Biology of Sex Differences最新文献

{"title":"A meta-analysis of sex differences in neonatal rodent ultrasonic vocalizations and the implication for the preclinical maternal immune activation model.","authors":"Alison M Randell, Stephanie Salia, Lucas F Fowler, Toe Aung, David A Puts, Ashlyn Swift-Gallant","doi":"10.1186/s13293-025-00685-9","DOIUrl":"10.1186/s13293-025-00685-9","url":null,"abstract":"<p><p>As the earliest measure of social communication in rodents, ultrasonic vocalizations (USVs) in response to maternal separation are critical in preclinical research on neurodevelopmental disorders (NDDs). While sex differences in both USV production and behavioral outcomes are reported, many studies overlook sex as a biological variable in preclinical NDD models. We aimed to evaluate sex differences in USV call parameters and determine if USVs are differently impacted based on sex in the preclinical maternal immune activation (MIA) model. Results indicate that sex differences in USVs vary with developmental stage and are more pronounced in MIA offspring. Specifically, developmental stage is a moderator of sex differences in USV call duration, with control females emitting longer calls than males in early development (up to postnatal day [PND] 8), but this pattern reverses after PND8. MIA leads to a reduction in call numbers for females compared to same-sex controls in early development, with a reversal post-PND8. MIA decreased call duration and increased total call duration in males, but unlike females, developmental stage did not influence these differences. In males, MIA effects varied by species, with decreased call numbers in rats but increased call numbers in mice. MIA timing (gestational day ≤ 12.5 vs. > 12.5) did not significantly affect results. Our findings highlight the importance of considering sex, developmental timing, and species in USVs research. We discuss how analyzing USV call types and incorporating sex as a biological variable can enhance our understanding of neonatal ultrasonic communication and its translational value in NDD research.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"4"},"PeriodicalIF":4.9,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice.","authors":"Yingbin Lin, Xinqun Luo, Fangyu Wang, Huange Cai, Yuanxiang Lin, Dezhi Kang, Wenhua Fang","doi":"10.1186/s13293-025-00684-w","DOIUrl":"10.1186/s13293-025-00684-w","url":null,"abstract":"<p><strong>Background: </strong>Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer's disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood.</p><p><strong>Methods: </strong>ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice's blood glucose was also recorded.</p><p><strong>Results: </strong>Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice.</p><p><strong>Conclusions: </strong>Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"3"},"PeriodicalIF":4.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age- and sex-specific differences in myocardial sympathetic tone and left ventricular remodeling following myocardial injury.","authors":"Achi Haider, Susan Bengs, Angela Portmann, Sandro Fröhlich, Dominik Etter, Monika Maredziak, Geoffrey I Warnock, Alexander Akhmedov, Sebastian Kozerke, Claudia Keller, Fabrizio Montecucco, Bruno Weber, Linjing Mu, Ronny R Buechel, Vera Regitz-Zagrosek, Philipp A Kaufmann, Giovanni G Camici, Simon M Ametamey, Catherine Gebhard","doi":"10.1186/s13293-024-00673-5","DOIUrl":"10.1186/s13293-024-00673-5","url":null,"abstract":"<p><strong>Background: </strong>Presentations and outcomes of acute myocardial infarction (MI) differ between women and men, with the worst outcomes being reported in younger women. Mental stress induced ischemia and sympathetic activation have been suggested to play a prominent role in the pathogenesis of MI in younger women, however, the impact of sex hormones on these parameters remains unknown.</p><p><strong>Methods: </strong>The effect of sex hormones and age on myocardial infarct size and myocardial sympathetic activity (MSA) was assessed in male and female, as well as young (4-6 months) and aged (20-22 months) FVB/N mice (n = 106, 60 gonadectomized and 46 sham-operated animals) who underwent in vivo [¹¹C]meta-hydroxyephedrine ([¹¹C]mHED) positron emission tomography (PET) and cardiac magnetic resonance (CMR) imaging 24 h after a 30 min myocardial ischemic injury.</p><p><strong>Results: </strong>MSA and catecholamine levels following myocardial injury were highest in young males (p = 0.008 and p = 0.043 vs. young females, respectively) and were reduced by orchiectomy. Accordingly, testosterone serum levels correlated positively with MSA (r = 0.66, p < 0.001). Males had a larger average infarct size and lower left ventricular contractility following myocardial injury than females (p < 0.05 vs. females). These sex differences were no longer evident in gonadectomized animals (p = NS vs. females). In female animals, estrogen depletion did not affect MSA (ovariectomy effect, p = 0.892). Female animals showed an age-dependent increase in MSA (p = 0.011), which was absent in males.</p><p><strong>Conclusion: </strong>Testosterone associates with an increase in sympathetic tone, contributing to adverse cardiac remodeling following MI. Conversely, females maintain sympathetic integrity, independent of sex hormones. Our results suggest a biological advantage of female sex in post MI recovery. Further research is warranted to confirm these findings in humans.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"2"},"PeriodicalIF":4.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KDM6A facilitates Xist upregulation at the onset of X inactivation.","authors":"Josephine Lin, Jinli Zhang, Li Ma, He Fang, Rui Ma, Camille Groneck, Galina N Filippova, Xinxian Deng, Chizuru Kinoshita, Jessica E Young, Wenxiu Ma, Christine M Disteche, Joel B Berletch","doi":"10.1186/s13293-024-00683-3","DOIUrl":"10.1186/s13293-024-00683-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;X chromosome inactivation (XCI) is a female-specific process in which one X chromosome is silenced to balance X-linked gene expression between the sexes. XCI is initiated in early development by upregulation of the lncRNA Xist on the future inactive X (Xi). A subset of X-linked genes escape silencing and thus have higher expression in females, suggesting female-specific functions. One of these genes is the highly conserved gene Kdm6a, which encodes a histone demethylase that removes methyl groups at H3K27 to facilitate gene expression. KDM6A mutations have been implicated in congenital disorders such as Kabuki Syndrome, as well as in sex differences in development and cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Kdm6a was knocked out (KO) using CRISPR/Cas9 gene editing in hybrid female mouse embryonic stem (ES) cells derived either from a 129 × Mus castaneus (cast) cross or a BL6 x cast cross. In one of the lines a transcriptional stop signal inserted in Tsix results in completely skewed X silencing upon differentiation. The effects of both homozygous and heterozygous Kdm6a KO on Xist expression during the onset of XCI were measured by RT-PCR and RNA-FISH. Changes in gene expression and in H3K27me3 enrichment were investigated using allele-specific RNA-seq and Cut&Run, respectively. KDM6A binding to the Xist gene was characterized by Cut&Run.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We observed impaired upregulation of Xist and reduced coating of the Xi during early stages of differentiation in Kdm6a KO cells, both homozygous and heterozygous, suggesting a threshold effect of KDM6A. This was associated with aberrant overexpression of genes from the Xi after differentiation, indicating loss of X inactivation potency. Consistent with KDM6A having a direct role in Xist regulation, we found that the histone demethylase binds to the Xist promoter and KO cells show an increase in H3K27me3 at Xist, consistent with reduced expression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;These results reveal a novel female-specific role for the X-linked histone demethylase, KDM6A in the initiation of XCI through histone demethylase-dependent activation of Xist during early differentiation. X chromosome inactivation is a female-specific mechanism that evolved to balance sex-linked gene dosage between females (XX) and males (XY) by silencing one X chromosome in females. X inactivation begins with the upregulation of the long noncoding RNA Xist on the future inactive X chromosome. While most genes become silenced on the inactive X chromosome some genes escape inactivation and thus have higher expression in females compared to males, suggesting that escape genes may have female-specific functions. One such gene encodes the histone demethylase KDM6A which function is to turn on gene expression by removing repressive histone modifications. In this study, we investigated the role of KDM6A in the regulation of Xist expression during the onset of X inactivation. ","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"1"},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities.","authors":"Jiaqi Zhou, Miao Li, Yu Chen, Shangzi Wang, Danke Wang, Chen Suo, Xingdong Chen","doi":"10.1186/s13293-024-00682-4","DOIUrl":"10.1186/s13293-024-00682-4","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation (DNAm) influences both sex differences and cancer development, yet the mechanisms connecting these factors remain unclear.</p><p><strong>Methods: </strong>Utilizing data from The Cancer Genome Atlas, we conducted a comprehensive analysis of sex-related DNAm effects in nine non-reproductive cancers, compared to paired normal adjacent tissues (NATs), and validated the results using independent datasets. First, we assessed the extent of sex differential DNAm between cancers and NATs to explore how sex-related DNAm differences change in cancerous tissues. Next, we employed a multivariate adaptive shrinkage approach to model the covariance of cancer-related DNAm effects between sexes, aiming to elucidate how sex impacts aberrant DNAm patterns in cancers. Finally, we investigated correlations between the methylome and transcriptome to identify key signals driving sex-biased DNAm regulation in cancers.</p><p><strong>Results: </strong>Our analysis revealed a significant attenuation of sex differences in DNAm within cancerous tissues compared to baseline differences in normal tissues. We identified 3,452 CpGs (P_bonf < 0.05) associated with this reduction, with 72% of the linked genes involved in X chromosome inactivation. Through covariance analysis, we demonstrated that sex differences in cancer are predominantly driven by variations in the magnitude of shared DNAm signals, referred to as \"amplification.\" Based on these patterns, we classified cancers into female- and male-biased groups and identified key CpGs exhibiting sex-specific amplification. These CpGs were enriched in binding sites of critical transcription factors, including P53, SOX2, and CTCF. Integrative multi-omics analyses uncovered 48 CpG-gene-cancer trios for females and 380 for males, showing similar magnitude differences in DNAm and gene expression, pointing to a sex-specific regulatory role of DNAm in cancer risk. Notably, several genes regulated by these trios were previously identified as drug targets for cancers, highlighting their potential as sex-specific therapeutic targets.</p><p><strong>Conclusions: </strong>These findings advance our understanding of how sex, DNAm, and gene expression interact in cancer, offering insights into the development of sex-specific biomarkers and precision medicine.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"106"},"PeriodicalIF":4.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in mitochondrial gene expression during viral myocarditis.","authors":"Damian N Di Florio, Gabriel J Weigel, David J Gorelov, Elizabeth J McCabe, Danielle J Beetler, Katie A Shapiro, Katelyn A Bruno, Isha Chekuri, Angita Jain, Emily R Whelan, Gary R Salomon, Sami Khatib, Natalie E Bonvie-Hill, Jessica J Fliess, Presley G Giresi, Charwan Hamilton, Cameron J Hartmoyer, Varsini Balamurugan, Ashley A Darakjian, Brandy H Edenfield, S Christian Kocsis, Christopher J McLeod, Leslie T Cooper, Étienne Audet-Walsh, Michael J Coronado, Jon Sin, DeLisa Fairweather","doi":"10.1186/s13293-024-00678-0","DOIUrl":"10.1186/s13293-024-00678-0","url":null,"abstract":"<p><strong>Background: </strong>Myocarditis is an inflammation of the heart muscle most often caused by viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood.</p><p><strong>Methods: </strong>Male and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis and functional validation to understand sex differences in the transcriptional landscape of myocarditis and identify factors that might drive sex differences in myocarditis.</p><p><strong>Results: </strong>As expected, the hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. Unique to this study, we found that males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial electron transport function while females were enriched for pathways related to mitochondrial homeostasis. Mitochondria isolated from the heart of males were confirmed to have worse mitochondrial respiration than females during myocarditis. Unbiased TRANSFAC analysis identified estrogen-related receptor alpha (ERRα) as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Transcript and protein levels of ERRα were confirmed as elevated in females with myocarditis compared to males. Differential binding analysis from chromatin immunoprecipitation (ChIP) sequencing confirmed that ERRα bound highly to select predicted respiratory chain genes in females more than males during myocarditis.</p><p><strong>Conclusions: </strong>Females with viral myocarditis regulate mitochondrial homeostasis by upregulating master regulators of mitochondrial transcription including ERRα.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"104"},"PeriodicalIF":4.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differentially affects pro-inflammatory cell subsets in adipose tissue depots in a diet induced obesity model.","authors":"Lisa T Schuetz, Gayel Duran, Paulien Baeten, Daphne Lintsen, Doryssa Hermans, Sarah Chenine, Janne Verreycken, Tim Vanmierlo, Kristiaan Wouters, Bieke Broux","doi":"10.1186/s13293-024-00677-1","DOIUrl":"10.1186/s13293-024-00677-1","url":null,"abstract":"<p><p>Obesity is a growing pandemic that increases the risk for cardiovascular diseases, type 2 diabetes, and particularly in women also the risk of cancer and neurodegenerative disorders such as dementia and multiple sclerosis. Preclinical studies on obesity focus on male mice as they gain bodyweight faster and show a clear pro-inflammatory phenotype. Here, using male and female mice, we induced obesity by feeding a high fat diet (HFD), and compared adipose tissue (AT) inflammation at the same adiposity stage (% AT/bodyweight) between both sexes. Doing so, we identified that female mice show an increase in the number of pro-inflammatory immune cells in the visceral AT at a lower adiposity stage than male mice, but the effect of HFD is diminished with higher adiposity. Interestingly, only female mice showed an increase in immune cells in the subcutaneous AT after HFD feeding. Nonetheless, we found that pro-inflammatory cytokines in blood plasma mirror the inflammatory stage of the visceral AT in both male and female mice. Uniquely in male mice, myeloid cells in the visceral AT showed a higher inflammasome activation upon HFD. In summary, we showed that adiposity differentially affects immune cells in fat depots based on sex.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"105"},"PeriodicalIF":4.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice.","authors":"Timothy M Griffin, Erika Barboza Prado Lopes, Dominic Cortassa, Albert Batushansky, Matlock A Jeffries, Dawid Makosa, Anita Jopkiewicz, Padmaja Mehta-D'souza, Ravi K Komaravolu, Michael T Kinter","doi":"10.1186/s13293-024-00680-6","DOIUrl":"10.1186/s13293-024-00680-6","url":null,"abstract":"<p><strong>Background: </strong>Women have a higher risk of developing osteoarthritis (OA) than men, including with obesity. To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA.</p><p><strong>Methods: </strong>Male and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age (n = 12 per diet and sex). We performed broad metabolic phenotyping, 16 S gut microbiome analysis, targeted gene expression analysis of synovium-infrapatellar fat tissue, targeted gene expression and proteomic analysis of articular cartilage, chondrocyte metabolic profiling, and OA histopathology. Two-way ANOVA statistics were utilized to determine the contribution of sex and diet and their interaction on outcomes.</p><p><strong>Results: </strong>Mice fed HFD weighed 1.76-fold (p < 0.0001) and 1.60-fold (p < 0.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 ± 2.2%; female: 44.1 ± 3.8%). HFD caused greater cartilage pathology (p < 0.024) and synovial hyperplasia (p < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (p = 0.048), and only male mice developed osteophytes with HFD (p = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (p < 0.0001), fatty liver (p < 0.0001), and elevated serum amylase (p < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (p = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of Bifidobacterium only in male mice. In knee synovium and infrapatellar fat tissue, HFD upregulated the expression of pro-inflammatory and pro-fibrotic genes predominantly in female mice. In cartilage, lipid metabolism proteins were more abundant with HFD in male mice, whereas proteins involved in glycolysis/gluconeogenesis and biosynthesis of amino acids were greater in cartilage of female mice. Sex-dependent metabolic differences were observed in cartilage from young, healthy mice prior to pubertal maturation, but not in primary juvenile chondrocytes studied in vitro.</p><p><strong>Conclusions: </strong>HFD induced numerous sex differences in metabolic and inflammatory outcomes, especially in joint tissues, suggesting that sex-specific cellular processes are involved during development of early-stage OA with obesity.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"103"},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"X-inactive-specific transcript: a long noncoding RNA with a complex role in sex differences in human disease.","authors":"Dan N Predescu, Babak Mokhlesi, Sanda A Predescu","doi":"10.1186/s13293-024-00681-5","DOIUrl":"10.1186/s13293-024-00681-5","url":null,"abstract":"&lt;p&gt;&lt;p&gt;In humans, the X and Y chromosomes determine the biological sex, XX specifying for females and XY for males. The long noncoding RNA X-inactive specific transcript (lncRNA XIST) plays a crucial role in the process of X chromosome inactivation (XCI) in cells of the female, a process that ensures the balanced expression of X-linked genes between sexes. Initially, it was believed that XIST can be expressed only from the inactive X chromosome (Xi) and is considered a typically female-specific transcript. However, accumulating evidence suggests that XIST can be detected in male cells as well, and it participates in the development of cancers and other human diseases by regulating gene expression at epigenetic, chromatin remodeling, transcriptional, and translational levels. XIST is abnormally expressed in many sexually dimorphic diseases, including autoimmune and neurological diseases, pulmonary arterial hypertension (PAH), and some types of cancers. However, the underlying mechanisms are not fully understood. Escape from XCI and skewed XCI also contributes to sex-biased diseases and their severity. Interestingly, in humans, similar to experimental animal models of human disease, the males with the XIST gene activated display the sex-biased disease condition at a rate close to females, and significantly greater than males who had not been genetically modified. For instance, the men with supernumerary X chromosomes, such as men with Klinefelter syndrome (47, XXY), are predisposed toward autoimmunity similar to females (46, XX), and have increased risk for strongly female biased diseases, compared to 46, XY males. Interestingly, chromosome X content has been linked to a longer life span, and the presence of two chromosome X contributes to increased longevity regardless of the hormonal status. In this review, we summarize recent knowledge about XIST structure/function correlation and involvement in human disease with focus on XIST abnormal expression in males. Many human diseases show differences between males and females in penetrance, presentation, progression, and survival. In humans, the X and Y sex chromosomes determine the biological sex, XX specifying for females and XY for males. This numeric imbalance, two X chromosomes in females and only one in males, known as sex chromosome dosage inequality, is corrected in the first days of embryonic development by inactivating one of the X chromosomes in females. While this \"dosage compensation\" should in theory solve the difference in the number of genes between sexes, the expressed doses of X genes are incompletely compensated by X chromosome inactivation in females. In this review we try to highlight how abnormal expression and function of XIST, a gene on the X chromosome responsible for this inactivation process, may explain the sex differences in human health and disease. A better understanding of the molecular mechanisms of XIST participation in the male-female differences in disease is highly r","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"101"},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent effects of chronic jet lag on circadian rhythm and metabolism in mice.","authors":"Tiantian Ma, Ryohei Matsuo, Kaito Kurogi, Shunsuke Miyamoto, Tatsumi Morita, Marina Shinozuka, Fuka Taniguchi, Keisuke Ikegami, Shinobu Yasuo","doi":"10.1186/s13293-024-00679-z","DOIUrl":"10.1186/s13293-024-00679-z","url":null,"abstract":"<p><strong>Background: </strong>The circadian clock integrates external environmental changes into the internal physiology of organisms. Perturbed circadian clocks due to misaligned light cycles increase the risk of diseases, including metabolic disorders. However, the effects of sex differences in this context remain unclear.</p><p><strong>Methods: </strong>Circadian misalignment was induced by a chronic jet lag (CJL) shift schedule (light-on time advanced by 6 h every 2 days) in C57BL/6N male and female mice. Core body temperature and activity rhythms were recorded using a nano tag, and the gene expression rhythms of clock and clock-controlled genes in the liver and adrenal glands were analyzed using qPCR. Glucose metabolism and insulin response were evaluated using glucose tolerance, insulin sensitivity, and glucose response assays. Castration and testosterone replacement were performed to assess the fundamental role of testosterone in male phenotypes under CJL.</p><p><strong>Results: </strong>Under CJL treatment, male mice exhibited increased weight gain, whereas females exhibited decreased weight gain compared to that of the respective controls. CJL treatment induced a lower robustness of circadian rhythms in core body temperature and a weaker rhythm of clock gene expression in the liver and adrenal glands in females, but not in males. Only male mice exhibited glucose intolerance under CJL conditions, without the development of insulin resistance. Castrated mice without testosterone exhibited decreased weight gain and reduced robustness of body temperature rhythm, as observed in intact females. Testosterone replacement in castrated mice recovered the CJL-induced weight gain, robustness of temperature rhythm, and glucose intolerance observed in intact males.</p><p><strong>Conclusions: </strong>Significant sex-based differences were observed in circadian clock organization and metabolism under CJL. Testosterone plays a crucial role in maintaining the circadian clock and regulating CJL metabolism in males.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"102"},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}