark; BRIDGE-Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark; Department of Neurology, Odense University Hospital, 5000 Odense C, Denmark
| | | | - Ulrich L M Eisel
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen 9713 AV, Netherlands
| | - Agnieszka Wlodarczyk
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark; BRIDGE-Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark
| | - Marta Fumagalli
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, 20133 Milan, Italy
| | - Bettina H Clausen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark; BRIDGE-Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark
| | - Roberta Brambilla
- BRIDGE-Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark; The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami FL, USA.
| | - Kate L Lambertsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark; BRIDGE-Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark; Department of Neurology, Odense University Hospital, 5000 Odense C, Denmark.
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14
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Green-Fulgham SM, Ball JB, Kwilasz AJ, Harland ME, Frank MG, Dragavon JM, Grace PM, Watkins LR. Interleukin-1beta and inflammasome expression in spinal cord following chronic constriction injury in male and female rats. Brain Behav Immun 2024; 115:157-168. [PMID: 37838078 PMCID: PMC10841465 DOI: 10.1016/j.bbi.2023.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 10/02/2023] [Accepted: 10/07/2023] [Indexed: 10/16/2023] Open
Abstract
Females represent a majority of chronic pain patients and show greater inflammatory immune responses in human chronic pain patient populations as well as in animal models of neuropathic pain. Recent discoveries in chronic pain research have revealed sex differences in inflammatory signaling, a key component of sensory pathology in chronic neuropathic pain, inviting more research into the nuances of these sex differences. Here we use the chronic constriction injury (CCI) model to explore similarities and differences in expression and production of Inflammatory cytokine IL-1beta in the lumbar spinal cord, as well as its role in chronic pain. We have discovered that intrathecal IL-1 receptor antagonist reverses established pain in both sexes, and increased gene expression of inflammasome NLRP3 is specific to microglia and astrocytes rather than neurons, while IL-1beta is specific to microglia in both sexes. We report several sex differences in the expression level of the genes coding for IL-1beta, as well as the four inflammasomes responsible for IL-1beta release: NLRP3, AIM2, NLRP1, and NLRC4 in the spinal cord. Total mRNA, but not protein expression of IL-1beta is greater in females than males after CCI. Also, while CCI increases all four inflammasomes in both sexes, there are sex differences in relative levels of inflammasome expression. NLRP3 and AIM2 are more highly expressed in females, whereas NLRP1 expression is greater in males.
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Affiliation(s)
- Suzanne M Green-Fulgham
- Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, United States
| | - Jayson B Ball
- Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, United States
| | - Andrew J Kwilasz
- Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, United States
| | - Michael E Harland
- Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, United States
| | - Matthew G Frank
- Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, United States
| | - Joseph M Dragavon
- Advanced Light Microscopy Core, BioFrontiers Institute, University of Colorado, Boulder, CO, United States
| | - Peter M Grace
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Linda R Watkins
- Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, United States.
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15
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Pierron F, Daramy F, Heroin D, Daffe G, Barré A, Bouchez O, Nikolski M. Sex-specific DNA methylation and transcription of zbtb38 and effects of gene-environment interactions on its natural antisense transcript in zebrafish. Epigenetics 2023; 18:2260963. [PMID: 37782752 PMCID: PMC10547075 DOI: 10.1080/15592294.2023.2260963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 09/06/2023] [Indexed: 10/04/2023] Open
Abstract
There is increasing evidence for the involvement of epigenetics in sex determination, maintenance, and plasticity, from plants to humans. In our previous work, we reported a transgenerational feminization of a zebrafish population for which the first generation was exposed to cadmium, a metal with endocrine disrupting effects. In this study, starting from the previously performed whole methylome analysis, we focused on the zbtb38 gene and hypothesized that it could be involved in sex differentiation and Cd-induced offspring feminization. We observed sex-specific patterns of both DNA methylation and RNA transcription levels of zbtb38. We also discovered that the non-coding exon 3 of zbtb38 encodes for a natural antisense transcript (NAT). The activity of this NAT was found to be influenced by both genetic and environmental factors. Furthermore, increasing transcription levels of this NAT in parental gametes was highly correlated with offspring sex ratios. Since zbtb38 itself encodes for a transcription factor that binds methylated DNA, our results support a non-negligible role of zbtb38 not only in orchestrating the sex-specific transcriptome (i.e., sex differentiation) but also, via its NAT, offspring sex ratios.
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Affiliation(s)
| | - Flore Daramy
- Univ Bordeaux, CNRS, Bordeaux INP, Pessac, France
| | | | | | - Aurélien Barré
- Univ Bordeaux, Bordeaux Bioinformatics Center, Bordeaux, France
| | - Olivier Bouchez
- INRAE, US 1426, GeT-PlaGe, Genotoul, Castanet-Tolosan, France
| | - Macha Nikolski
- Univ Bordeaux, Bordeaux Bioinformatics Center, Bordeaux, France
- Univ Bordeaux, CNRS, IBGC, Bordeaux, France
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16
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Serio B, Hettwer MD, Wiersch L, Bignardi G, Sacher J, Weis S, Eickhoff SB, Valk SL. Sex differences in intrinsic functional cortical organization reflect differences in network topology rather than cortical morphometry. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.23.568437. [PMID: 38045320 PMCID: PMC10690290 DOI: 10.1101/2023.11.23.568437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Brain size robustly differs between sexes. However, the consequences of this anatomical dimorphism on sex differences in intrinsic brain function remain unclear. We investigated the extent to which sex differences in intrinsic cortical functional organization may be explained by differences in cortical morphometry, namely brain size, microstructure, and the geodesic distances of connectivity profiles. For this, we computed a low dimensional representation of functional cortical organization, the sensory-association axis, and identified widespread sex differences. Contrary to our expectations, observed sex differences in functional organization were not fundamentally associated with differences in brain size, microstructural organization, or geodesic distances, despite these morphometric properties being per se associated with functional organization and differing between sexes. Instead, functional sex differences in the sensory-association axis were associated with differences in functional connectivity profiles and network topology. Collectively, our findings suggest that sex differences in functional cortical organization extend beyond sex differences in cortical morphometry.
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Affiliation(s)
- Bianca Serio
- Max Planck School of Cognition, Leipzig, Germany
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Meike D. Hettwer
- Max Planck School of Cognition, Leipzig, Germany
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Lisa Wiersch
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Giacomo Bignardi
- Max Planck School of Cognition, Leipzig, Germany
- Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
| | - Julia Sacher
- Max Planck School of Cognition, Leipzig, Germany
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Clinic for Cognitive Neurology, University Medical Center Leipzig, Leipzig, Germany
| | - Susanne Weis
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Simon B. Eickhoff
- Max Planck School of Cognition, Leipzig, Germany
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Sofie L. Valk
- Max Planck School of Cognition, Leipzig, Germany
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Institute of Neuroscience and Medicine, Brain & Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
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17
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Kumar P, Brooks HL. Sex-specific epigenetic programming in renal fibrosis and inflammation. Am J Physiol Renal Physiol 2023; 325:F578-F594. [PMID: 37560775 PMCID: PMC11550885 DOI: 10.1152/ajprenal.00091.2023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/18/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023] Open
Abstract
The growing prevalence of hypertension, heart disease, diabetes, and obesity along with an aging population is leading to a higher incidence of renal diseases in society. Chronic kidney disease (CKD) is characterized mainly by persistent inflammation, fibrosis, and gradual loss of renal function leading to renal failure. Sex is a known contributor to the differences in incidence and progression of CKD. Epigenetic programming is an essential regulator of renal physiology and is critically involved in the pathophysiology of renal injury and fibrosis. Epigenetic signaling integrates intrinsic and extrinsic signals onto the genome, and various environmental and hormonal stimuli, including sex hormones, which regulate gene expression and downstream cellular responses. The most extensively studied epigenetic alterations that play a critical role in renal damage include histone modifications and DNA methylation. Notably, these epigenetic alterations are reversible, making them candidates for potential therapeutic targets for the treatment of renal diseases. Here, we will summarize the current knowledge on sex differences in epigenetic modulation of renal fibrosis and inflammation and highlight some possible epigenetic therapeutic strategies for CKD treatment.
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Affiliation(s)
- Prerna Kumar
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
| | - Heddwen L Brooks
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
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18
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Bernstein SR, Kelleher C, Khalil RA. Gender-based research underscores sex differences in biological processes, clinical disorders and pharmacological interventions. Biochem Pharmacol 2023; 215:115737. [PMID: 37549793 PMCID: PMC10587961 DOI: 10.1016/j.bcp.2023.115737] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 08/09/2023]
Abstract
Earlier research has presumed that the male and female biology is similar in most organs except the reproductive system, leading to major misconceptions in research interpretations and clinical implications, with serious disorders being overlooked or misdiagnosed. Careful research has now identified sex differences in the cardiovascular, renal, endocrine, gastrointestinal, immune, nervous, and musculoskeletal systems. Also, several cardiovascular, immunological, and neurological disorders have shown differences in prevalence and severity between males and females. Genetic variations in the sex chromosomes have been implicated in several disorders at young age and before puberty. The levels of the gonadal hormones estrogen, progesterone and testosterone and their receptors play a role in the sex differences between adult males and premenopausal women. Hormonal deficiencies and cell senescence have been implicated in differences between postmenopausal and premenopausal women. Specifically, cardiovascular disorders are more common in adult men vs premenopausal women, but the trend is reversed with age with the incidence being greater in postmenopausal women than age-matched men. Gender-specific disorders in females such as polycystic ovary syndrome, hypertension-in-pregnancy and gestational diabetes have attained further research recognition. Other gender-related research areas include menopausal hormone therapy, the "Estrogen Paradox" in pulmonary arterial hypertension being more predominant but less severe in young females, and how testosterone may cause deleterious effects in the kidney while having vasodilator effects in the coronary circulation. This has prompted the National Institutes of Health (NIH) initiative to consider sex as a biological variable in research. The NIH and other funding agencies have provided resources to establish state-of-the-art centers for women health and sex differences in biology and disease in several academic institutions. Scientific societies and journals have taken similar steps to organize specialized conferences and publish special issues on gender-based research. These combined efforts should promote research to enhance our understanding of the sex differences in biological systems beyond just the reproductive system, and provide better guidance and pharmacological tools for the management of various clinical disorders in a gender-specific manner.
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Affiliation(s)
- Sofia R Bernstein
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA
| | - Caroline Kelleher
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA
| | - Raouf A Khalil
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
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19
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Zhang Y, Barupal DK, Fan S, Gao B, Zhu C, Flenniken AM, McKerlie C, Nutter LMJ, Lloyd KCK, Fiehn O. Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines. Metabolites 2023; 13:947. [PMID: 37623890 PMCID: PMC10456929 DOI: 10.3390/metabo13080947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/03/2023] [Accepted: 08/08/2023] [Indexed: 08/26/2023] Open
Abstract
Although metabolic alterations are observed in many monogenic and complex genetic disorders, the impact of most mammalian genes on cellular metabolism remains unknown. Understanding the effect of mouse gene dysfunction on metabolism can inform the functions of their human orthologues. We investigated the effect of loss-of-function mutations in 30 unique gene knockout (KO) lines on plasma metabolites, including genes coding for structural proteins (11 of 30), metabolic pathway enzymes (12 of 30) and protein kinases (7 of 30). Steroids, bile acids, oxylipins, primary metabolites, biogenic amines and complex lipids were analyzed with dedicated mass spectrometry platforms, yielding 827 identified metabolites in male and female KO mice and wildtype (WT) controls. Twenty-two percent of 23,698 KO versus WT comparison tests showed significant genotype effects on plasma metabolites. Fifty-six percent of identified metabolites were significantly different between the sexes in WT mice. Many of these metabolites were also found to have sexually dimorphic changes in KO lines. We used plasma metabolites to complement phenotype information exemplified for Dhfr, Idh1, Mfap4, Nek2, Npc2, Phyh and Sra1. The association of plasma metabolites with IMPC phenotypes showed dramatic sexual dimorphism in wildtype mice. We demonstrate how to link metabolomics to genotypes and (disease) phenotypes. Sex must be considered as critical factor in the biological interpretation of gene functions.
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Affiliation(s)
- Ying Zhang
- West Coast Metabolomics Center, University of California Davis, Davis, CA 95616, USA
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
| | - Dinesh K. Barupal
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Sili Fan
- West Coast Metabolomics Center, University of California Davis, Davis, CA 95616, USA
| | - Bei Gao
- School of Marine Sciences, Nanjing University of Information Science and Technology, Nanjing 210044, China
| | - Chao Zhu
- College of Medicine & Nursing, Dezhou University, Dezhou 253023, China
| | - Ann M. Flenniken
- The Centre for Phenogenomics, Toronto, ON M5T 3H7, Canada; (A.M.F.); (C.M.); (L.M.J.N.)
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Colin McKerlie
- The Centre for Phenogenomics, Toronto, ON M5T 3H7, Canada; (A.M.F.); (C.M.); (L.M.J.N.)
- The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Lauryl M. J. Nutter
- The Centre for Phenogenomics, Toronto, ON M5T 3H7, Canada; (A.M.F.); (C.M.); (L.M.J.N.)
- The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Kevin C. Kent Lloyd
- Department of Surgery, School of Medicine, and Mouse Biology Program, University of California Davis, Davis, CA 95616, USA;
| | - Oliver Fiehn
- West Coast Metabolomics Center, University of California Davis, Davis, CA 95616, USA
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20
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Clive J, Flintham E, Savolainen V. Same-sex sociosexual behaviour is widespread and heritable in male rhesus macaques. Nat Ecol Evol 2023; 7:1287-1301. [PMID: 37429903 DOI: 10.1038/s41559-023-02111-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 06/01/2023] [Indexed: 07/12/2023]
Abstract
Numerous reports have documented the occurrence of same-sex sociosexual behaviour (SSB) across animal species. However, the distribution of the behaviour within a species needs to be studied to test hypotheses describing its evolution and maintenance, in particular whether the behaviour is heritable and can therefore evolve by natural selection. Here we collected detailed observations across 3 yr of social and mounting behaviour of 236 male semi-wild rhesus macaques, which we combined with a pedigree dating back to 1938, to show that SSB is both repeatable (19.35%) and heritable (6.4%). Demographic factors (age and group structure) explained SSB variation only marginally. Furthermore, we found a positive genetic correlation between same-sex mounter and mountee activities, indicating a common basis to different forms of SSB. Finally, we found no evidence of fitness costs to SSB, but show instead that the behaviour mediated coalitionary partnerships that have been linked to improved reproductive success. Together, our results demonstrate that SSB is frequent in rhesus macaques, can evolve, and is not costly, indicating that SSB may be a common feature of primate reproductive ecology.
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Affiliation(s)
- Jackson Clive
- Georgina Mace Centre for the Living Planet, Department of Life Sciences, Silwood Park Campus, Imperial College London, Ascot, UK
| | - Ewan Flintham
- Georgina Mace Centre for the Living Planet, Department of Life Sciences, Silwood Park Campus, Imperial College London, Ascot, UK
| | - Vincent Savolainen
- Georgina Mace Centre for the Living Planet, Department of Life Sciences, Silwood Park Campus, Imperial College London, Ascot, UK.
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21
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Vosberg DE, Pausova Z, Paus T. The genetics of a "femaleness/maleness" score in cardiometabolic traits in the UK biobank. Sci Rep 2023; 13:9109. [PMID: 37277458 DOI: 10.1038/s41598-023-36132-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 05/30/2023] [Indexed: 06/07/2023] Open
Abstract
We recently devised continuous "sex-scores" that sum up multiple quantitative traits, weighted by their respective sex-difference effect sizes, as an approach to estimating polyphenotypic "maleness/femaleness" within each binary sex. To identify the genetic architecture underlying these sex-scores, we conducted sex-specific genome-wide association studies (GWASs) in the UK Biobank cohort (females: n = 161,906; males: n = 141,980). As a control, we also conducted GWASs of sex-specific "sum-scores", simply aggregating the same traits, without weighting by sex differences. Among GWAS-identified genes, while sum-score genes were enriched for genes differentially expressed in the liver in both sexes, sex-score genes were enriched for genes differentially expressed in the cervix and across brain tissues, particularly for females. We then considered single nucleotide polymorphisms with significantly different effects (sdSNPs) between the sexes for sex-scores and sum-scores, mapping to male-dominant and female-dominant genes. Here, we identified brain-related enrichment for sex-scores, especially for male-dominant genes; these findings were present but weaker for sum-scores. Genetic correlation analyses of sex-biased diseases indicated that both sex-scores and sum-scores were associated with cardiometabolic, immune, and psychiatric disorders.
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Affiliation(s)
- Daniel E Vosberg
- Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada
- Department of Neuroscience, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
- Research Institute of the Hospital for Sick Children, Toronto, ON, Canada
| | - Zdenka Pausova
- Research Institute of the Hospital for Sick Children, Toronto, ON, Canada
- Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada
| | - Tomáš Paus
- Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada.
- Department of Neuroscience, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
- Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada.
- ECOGENE-21, Chicoutimi, QC, Canada.
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
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22
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Broyles EE, Corell DH, Gidday JM. Maternal repetitive hypoxia prior to mating confers epigenetic resilience to memory impairment in male progeny. Behav Neurosci 2023; 137:178-183. [PMID: 36862475 PMCID: PMC10828958 DOI: 10.1037/bne0000554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023]
Abstract
We showed previously in a mouse model of vascular cognitive impairment and dementia involving chronic cerebral hypoperfusion (CCH) that repetitive hypoxic conditioning (RHC) of both parents results in the epigenetic, intergenerational transmission of resilience to recognition memory loss in adult progeny, as assessed by the novel object recognition test. The present study was undertaken in the same model to determine whether RHC treatment of one or both parents is required to confer dementia resilience intergenerationally. We found inherited resilience to 3 months of CCH in males is maternally mediated (p = .006). Statistically, we observed a strong trend for the paternal germline to contribute as well (p = .052). We also found that, in contrast to what is widely observed in males, females display intact recognition memory (p = .001) after 3 months of CCH, revealing a heretofore unidentified sexual dimorphism with respect to cognitive impact during disease progression. Overall, results of our study strongly implicate epigenetic changes in maternal germ cells, induced by our repetitive systemic hypoxic stimulus, contributing to a modified differentiation program capable of establishing a dementia-resilient phenotype in adult male first-generation progeny. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Affiliation(s)
- Emrey E. Broyles
- Department of Ophthalmology, Louisiana State University School of Medicine
| | - David H. Corell
- Department of Ophthalmology, Louisiana State University School of Medicine
| | - Jeffrey M. Gidday
- Department of Ophthalmology, Louisiana State University School of Medicine
- Department of Neuroscience, Louisiana State University School of Medicine
- Department of Physiology, Louisiana State University School of Medicine
- Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine
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23
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Wei S, Lu K, Xing J, Yu W. A multidimensional pan-cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma. FASEB J 2023; 37:e22849. [PMID: 36884358 PMCID: PMC11977603 DOI: 10.1096/fj.202201022rrr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 01/31/2023] [Accepted: 02/17/2023] [Indexed: 03/09/2023]
Abstract
DCAF13 is a substrate recognition protein in the ubiquitin-proteasome system with oncogenic effects in several malignant tumors. However, it is unclear that the relationship between DCAF13 expression pattern and prognosis across different cancer types. Also unknown is the biological function or effects on the immune microenvironment of DCAF13. In this study, we parsed multiple public databases to explore the potential tumorigenic actions of DCAF13, including correlations with prognosis, microsatellite instability (MSI), tumor mutational burden (TMB), immune checkpoint genes, immune cell infiltration, and immunotherapy response in pan-cancer. Moreover, we validated DCAF13 expression in a tissue microarray by immunohistochemistry and investigate its effects in vitro and in vivo. The results showed that DCAF13 was upregulated in 17 cancer types and correlated with poor prognosis in many cancers. Also, the correlation between DCAF13 and TMB was found in 14 cancers as well as MSI in nine. The expression level of DCAF13 was found to be notably correlated with immune cell infiltration, showing a negative correlation with CD4 T cell infiltration and a positive correlation with neutrophil infiltration. The oncogene DCAF13 expression was shown to have a positive correlation with CD274 or ADORA2A and negative correlation with VSIR, TNFRSF4, or TNFRSF14 across large subsets of human cancers. Finally, we observed that DCAF13 was highly expressed in a tissue microarray of lung cancer. In immunocompromised mouse models, xenograft growth of human lung cancer cells was significantly inhibited by DCAF13 knockdown. Our results highlighted the value of DCAF13 as a promising independent predictor of poor prognosis through numerous biological processes. High DCAF13 expression often predicts suppressive immune microenvironment and immunotherapy resistance in a pan-cancer context.
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Affiliation(s)
- Shan Wei
- Department of Respiratory and Critical Care MedicineThe Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital)NingboPeople's Republic of China
| | - Kaining Lu
- Department of UrologyNingbo First HospitalNingboPeople's Republic of China
| | - Jing Xing
- Department of Respiratory and Critical Care MedicineThe Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital)NingboPeople's Republic of China
| | - Wanjun Yu
- Department of Respiratory and Critical Care MedicineThe Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital)NingboPeople's Republic of China
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24
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Pilipović I, Stojić-Vukanić Z, Prijić I, Jasnić N, Djordjević J, Leposavić G. β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cell Mol Neurobiol 2023; 43:1237-1265. [PMID: 35798933 PMCID: PMC11414456 DOI: 10.1007/s10571-022-01246-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/18/2022] [Indexed: 11/03/2022]
Abstract
Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimorphism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β2-adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte trafficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them. Propranolol moderated EAE severity more effectively in male rats, exhibiting greater spinal cord noradrenaline (NA) levels and myeloid cell β2-adrenoceptor (β2-AR) expression than females. Propranolol affected CX3CR1/Nrf2/HO-1 and Stat3/Socs3 signaling axes in myeloid cells, favored their anti-inflammatory/neuroprotective phenotype and, consequently, reduced Th cell reactivation and differentiation into highly pathogenic IL-17/IFN-γ/GM-CSF-producing cells.
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Affiliation(s)
- Ivan Pilipović
- Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Zorica Stojić-Vukanić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Ivana Prijić
- Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Nebojša Jasnić
- Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Jelena Djordjević
- Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Gordana Leposavić
- Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221, Belgrade, Serbia.
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25
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Holladay SD. Environmental contaminants, endocrine disruption, and transgender: Can "born that way" in some cases be toxicologically real? Hum Exp Toxicol 2023; 42:9603271231203382. [PMID: 37751728 DOI: 10.1177/09603271231203382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Abstract
Gender is viewed by many as strictly binary based on a collection of body traits typical of a female or male phenotype, presence of a genotype that includes at least one copy of a Y chromosome, or ability to produce either egg or sperm cells. A growing non-binary view is that these descriptors, while compelling, may nonetheless fail to accurately capture an individual's true gender. The position of the American Psychological Association (APA) agrees with this view and is that transgender people are a defendable and real part of the human population. The considerable diversity of transgender expression then argues against any unitary or simple explanations, however, prenatal hormone levels, genetic influences, and early and later life experiences have been suggested as playing roles in development of transgender identities. The present review considers existing and emerging toxicologic data that may also support an environmental chemical contribution to some transgender identities, and suggest the possibility of a growing nonbinary brain gender continuum in the human population.
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Affiliation(s)
- Steven David Holladay
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
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26
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Rao S. Sex differences in HIV-1 persistence and the implications for a cure. Front Glob Womens Health 2022; 3:942345. [PMID: 36212905 PMCID: PMC9538461 DOI: 10.3389/fgwh.2022.942345] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Of the 38 million people currently living with Human Immunodeficiency Virus type-1 (HIV-1), women, especially adolescents and young women, are disproportionally affected by the HIV-1 pandemic. Acquired immunodeficiency syndrome (AIDS) - related illnesses are the leading cause of death in women of reproductive age worldwide. Although combination antiretroviral therapy (cART) can suppress viral replication, cART is not curative due to the presence of a long-lived viral reservoir that persists despite treatment. Biological sex influences the characteristics of the viral reservoir as well as the immune responses to infection, factors that can have a significant impact on the design and quantification of HIV-1 curative interventions in which women are grossly underrepresented. This mini-review will provide an update on the current understanding of the impact of biological sex on the viral reservoir and will discuss the implications of these differences in the context of the development of potential HIV-1 curative strategies, with a focus on the shock and kill approach to an HIV-1 cure. This mini-review will also highlight the current gaps in the knowledge of sex-based differences in HIV-1 persistence and will speculate on approaches to address them to promote the development of more scalable, effective curative approaches for people living with HIV-1.
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27
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Govender P, Ghai M, Okpeku M. Sex-specific DNA methylation: impact on human health and development. Mol Genet Genomics 2022; 297:1451-1466. [PMID: 35969270 DOI: 10.1007/s00438-022-01935-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 07/28/2022] [Indexed: 11/26/2022]
Abstract
Human evolution has shaped gender differences between males and females. Over the years, scientific studies have proposed that epigenetic modifications significantly influence sex-specific differences. The evolution of sex chromosomes with epigenetics as the driving force may have led to one sex being more adaptable than the other when exposed to various factors over time. Identifying and understanding sex-specific differences, particularly in DNA methylation, will help determine how each gender responds to factors, such as disease susceptibility, environmental exposure, brain development and neurodegeneration. From a medicine and health standpoint, sex-specific methylation studies have shed light on human disease severity, progression, and response to therapeutic intervention. Interesting findings in gender incongruent individuals highlight the role of genetic makeup in influencing DNA methylation differences. Sex-specific DNA methylation studies will empower the biotechnology and pharmaceutical industry with more knowledge to identify biomarkers, design and develop sex bias drugs leading to better treatment in men and women based on their response to different diseases.
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Affiliation(s)
- Priyanka Govender
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa
| | - Meenu Ghai
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa.
| | - Moses Okpeku
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa
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28
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Piloto JH, Rodriguez M, Choe KP. Sexual dimorphism in Caenorhabditis elegans stress resistance. PLoS One 2022; 17:e0272452. [PMID: 35951614 PMCID: PMC9371273 DOI: 10.1371/journal.pone.0272452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 07/19/2022] [Indexed: 11/18/2022] Open
Abstract
Physiological responses to the environment, disease, and aging vary by sex in many animals, but mechanisms of dimorphism have only recently begun to receive careful attention. The genetic model nematode Caenorhabditis elegans has well-defined mechanisms of stress response, aging, and sexual differentiation. C. elegans has males, but the vast majority of research only uses hermaphrodites. We found that males of the standard N2 laboratory strain were more resistant to hyperosmolarity, heat, and a natural pro-oxidant than hermaphrodites when in mixed-sex groups. Resistance to heat and pro-oxidant were also male-biased in three genetically and geographically diverse C. elegans strains consistent with a species-wide dimorphism that is not specific to domestication. N2 males were also more resistant to heat and pro-oxidant when keep individually indicating that differences in resistance do not require interactions between worms. We found that males induce canonical stress response genes by similar degrees and in similar tissues as hermaphrodites suggesting the importance of other mechanisms. We find that resistance to heat and pro-oxidant are influenced by the sex differentiation transcription factor TRA-1 suggesting that downstream organ differentiation pathways establish differences in stress resistance. Environmental stress influences survival in natural environments, degenerative disease, and aging. Understanding mechanisms of stress response dimorphism can therefore provide insights into sex-specific population dynamics, disease, and longevity.
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Affiliation(s)
- Juan H. Piloto
- Department of Biology and Genetics Institute, University of Florida, Gainesville, FL, United States of America
| | - Michael Rodriguez
- Department of Biology and Genetics Institute, University of Florida, Gainesville, FL, United States of America
| | - Keith P. Choe
- Department of Biology and Genetics Institute, University of Florida, Gainesville, FL, United States of America
- * E-mail:
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29
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Islam M, Strawn M, Behura SK. Fetal origin of sex‐bias brain aging. FASEB J 2022; 36:e22463. [DOI: 10.1096/fj.202200255rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 06/30/2022] [Accepted: 07/11/2022] [Indexed: 02/01/2023]
Affiliation(s)
- Maliha Islam
- Division of Animal Sciences University of Missouri Columbia Missouri USA
| | - Monica Strawn
- Division of Animal Sciences University of Missouri Columbia Missouri USA
| | - Susanta K. Behura
- Division of Animal Sciences University of Missouri Columbia Missouri USA
- MU Institute for Data Science and Informatics University of Missouri Columbia Missouri USA
- Interdisciplinary Neuroscience Program University of Missouri Columbia Missouri USA
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30
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Antunes C, Da Silva JD, Guerra-Gomes S, Alves ND, Loureiro-Campos E, Pinto L, Marques CJ. Tet3 Deletion in Adult Brain Neurons of Female Mice Results in Anxiety-like Behavior and Cognitive Impairments. Mol Neurobiol 2022; 59:4892-4901. [PMID: 35665901 DOI: 10.1007/s12035-022-02883-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 05/16/2022] [Indexed: 11/28/2022]
Abstract
TET enzymes (TET1-3) are dioxygenases that oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and are involved in the DNA demethylation process. In line with the observed 5hmC abundance in the brain, Tet genes are highly transcribed, with Tet3 being the predominant member. We have previously shown that Tet3 conditional deletion in the brain of male mice was associated with anxiety-like behavior and impairment in hippocampal-dependent spatial orientation. In the current study, we addressed the role of Tet3 in female mice and its impact on behavior, using in vivo conditional and inducible deletion from post-mitotic neurons. Our results indicate that conditional and inducible deletion of Tet3 in female mice increases anxiety-like behavior and impairs both spatial orientation and short-term memory. At the molecular level, we identified upregulation of immediate-early genes, particularly Npas4, in both the dorsal and ventral hippocampus and in the prefrontal cortex. This study shows that deletion of Tet3 in female mice differentially affects behavioral dimensions as opposed to Tet3 deletion in males, highlighting the importance of studying both sexes in behavioral studies. Moreover, it contributes to expand the knowledge on the role of epigenetic regulators in brain function and behavioral outcome.
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Affiliation(s)
- Cláudia Antunes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Jorge D Da Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Sónia Guerra-Gomes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Nuno D Alves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Eduardo Loureiro-Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal. .,ICVS/3B's - PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal.
| | - C Joana Marques
- Genetics - Department of Pathology, Faculty of Medicine, University of Porto (FMUP), 4200-319, Porto, Portugal. .,i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, 4200-135, Porto, Portugal.
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31
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Lynch MA. Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine. Front Aging Neurosci 2022; 14:868448. [PMID: 35431903 PMCID: PMC9009390 DOI: 10.3389/fnagi.2022.868448] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/08/2022] [Indexed: 12/16/2022] Open
Abstract
One area of microglial biology that has been relatively neglected until recently is sex differences and this is in spite of the fact that sex is a risk factor in several diseases that are characterized by neuroinflammation and, by extension, microglial activation. Why these sex differences exist is not known but the panoply of differences extend to microglial number, genotype and phenotype. Significantly, several of these sex-related differences are also evident in health and change during life emphasizing the dynamic and plastic nature of microglia. This review will consider how age impacts on sex-related differences in microglia and ask whether the advancement of personalized medicine demands that a greater focus is placed on studying sex-related differences in microglia in Alzheimer's disease, Parkinson's disease and models of inflammatory stress and trauma in order to make true progress in dealing with these conditions.
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Affiliation(s)
- Marina A. Lynch
- Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
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32
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Histone Modifications in Neurological Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1382:95-107. [DOI: 10.1007/978-3-031-05460-0_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Sex differences in the genetic regulation of the blood transcriptome response to glucocorticoid receptor activation. Transl Psychiatry 2021; 11:632. [PMID: 34903727 PMCID: PMC8669026 DOI: 10.1038/s41398-021-01756-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022] Open
Abstract
Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.
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Irwin AB, Bahabry R, Lubin FD. A putative role for lncRNAs in epigenetic regulation of memory. Neurochem Int 2021; 150:105184. [PMID: 34530054 PMCID: PMC8552959 DOI: 10.1016/j.neuint.2021.105184] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022]
Abstract
The central dogma of molecular genetics is defined as encoded genetic information within DNA, transcribed into messenger RNA, which contain the instructions for protein synthesis, thus imparting cellular functionality and ultimately life. This molecular genetic theory has given birth to the field of neuroepigenetics, and it is now well established that epigenetic regulation of gene transcription is critical to the learning and memory process. In this review, we address a potential role for a relatively new player in the field of epigenetic crosstalk - long non-coding RNAs (lncRNAs). First, we briefly summarize epigenetic mechanisms in memory formation and examine what little is known about the emerging role of lncRNAs during this process. We then focus discussions on how lncRNAs interact with epigenetic mechanisms to control transcriptional programs under various conditions in the brain, and how this may be applied to regulation of gene expression necessary for memory formation. Next, we explore how epigenetic crosstalk in turn serves to regulate expression of various individual lncRNAs themselves. To highlight the importance of further exploring the role of lncRNA in epigenetic regulation of gene expression, we consider the significant relationship between lncRNA dysregulation and declining memory reserve with aging, Alzheimer's disease, and epilepsy, as well as the promise of novel therapeutic interventions. Finally, we conclude with a discussion of the critical questions that remain to be answered regarding a role for lncRNA in memory.
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Affiliation(s)
- Ashleigh B Irwin
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rudhab Bahabry
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Farah D Lubin
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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35
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Engdahl E, Svensson K, Lin PID, Alavian-Ghavanini A, Lindh C, Rüegg J, Bornehag CG. DNA methylation at GRIN2B partially mediates the association between prenatal bisphenol F exposure and cognitive functions in 7-year-old children in the SELMA study. ENVIRONMENT INTERNATIONAL 2021; 156:106617. [PMID: 34015668 DOI: 10.1016/j.envint.2021.106617] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Accumulating evidence suggests that prenatal chemical exposure triggers epigenetic modifications that could influence health outcomes later in life. In this study, we investigated whether DNA methylation (DNAm) levels at the glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) gene underlies the association between prenatal exposure to an endocrine disrupting chemical (EDC), bisphenol F (BPF), and lower cognitive functions in 7-year-old children. METHODS Data from 799 children participating in the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) pregnancy cohort was analyzed. Prenatal BPF exposure was assessed by measuring BPF levels in maternal urine. At age 7, DNAm of three CpG sites in a regulatory region of the GRIN2B gene was analyzed from buccal swabs using bisulfite-Pyrosequencing. Cognitive functions, including full-scale IQ and four subscales, were evaluated using the Wechsler Intelligence Scale for Children (WISC-IV). Associations between prenatal BPF exposure and GRIN2B DNAm, as well as between GRIN2B DNAm and cognitive functions, were determined using regression models adjusted for potential confounders. Generalized structural equation models (gSEM) were used to evaluate if GRIN2B DNAm mediates the association between prenatal BPF exposure and cognitive functions at 7 years of age. RESULTS Prenatal BPF exposure was positively associated with GRIN2B DNAm levels at the third CpG site (CpG3), while CpG3 methylation was inversely associated with cognitive test scores. Mediation analyses showed that CpG3 methylation exerted 6-9% of the association between BPF exposure and full-scale IQ, as well as verbal comprehension and perceptual reasoning in boys, while not significant in girls. CONCLUSIONS This study is the first to identify locus-specific DNAm as a mediating factor underlying an epidemiological association between prenatal EDC exposure and cognitive functions in childhood. It also confirms previous findings, that GRIN2B DNAm is responsive to environmental exposures.
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Affiliation(s)
- Elin Engdahl
- Uppsala University, Department of Organismal Biology, 752 36 Uppsala, Sweden.
| | - Katherine Svensson
- Karlstad University, Department of Health Sciences, 651 88 Karlstad, Sweden
| | - Ping-I Daniel Lin
- Karlstad University, Department of Health Sciences, 651 88 Karlstad, Sweden
| | - Ali Alavian-Ghavanini
- Karolinska Institutet, Swetox, Unit of Toxicology Sciences, 151 36 Södertälje, Sweden
| | - Christian Lindh
- Lund University, Division of Occupational and Environmental Medicine, 223 81 Lund, Sweden
| | - Joëlle Rüegg
- Uppsala University, Department of Organismal Biology, 752 36 Uppsala, Sweden; Karlstad University, Department of Health Sciences, 651 88 Karlstad, Sweden
| | - Carl-Gustaf Bornehag
- Karlstad University, Department of Health Sciences, 651 88 Karlstad, Sweden; Icahn School of Medicine at Mount Sinai, NY 10029, USA
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36
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Riva D. Sex and gender difference in cognitive and behavioral studies in developmental age: An introduction. J Neurosci Res 2021; 101:543-552. [PMID: 34687075 DOI: 10.1002/jnr.24970] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 09/01/2021] [Accepted: 09/03/2021] [Indexed: 11/09/2022]
Abstract
This paper introduces a special issue focused on sex and gender (s/g) cognitive/behavioral differences at developmental ages providing an overview of this multifaceted and debated topic. It will provide a description of the biological systems that are strongly interconnected to generate s/g differences, that is, genetic determinants, sex hormones, differences in brain structure, organization, and/or function, inherited or modifiable under environmental pressures. Developmental studies are rare. Some addressed whether s/g differences in cognitive/behavioral characteristics are evident early in life and are consistent throughout development, entailing that s/g differences can follow the evolving steps in girls and boys in different domains. The data are far from being homogeneous and consistent about s/g difference in language, social skills, and visuo/spatial abilities. The differences are small, often with overlapping performances, similar to what is seen in adulthood. Given that several variables and the interactions between them are implicated, further longitudinal studies adopting adequate assessment tools, very large size multicultural samples stratified in different, well-sized and precise age groups, considering biological and sociocultural variables, are needed. Due to the complexity of the issue, there is still the need to support and adopt an s/g difference approach also in cognitive and behavioral studies at developmental ages. Finally, these studies have not only scientific importance and relevant cultural, anthropological, and social implications, but are also useful for pedagogical programming as well as for the study of the different susceptibility to develop CNS diseases and consequently to promote different therapies and treatments.
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Affiliation(s)
- Daria Riva
- Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.,Fondazione Pierfranco e Luisa Mariani, Milano, Italy.,Fondazione Together To Go, Milano, Italy
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37
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Torres-Perez JV, Irfan J, Febrianto MR, Di Giovanni S, Nagy I. Histone post-translational modifications as potential therapeutic targets for pain management. Trends Pharmacol Sci 2021; 42:897-911. [PMID: 34565578 DOI: 10.1016/j.tips.2021.08.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 11/26/2022]
Abstract
Effective pharmacological management of pain associated with tissue pathology is an unmet medical need. Transcriptional modifications in nociceptive pathways are pivotal for the development and the maintenance of pain associated with tissue damage. Accumulating evidence has shown the importance of the epigenetic control of transcription in nociceptive pathways via histone post-translational modifications (PTMs). Hence, histone PTMs could be targets for novel effective analgesics. Here, we discuss the current understanding of histone PTMs in the modulation of gene expression affecting nociception and pain phenotypes following tissue injury. We also provide a critical view of the translational implications of preclinical models and discuss opportunities and challenges of targeting histone PTMs to relieve pain in clinically relevant tissue injuries.
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Affiliation(s)
- Jose V Torres-Perez
- UK Dementia Research Institute at Imperial College London and Department of Brain Sciences, Imperial College London, 86 Wood Lane, London W12 0BZ, UK.
| | - Jahanzaib Irfan
- Nociception Group, Division of Anaesthesia, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London SW10 9FJ, UK
| | - Muhammad Rizki Febrianto
- Nociception Group, Division of Anaesthesia, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London SW10 9FJ, UK
| | - Simone Di Giovanni
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, E505, Burlington Danes, Du Cane Road, London W12 ONN, UK.
| | - Istvan Nagy
- Nociception Group, Division of Anaesthesia, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London SW10 9FJ, UK.
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38
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Jang EH, Bae YH, Yang EM, Gim Y, Suh HJ, Kim S, Park SM, Park JB, Hur EM. Comparing axon regeneration in male and female mice after peripheral nerve injury. J Neurosci Res 2021; 99:2874-2887. [PMID: 34510521 DOI: 10.1002/jnr.24955] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 07/07/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023]
Abstract
Axons in the adult mammalian central nervous system fail to regenerate after injury. By contrast, spontaneous axon regeneration occurs in the peripheral nervous system (PNS) due to a supportive PNS environment and an increase in the intrinsic growth potential induced by injury via cooperative activation of multifaceted biological pathways. This study compared axon regeneration and injury responses in C57BL/6 male and female mice after sciatic nerve crush (SNC) injury. The extent of axon regeneration in vivo was indistinguishable in male and female mice when observed at 3 days after SNC injury, and primary dorsal root ganglion (DRG) neurons from injured, male and female mice extended axons to a similar length. Moreover, the induction of selected regeneration-associated genes (RAGs), such as Atf3, Sprr1a, Gap43, Sox11, Jun, Gadd45a, and Smad1 were comparable in male and female DRGs when assessed by quantitative real-time reverse transcription polymerase chain reaction. Furthermore, the RNA-seq analysis of male and female DRGs revealed that differentially expressed genes (DEGs) in SNC groups compared to sham-operated groups included many common genes associated with neurite outgrowth. However, we also found that a large number of genes in the DEGs were sex dependent, implicating the involvement of distinct gene regulatory network in the two sexes following peripheral nerve injury. In conclusion, we found that male and female mice mounted a comparable axon regeneration response and many RAGs were commonly induced in response to SNC. However, given that many DEGs were sex-dependently expressed, future studies are needed to investigate whether they contribute to peripheral axon regeneration, and if so, to what extent.
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Affiliation(s)
- Eun-Hae Jang
- Laboratory of Neuroscience, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Yun-Hee Bae
- Laboratory of Neuroscience, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Eun Mo Yang
- Laboratory of Neuroscience, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.,BK21 Four Future Veterinary Medicine Leading Education & Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Yunho Gim
- Laboratory of Neuroscience, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Hyun-Jun Suh
- Laboratory of Neuroscience, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Subin Kim
- Laboratory of Neuroscience, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Seong-Min Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea
| | - Jong Bae Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.,Rare Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
| | - Eun-Mi Hur
- Laboratory of Neuroscience, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.,BK21 Four Future Veterinary Medicine Leading Education & Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.,Interdisciplinary Program in Neuroscience, College of Natural Sciences, Seoul National University, Seoul, South Korea
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Checknita D, Tiihonen J, Hodgins S, Nilsson KW. Associations of age, sex, sexual abuse, and genotype with monoamine oxidase a gene methylation. J Neural Transm (Vienna) 2021; 128:1721-1739. [PMID: 34424394 PMCID: PMC8536631 DOI: 10.1007/s00702-021-02403-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/06/2021] [Indexed: 12/16/2022]
Abstract
Epigenome-wide studies report higher methylation among women than men with decreasing levels with age. Little is known about associations of sex and age with methylation of monoamine oxidase A (MAOA). Methylation of the first exonic and partial first intronic region of MAOA has been shown to strengthen associations of interactions of MAOA-uVNTR genotypes and adversity with aggression and substance misuse. Our study examined associations of sex and age with MAOA first exon and intron methylation levels in 252 women and 157 men aged 14–73 years. Participants included adolescents recruited at a substance misuse clinic, their siblings and parents, and healthy women. Women showed ~ 50% higher levels of exonic, and ~ 15% higher intronic, methylation than men. Methylation levels were similar between younger (M = 22.7 years) and older (M = 46.1 years) participants, and stable across age. Age modified few associations of methylation levels with sex. MAOA genotypes modified few associations of methylation with sex and age. Higher methylation levels among women were not explained by genotype, nor interaction of genotype and sexual abuse. Findings were similar after adjusting for lifetime diagnoses of substance dependence (women = 24.3%; men = 34.2%). Methylation levels were higher among women who experienced sexual abuse than women who did not. Results extend on prior studies by showing that women display higher levels of methylation than men within first intronic/exonic regions of MAOA, which did not decrease with age in either sex. Findings were not conditioned by genotype nor interactions of genotype and trauma, and indicate X-chromosome inactivation.
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Affiliation(s)
- David Checknita
- Department of Neuroscience, Uppsala University, Uppsala, Sweden. .,Department of Clinical Neuroscience, Karolinska Institutet, Psychiatry Building R5:00 c/o Jari Tiihonen, Karolinska Universitetssjukhuset, 171 76, Stockholm, Sweden. .,Centre for Clinical Research, Västmanland County Council, Uppsala University, Uppsala, Sweden.
| | - Jari Tiihonen
- Department of Clinical Neuroscience, Karolinska Institutet, Psychiatry Building R5:00 c/o Jari Tiihonen, Karolinska Universitetssjukhuset, 171 76, Stockholm, Sweden.,Center for Psychiatry Research, Stockholm City Council, Stockholm, Sweden.,Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland
| | - Sheilagh Hodgins
- Department of Clinical Neuroscience, Karolinska Institutet, Psychiatry Building R5:00 c/o Jari Tiihonen, Karolinska Universitetssjukhuset, 171 76, Stockholm, Sweden.,Département de Psychiatrie et Addictologie, Centre de Recherche de l'Institut Universitaire en Santé Mentale de Montréal, Université de Montréal, Montréal, QC, Canada
| | - Kent W Nilsson
- Department of Neuroscience, Uppsala University, Uppsala, Sweden.,Centre for Clinical Research, Västmanland County Council, Uppsala University, Uppsala, Sweden
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Clive J, Wisden W, Savolainen V. The De-Scent of Sexuality: Should We Smell a Rat? ARCHIVES OF SEXUAL BEHAVIOR 2021; 50:2283-2288. [PMID: 31808032 PMCID: PMC8416816 DOI: 10.1007/s10508-019-01591-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/14/2019] [Accepted: 11/18/2019] [Indexed: 05/17/2023]
Affiliation(s)
- Jackson Clive
- Department of Life Sciences, Silwood Park Campus, Imperial College London, Ascot, SL5 7PY, UK
| | - William Wisden
- Department of Life Sciences, South Kensington Campus, Imperial College London, London, UK
| | - Vincent Savolainen
- Department of Life Sciences, Silwood Park Campus, Imperial College London, Ascot, SL5 7PY, UK.
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41
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Wang J, Kazmi MM, Huxley VH. Microvascular Sex- and Age- Dependent Phosphodiesterase Expression. FRONTIERS IN AGING 2021; 2:719698. [PMID: 35822023 PMCID: PMC9261398 DOI: 10.3389/fragi.2021.719698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/12/2021] [Indexed: 02/05/2023]
Abstract
Objective: The cyclic nucleotide second messengers, cAMP and cGMP, are pivotal regulators of vascular functions; their cellular levels are tightly controlled by the cyclic nucleotide hydrolases, phosphodiesterases (PDE). Biologic sex and age are recognized as independent factors impacting the mechanisms mediating both vascular health and dysfunction. This study focused on microvessels isolated from male and female rats before (juvenile) and after (adult) sexual maturity under resting conditions. We tested the hypothesis that sexual dimorphism in microvascular PDE expression would be absent in juvenile rats, but would manifest in adult rats. Methods: Abdominal skeletal muscle arterioles and venules were isolated from age-matched juvenile and adult male and female rats under resting conditions. Transcripts of five PDE families (1–5) associated with coronary and vascular function with a total of ten genes were measured using TaqMan real-time RT-PCR and protein expression of microvessel PDE4 was assessed using immunoblotting and immunofluorescence. Results: Overall expression levels of PDE5A were highest while PDE3 levels were lowest among the five PDE families (p < 0.05) regardless of age or sex. Contrary to our hypothesis, in juveniles, sexual dimorphism in PDE expression was observed in three genes: arterioles (PDE1A, female > male) and venules (PDE1B and 3A, male > female). In adults, gene expression levels in males were higher than females for five genes in arterioles (PDE1C, 3A, 3B, 4B, 5A) and three genes (PDE3A, 3B, and 5A) in venules. Furthermore, age-related differences were observed in PDE1-5 (in males, adult > juvenile for most genes in arterioles; in females, adult > juvenile for arteriolar PDE3A; juvenile gene expression > adult for two genes in arterioles and three genes in venules). Immunoblotting and immunofluorescence analysis revealed protein expression of microvessel PDE4. Conclusion: This study revealed sexual dimorphism in both juvenile and adult rats, which is inconsistent with our hypothesis. The sex- and age-dependent differences in PDE expression implicate different modulations of cAMP and cGMP pathways for microvessels in health. The implication of these sex- and age-dependent differences, as well as the duration and microdomain of PDE1-5 activities in skeletal muscle microvessels, in both health and disease, require further investigation.
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Affiliation(s)
- Jianjie Wang
- Department of Biomedical Sciences, Missouri State University, Springfield, MO, United States
- *Correspondence: Jianjie Wang,
| | - Murtaza M. Kazmi
- Department of Medicine, The Aga Khan University, Karachi, Pakistan
| | - Virginia H. Huxley
- Department of Medical Pharmacology and Physiology, National Center for Gender Physiology, Dalton Cardiovascular Research Center, Columbia, MO, United States
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Salviato BZ, Raymundi AM, Rodrigues da Silva T, Salemme BW, Batista Sohn JM, Araújo FS, Guimarães FS, Bertoglio LJ, Stern CA. Female but not male rats show biphasic effects of low doses of Δ 9-tetrahydrocannabinol on anxiety: can cannabidiol interfere with these effects? Neuropharmacology 2021; 196:108684. [PMID: 34181978 DOI: 10.1016/j.neuropharm.2021.108684] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/07/2021] [Accepted: 06/17/2021] [Indexed: 01/17/2023]
Abstract
Δ9-tetrahydrocannabinol (THC) is the main phytocannabinoid present in the Cannabis sativa. It can produce dose-dependent anxiolytic or anxiogenic effects in males. THC effects on anxiety have scarcely been studied in females, despite their higher prevalence of anxiety disorders. Cannabidiol, another phytocannabinoid, has been reported to attenuate anxiety and some THC-induced effects. The present study aimed to investigate the behavioral and neurochemical effects of THC administered alone or combined with CBD in naturally cycling female rats tested in the elevated plus-maze. Systemically administered THC produced biphasic effects in females, anxiolytic at low doses (0.075 or 0.1 mg/kg) and anxiogenic at a higher dose (1.0 mg/kg). No anxiety changes were observed in males treated with the same THC dose range. The anxiogenic effect of THC was prevented by co-administration of CBD (1.0 or 3.0 mg/kg). CBD (3.0 mg/kg) caused an anxiolytic effect. At a lower dose (1.0 mg/kg), it facilitated the anxiolytic effect of the low THC dose. The anxiogenic effect of THC was accompanied by increased dopamine levels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). In contrast, its anxiolytic effect was associated with increased mPFC serotonin concentrations. The anxiolytic effect of CBD was accompanied by increased mPFC serotonin turnover. Together, these results indicate that female rats are susceptible to the biphasic effects of low THC doses on anxiety. These effects could depend on mPFC and NAc dopaminergic and serotoninergic neurotransmissions. CBD could minimize potential THC high-dose side effects whereas enhancing the anxiolytic action of its low doses in females.
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Affiliation(s)
| | - Ana Maria Raymundi
- Department of Pharmacology, Federal University of Parana, Curitiba, PR, Brazil
| | | | | | | | | | | | - Leandro José Bertoglio
- Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil
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Casas L, Saborido-Rey F. Environmental Cues and Mechanisms Underpinning Sex Change in Fish. Sex Dev 2021; 15:108-121. [PMID: 34111868 DOI: 10.1159/000515274] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 02/07/2021] [Indexed: 11/19/2022] Open
Abstract
Fishes are the only vertebrates that undergo sex change during their lifetime, but even within this group, a unique reproductive strategy is displayed by only 1.5% of the teleosts. This lability in alternating sexual fate is the result of the simultaneous suppression and activation of opposing male and female networks. Here, we provide a brief review summarizing recent advances in our understanding of the environmental cues that trigger sex change and their perception, integration, and translation into molecular cascades that convert the sex of an individual. We particularly focus on molecular events underpinning the complex behavioral and morphological transformation involved in sex change, dissecting the main molecular players and regulatory networks that shape the transformation of one sex into the opposite. We show that histological changes and molecular pathways governing gonadal reorganization are better described than the neuroendocrine basis of sex change and that, despite important advances, information is lacking for the majority of hermaphrodite species. We highlight significant gaps in our knowledge of how sex change takes place and suggest future research directions.
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Affiliation(s)
- Laura Casas
- Ecology and Marine Resources, Institute of Marine Research (IIM-CSIC), Vigo, Spain
| | - Fran Saborido-Rey
- Ecology and Marine Resources, Institute of Marine Research (IIM-CSIC), Vigo, Spain
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44
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Choe HN, Jarvis ED. The role of sex chromosomes and sex hormones in vocal learning systems. Horm Behav 2021; 132:104978. [PMID: 33895570 DOI: 10.1016/j.yhbeh.2021.104978] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 12/12/2022]
Abstract
Vocal learning is the ability to imitate and modify sounds through auditory experience, a rare trait found in only a few lineages of mammals and birds. It is a critical component of human spoken language, allowing us to verbally transmit speech repertoires and knowledge across generations. In many vocal learning species, the vocal learning trait is sexually dimorphic, where it is either limited to males or present in both sexes to different degrees. In humans, recent findings have revealed subtle sexual dimorphism in vocal learning/spoken language brain regions and some associated disorders. For songbirds, where the neural mechanisms of vocal learning have been well studied, vocal learning appears to have been present in both sexes at the origin of the lineage and was then independently lost in females of some subsequent lineages. This loss is associated with an interplay between sex chromosomes and sex steroid hormones. Even in species with little dimorphism, like humans, sex chromosomes and hormones still have some influence on learned vocalizations. Here we present a brief synthesis of these studies, in the context of sex determination broadly, and identify areas of needed investigation to further understand how sex chromosomes and sex steroid hormones help establish sexually dimorphic neural structures for vocal learning.
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Affiliation(s)
- Ha Na Choe
- Duke University Medical Center, The Rockefeller University, Howard Hughes Medical Institute, United States of America.
| | - Erich D Jarvis
- Duke University Medical Center, The Rockefeller University, Howard Hughes Medical Institute, United States of America.
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45
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Srancikova A, Bacova Z, Bakos J. The epigenetic regulation of synaptic genes contributes to the etiology of autism. Rev Neurosci 2021; 32:791-802. [PMID: 33939901 DOI: 10.1515/revneuro-2021-0014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/12/2021] [Indexed: 12/30/2022]
Abstract
Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.
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Affiliation(s)
- Annamaria Srancikova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Zuzana Bacova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Jan Bakos
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
- Institute of Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
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Genolet O, Monaco AA, Dunkel I, Boettcher M, Schulz EG. Identification of X-chromosomal genes that drive sex differences in embryonic stem cells through a hierarchical CRISPR screening approach. Genome Biol 2021; 22:110. [PMID: 33863351 PMCID: PMC8051100 DOI: 10.1186/s13059-021-02321-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND X-chromosomal genes contribute to sex differences, in particular during early development, when both X chromosomes are active in females. Double X-dosage shifts female pluripotent cells towards the naive stem cell state by increasing pluripotency factor expression, inhibiting the differentiation-promoting MAP kinase (MAPK) signaling pathway, and delaying differentiation. RESULTS To identify the genetic basis of these sex differences, we use a two-step CRISPR screening approach to comprehensively identify X-linked genes that cause the female pluripotency phenotype in murine embryonic stem cells. A primary chromosome-wide CRISPR knockout screen and three secondary screens assaying for different aspects of the female pluripotency phenotype allow us to uncover multiple genes that act in concert and to disentangle their relative roles. Among them, we identify Dusp9 and Klhl13 as two central players. While Dusp9 mainly affects MAPK pathway intermediates, Klhl13 promotes pluripotency factor expression and delays differentiation, with both factors jointly repressing MAPK target gene expression. CONCLUSIONS Here, we elucidate the mechanisms that drive sex-induced differences in pluripotent cells and our approach serves as a blueprint to discover the genetic basis of the phenotypic consequences of other chromosomal effects.
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Affiliation(s)
- Oriana Genolet
- Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Anna A Monaco
- Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Present address: BIMSB, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Ilona Dunkel
- Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Michael Boettcher
- Medical Faculty, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Edda G Schulz
- Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Han J, Fan Y, Zhou K, Blomgren K, Harris RA. Uncovering sex differences of rodent microglia. J Neuroinflammation 2021; 18:74. [PMID: 33731174 PMCID: PMC7972194 DOI: 10.1186/s12974-021-02124-z] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.
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Affiliation(s)
- Jinming Han
- Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, CMM L8:04, Karolinska Sjukhuset, S-171 76, Stockholm, Sweden.
| | - Yueshan Fan
- Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, CMM L8:04, Karolinska Sjukhuset, S-171 76, Stockholm, Sweden
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Tianjin, China
- Tianjin Medical University, Tianjin, China
| | - Kai Zhou
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Children's Hospital of Zhengzhou, Zhengzhou, China
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Robert A Harris
- Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, CMM L8:04, Karolinska Sjukhuset, S-171 76, Stockholm, Sweden.
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48
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Alshammari TK. Sexual dimorphism in pre-clinical studies of depression. Prog Neuropsychopharmacol Biol Psychiatry 2021; 105:110120. [PMID: 33002519 DOI: 10.1016/j.pnpbp.2020.110120] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 09/17/2020] [Accepted: 09/25/2020] [Indexed: 12/21/2022]
Abstract
Although there is a sex bias in the pathological mechanisms exhibited by brain disorders, investigation of the female brain in biomedical science has long been neglected. Use of the male model has generally been the preferred option as the female animal model exhibits both biological variability and hormonal fluctuations. Existing studies that compare behavioral and/or molecular alterations in animal models of brain diseases are generally underrepresented, and most utilize the male model. Nevertheless, in recent years there has been a trend toward the increased inclusion of females in brain studies. However, current knowledge regarding sex-based differences in depression and stress-related disorders is limited. This can be improved by reviewing preclinical studies that highlight sex differences in depression. This paper therefore presents a review of sex-based preclinical studies of depression. These shed light on the discrepancies between males and females regarding the biological mechanisms that underpin mechanistic alterations in the diseased brain. This review also highlights the conclusions drawn by preclinical studies to advance our understanding of mood disorders, encouraging researchers to promote ways of investigating and managing sexually dimorphic disorders.
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Affiliation(s)
- Tahani K Alshammari
- Department of Pharmacology and Toxicology, Pharmacy College, King Saud University, Saudi Arabia; Prince Naïf Bin Abdul-Aziz Health Research Center, King Saud University, Saudi Arabia.
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Scott H, Phillips TJ, Sze Y, Alfieri A, Rogers MF, Volpato V, Case CP, Brunton PJ. Maternal antioxidant treatment prevents the adverse effects of prenatal stress on the offspring's brain and behavior. Neurobiol Stress 2020; 13:100281. [PMID: 33344732 PMCID: PMC7739187 DOI: 10.1016/j.ynstr.2020.100281] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/17/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Abstract
Maternal exposure to stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. The mechanisms through which the effects of maternal stress are transmitted to the fetus are unclear, however the placenta, as the interface between mother and fetus, is likely to play a key role. Using a rat model, we investigated a role for placental oxidative stress in conveying the effects of maternal social stress to the fetus and the potential for treatment using a nanoparticle-bound antioxidant to prevent adverse outcomes in the offspring. Maternal psychosocial stress increased circulating corticosterone in the mother, but not in the fetuses. Maternal stress also induced oxidative stress in the placenta, but not in the fetal brain. Blocking oxidative stress using an antioxidant prevented the prenatal stress-induced anxiety phenotype in the male offspring, and prevented sex-specific neurobiological changes, specifically a reduction in dendrite lengths in the hippocampus, as well as reductions in the number of parvalbumin-positive neurons and GABA receptor subunits in the hippocampus and basolateral amygdala of the male offspring. Importantly, many of these effects were mimicked in neuronal cultures by application of placental-conditioned medium or fetal plasma from stressed pregnancies, indicating molecules released from the placenta may mediate the effects of prenatal stress on the fetal brain. Indeed, both placenta-conditioned medium and fetal plasma contained differentially abundant microRNAs following maternal stress, and their predicted targets were enriched for genes relevant to nervous system development and psychiatric disorders. The results highlight placental oxidative stress as a key mediator in transmitting the maternal social stress effects on the offspring's brain and behavior, and offer a potential intervention to prevent stress-induced fetal programming of affective disorders.
Social stress in pregnancy induces oxidative stress but is prevented by antioxidant. Prenatal stress induces behavioural, neuroanatomical and neurochemical changes. Maternal antioxidant treatment prevents stress-induced effects in the offspring. Maternal stress alters the balance of microRNAs secreted from the placenta. Placental oxidative stress mediates maternal social stress effects on the offspring.
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Affiliation(s)
- H Scott
- School of Clinical Sciences, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol, BS10 5NB, UK
| | - T J Phillips
- School of Clinical Sciences, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol, BS10 5NB, UK
| | - Y Sze
- Division of Neurobiology, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.,Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK
| | - A Alfieri
- Division of Neurobiology, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - M F Rogers
- Intelligent Systems Laboratory, University of Bristol, Merchant Venturers Building, Woodland Road, Bristol, BS8 1UB, UK
| | - V Volpato
- UK Dementia Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - C P Case
- School of Clinical Sciences, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol, BS10 5NB, UK
| | - P J Brunton
- Division of Neurobiology, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.,Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.,Zhejiang University-University of Edinburgh Joint Institute, Zhejiang University School of Medicine, International Campus, Haining, Zhejiang, 314400, PR China
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50
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Sundman AS, Pértille F, Lehmann Coutinho L, Jazin E, Guerrero-Bosagna C, Jensen P. DNA methylation in canine brains is related to domestication and dog-breed formation. PLoS One 2020; 15:e0240787. [PMID: 33119634 PMCID: PMC7595415 DOI: 10.1371/journal.pone.0240787] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 10/02/2020] [Indexed: 11/19/2022] Open
Abstract
Epigenetic factors such as DNA methylation act as mediators in the interaction between genome and environment. Variation in the epigenome can both affect phenotype and be inherited, and epigenetics has been suggested to be an important factor in the evolutionary process. During domestication, dogs have evolved an unprecedented between-breed variation in morphology and behavior in an evolutionary short period. In the present study, we explore DNA methylation differences in brain, the most relevant tissue with respect to behavior, between wolf and dog breeds. We optimized a combined method of genotype-by-sequencing (GBS) and methylated DNA immunoprecipitation (MeDIP) for its application in canines. Genomic DNA from the frontal cortex of 38 dogs of 8 breeds and three wolves was used. GBS and GBS-MeDIP libraries were prepared and sequenced on Illuma HiSeq2500 platform. The reduced sample represented 1.18 ± 0.4% of the total dog genome (2,4 billion BP), while the GBS-MeDIP covered 11,250,788 ± 4,042,106 unique base pairs. We find substantial DNA methylation differences between wolf and dog and between the dog breeds. The methylation profiles of the different groups imply that epigenetic factors may have been important in the speciation from dog to wolf, but also in the divergence of different dog breeds. Specifically, we highlight methylation differences in genes related to behavior and morphology. We hypothesize that these differences are involved in the phenotypic variation found among dogs, whereas future studies will have to find the specific mechanisms. Our results not only add an intriguing new dimension to dog breeding but are also useful to further understanding of epigenetic involvement.
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Affiliation(s)
- Ann-Sofie Sundman
- AVIAN Behaviour Genomics and Physiology Group, IFM Biology, Linköping University, Linköping, Sweden
| | - Fábio Pértille
- AVIAN Behaviour Genomics and Physiology Group, IFM Biology, Linköping University, Linköping, Sweden
- Animal Biotechnology Laboratory, Animal Science and Pastures Department, University of São Paulo (USP)/ Luiz de Queiroz College of Agriculture (ESALQ), Piracicaba, São Paulo, Brazil
| | - Luiz Lehmann Coutinho
- Animal Biotechnology Laboratory, Animal Science and Pastures Department, University of São Paulo (USP)/ Luiz de Queiroz College of Agriculture (ESALQ), Piracicaba, São Paulo, Brazil
| | - Elena Jazin
- Department of Organismal Biology, EBC, Uppsala University, Uppsala, Sweden
| | - Carlos Guerrero-Bosagna
- AVIAN Behaviour Genomics and Physiology Group, IFM Biology, Linköping University, Linköping, Sweden
| | - Per Jensen
- AVIAN Behaviour Genomics and Physiology Group, IFM Biology, Linköping University, Linköping, Sweden
- * E-mail:
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