Biology of Sex Differences最新文献

{"title":"Circadian dysregulation as a factor in impaired hepatic protein-synthetic function under chronic photoperiod disruption: the role of sex and chronobiotic correction.","authors":"David A Areshidze, Maria A Kozlova, Anna I Anurkina, Valery P Chernikov, Nikita S Gladyshev","doi":"10.1186/s13293-026-00949-y","DOIUrl":"https://doi.org/10.1186/s13293-026-00949-y","url":null,"abstract":"<p><strong>Background: </strong>Liver metabolism is under tight control of the circadian system. Disruption of key clock gene expression (desynchronosis) leads to the misalignment of metabolic pathways. However, the relationship between circadian dysregulation and hepatic protein-synthetic function, as well as its sexual dimorphism, remains poorly understood. To evaluate the effect of chronic photoperiod disruption on hepatic protein-synthetic function (total protein, albumin) and to establish its relationship with the expression of key circadian proteins (BMAL1, CLOCK, PER2) in male and female rats, as well as to assess the efficacy of exogenous melatonin in correcting the identified disturbances.</p><p><strong>Methods: </strong>The study was performed on 240 adult Wistar rats (120 males, 120 females). Animals were divided into 3 groups: control (light: dark 10:14 h), dark deprivation (LL, constant light for 21 days), and LL + melatonin (12 mg/L drinking water). Plasma levels of total protein and albumin were measured. Immunohistochemistry was used to assess the percentage of positively stained hepatocytes for BMAL1, CLOCK, and PER2. Statistical analysis included two-way ANOVA, Pearson correlation analysis, ANCOVA, and ROC analysis.</p><p><strong>Results: </strong>Dark deprivation reduced albumin levels by 15.7% in males and by 15.9% in females compared to controls. Two-way ANOVA revealed significant effects of \"lighting conditions\" (F = 145.3, p < 0.0001), \"sex\" (F = 18.7, p < 0.01), and their interaction (F = 7.2, p < 0.05). BMAL1 and CLOCK expression decreased by more than 70% in both sexes, whereas PER2 expression paradoxically increased by 28.9-35.0%. Strong correlations were found between albumin levels and expression of BMAL1 (r = 0.79-0.81, p < 0.001), CLOCK (r = 0.69-0.74, p < 0.001), and PER2 (r= - 0.68 to - 0.71, p < 0.001). ANCOVA (R²=0.71, p < 0.0001) identified BMAL1 expression as the most significant independent predictor of albumin levels (β = 0.52, p < 0.0001), with sex retaining independent significance (p = 0.02). ROC analysis demonstrated high predictive performance of BMAL1 expression for hypoalbuminemia (AUC = 0.87-0.89, p < 0.0001). Melatonin treatment fully restored the expression of all examined circadian proteins and normalized protein synthetic parameters to control levels in both sexes.</p><p><strong>Conclusion: </strong>Chronic photoperiod disruption induces profound hepatic desynchronosis characterized by suppression of BMAL1/CLOCK and accumulation of PER2, which is associated with decreased protein synthetic function. A pronounced sexual dimorphism in susceptibility to desynchronosis was identified. BMAL1 expression is a highly informative predictor of hypoalbuminemia. Exogenous melatonin fully restores the impaired parameters, supporting its use as an effective chronobiotic.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexually-dimorphic offspring outcomes following antenatal corticosteroids: a review of the evidence for congenital adrenal hyperplasia and preterm birth risk.","authors":"Lulu Y L Birch, Amanda N Sferruzzi-Perri","doi":"10.1186/s13293-026-00938-1","DOIUrl":"https://doi.org/10.1186/s13293-026-00938-1","url":null,"abstract":"<p><strong>Background: </strong>Pregnant individuals may receive antenatal corticosteroids for various conditions, including congenital adrenal hyperplasia (to prevent virilisation in female fetuses) and preterm birth risk (to hasten fetal maturation and improve perinatal survival). This narrative review aimed to evaluate the evidence of sexually-dimorphic offspring outcomes following antenatal corticosteroids for such conditions and explore the potential underlying mechanisms.</p><p><strong>Methods: </strong>A comprehensive MEDLINE search identified twenty-eight studies for inclusion: seven focused on congenital adrenal hyperplasia and twenty-one focused on preterm birth risk.</p><p><strong>Results: </strong>For congenital adrenal hyperplasia, evidence suggests that antenatal corticosteroids are associated with sexually-dimorphic outcomes across cognition, behaviour and brain structure. Females demonstrated more consistently negative outcomes, particularly within the congenital adrenal hyperplasia-affected population, where females were exposed to longer treatment durations than males. The outcomes for males were more heterogenous. For preterm birth, some studies suggest preterm males remain at increased risk for mortality and morbidity, while in term-born infants, females may have worse outcomes. The nature of these effects, however, differed with antenatal corticosteroid types, and conflicting findings also existed. Potential mechanisms for sexually-dimorphic outcomes include differences in placental enzyme and receptor expression and activity, fetal hypothalamic-pituitary-adrenal (HPA) axis function, and susceptibility to developing respiratory conditions.</p><p><strong>Conclusions: </strong>The current literature suggests potential sex differences following antenatal corticosteroids, which differ between congenital adrenal hyperplasia and preterm birth risk. Owing to surmounting evidence of negative outcomes and the retracting use of antenatal corticosteroids for congenital adrenal hyperplasia, further research will be challenging. Whereas studies concerning sexually-dimorphic responses to antenatal corticosteroids for preterm birth risk are essential, given their widespread use. Further research in this area may help to understand whether the clinical management of preterm birth should be adjusted according to sex.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neonatal estradiol influences regional gene expression for early sex-specific inflammatory responses in the 5xFAD mouse model.","authors":"Phaedra R Keller-Norrell, Brad T Casali, Logan N Yost, Erin G Reed","doi":"10.1186/s13293-026-00948-z","DOIUrl":"10.1186/s13293-026-00948-z","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD), the most prevalent form of dementia, exhibits a strong sex bias, with women comprising two-thirds of all patients, for reasons that remain unclear. Microglia, as the brain's resident immune cell, are key players in AD pathogenesis and are increasingly understood as being sex-specific. However, the mechanisms underlying these differences, and how they may in turn contribute to distinct pathogenesis has not been well examined. Therefore, this study aimed to investigate the organizational role of neonatal estradiol (E2) in early-life sex-patterning of microglia for disease onset and progression.</p><p><strong>Methods: </strong>We assessed the effect of neonatal estradiol exposure on microglial and neuronal density, microgliosis, and gene expression related to microglial identity and responses using immunohistochemistry, qPCR, and ProteinSimple Jess on-capillary immunoblotting.</p><p><strong>Results: </strong>We find neonatal estradiol administration influences the expression of genes and proteins involved in inflammation and X chromosome inactivation, without affecting cellular composition of the cortex and hippocampus. Additionally, we observed genotype-dependent changes to the female reproductive cycle in E2 treated 5xFAD females.</p><p><strong>Conclusions: </strong>Overall, the results of the present study provide novel insight into the role of steroid sex hormones in neonatal microglial programing, and how this programming may set the stage for further sex- and disease-linked alterations later in life.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and gender classification in clinical decision-support tools: a cross-sectional review of tools on MDCalc.","authors":"Brototo Deb, Timothy Lim, Ian K Everitt, Carl G Streed","doi":"10.1186/s13293-026-00946-1","DOIUrl":"https://doi.org/10.1186/s13293-026-00946-1","url":null,"abstract":"<p><strong>Background: </strong>As algorithm-based decision support tools become increasingly integrated into clinical workflows, particularly with the popularization of artificial intelligence, the conceptualization and operationalization of demographic variables such as sex and gender have implications for how these variables are measured and interpreted. Misalignment between variable labels, response categories, and underlying data sources may introduce measurement error or ambiguity in algorithm inputs, potentially affecting clinical interpretation and downstream decision-making. This concern reflects issues of variable specification rather than terminology alone. The objective of this study is to evaluate how sex and gender are labeled, operationalized, and aligned with underlying source data in clinical decision-support tools.</p><p><strong>Methods: </strong>In May 2025, we conducted a cross-sectional review of clinical tools available on MDCalc, a widely-used online repository of clinical decision-support tools derived from biomedical research and clinical guidelines. We assessed tools with a demographic input labeled as sex, gender, or both. Main measures were the presence and operationalization of sex or gender variables within tool interfaces and corresponding primary references. Variable labeling (sex or gender), response categories (e.g., male/female or man/woman), reported data collection methods in primary references, and concordance between tool interfaces and source literature. Tools were also qualitatively categorized by potential clinical impact (high, medium, low).</p><p><strong>Results: </strong>Among 821 tools screened, 84 (10.2%) included a sex or gender variable. Of these, 69 (82.1%) labeled the variable as sex and 15 (17.9%) as gender. Binary response categories were used in 83 tools (98.8%). Sex-gender conflation occurred in 16 tools (19.0%), reflecting inconsistencies between variable labels and response categories used as inputs. Primary references were available for 76 tools (90.5%); among those that explicitly reported sex or gender collection, 18 (25.7%) demonstrated sex-gender conflation. Most tools were classified as having medium (51.2%) or high (33.3%) potential clinical impact.</p><p><strong>Conclusion: </strong>Sex and gender are inconsistently labeled and operationalized in clinical decision-support tools. One in five tools demonstrated misalignment between variable labels, response categories, and underlying source data. Greater conceptual clarity and transparency of sex and gender variables may reduce ambiguity and strengthen the validity, interpretability, and equity of algorithm-based clinical decision tools.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why males scar more: hormonal and chromosomal clues to idiopathic pulmonary fibrosis.","authors":"Sharon J Elliot, Kristina Clark, Gina Civettini, Ben Roos, Xiaomei Xia, Eva Galdikaite, Simone Pereira-Simon, Austin Kaboff, Paola Catanuto, Sam Grimaldo, Shahriar Shahzeidi, Arthur P Arnold, Marilyn K Glassberg","doi":"10.1186/s13293-026-00942-5","DOIUrl":"https://doi.org/10.1186/s13293-026-00942-5","url":null,"abstract":"<p><strong>Background: </strong>There is a gap in understanding the predominance of males with idiopathic pulmonary fibrosis (IPF). While gonadal hormones contribute to fibrosis susceptibility, evidence suggests a role for sex chromosomes.</p><p><strong>Methods: </strong>We used The Four Core Genotypes (FCG) mouse model, which uncouples gonadal sex from sex chromosomes, in aged mice before and after bleomycin (BLM)-induced lung injury. Fibrosis severity was assessed by histology, collagen content, and profibrotic gene expression, along with analysis of estrogen receptor (ER)α and ERβ signaling, matrix metalloproteinase activity, insulin-like growth factor-1 (IGF-1), and microRNAs. Data were analyzed using two-way ANOVA to test effects of gonadal sex, sex chromosome complement, and their interaction; gonadectomy experiments used three-way ANOVA including gonadal status.</p><p><strong>Results: </strong>BLM-induced lung injury resulted in the greatest fibrosis in XY mice with ovaries, which was associated with elevated ERα expression and increased ERα:ERβ ratio. In contrast, ERβ expression was highest in XX mice with testes and associated with attenuated fibrosis. Multiple fibrotic pathways were regulated by gonadal sex, sex chromosome complement, or their interaction. Gonadectomy revealed organizational and activational effects of sex hormones and uncovers interactions between gonadal sex, sex chromosomes, and hormone status. Sex chromosome-dependent regulation of let-7d and miR-29a linked chromosomal dosage to ERα-IGF-1 mediated remodeling.</p><p><strong>Conclusions: </strong>These findings identify hormonal and chromosomal mechanisms contributing to sex bias in pulmonary fibrosis and suggest sex-informed therapeutic targets for IPF.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal BPA exposure perturbs RNA-binding protein-mediated splicing regulation and synaptogenesis in the developing cerebellum in a sex-dependent manner.","authors":"Thanawin Jantheang, Songphon Kanlayaprasit, Kwanjira Songsritaya, Pawinee Panjabud, Pattanachat Lertpeerapan, Kasidit Kasitipradit, Surangrat Thongkorn, Depicha Jindatip, Valerie W Hu, Thanit Saeliw, Tewarit Sarachana","doi":"10.1186/s13293-026-00941-6","DOIUrl":"10.1186/s13293-026-00941-6","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social communication deficits, exhibiting a male bias in prevalence. Emerging evidence suggests that prenatal exposure to bisphenol A (BPA) may perturb neurodevelopmental trajectories relevant to ASD. While the cerebellum is increasingly recognized as a brain region implicated in ASD pathophysiology, the impact of gestational BPA exposure on its post-transcriptional alternative splicing machinery remains fundamentally undefined.</p><p><strong>Methods: </strong>Here, we investigated sex-dependent effects of prenatal BPA exposure on the alternative splicing landscape of the neonatal rat cerebellum. We utilized RNA-seq to profile differential alternative splicing (DAS) events. Ingenuity Pathway Analysis (IPA) was used to predict biological functions and canonical pathways, and to construct the interactome network of DAS genes. To explore candidate upstream regulatory mechanisms, we performed in silico molecular docking and used high-resolution melting (HRM) qRT-PCR to validate selected splicing events. Furthermore, we assessed in vitro cellular phenotypes in primary cerebellar neurons by measuring MTS-based viability and Syn1/Psd95 puncta colocalization.</p><p><strong>Results: </strong>Prenatal BPA exposure was associated with widespread DAS in genes enriched for ASD-relevant pathways in the neonatal rat cerebellum. To our knowledge, this study is the first to report molecular docking analyses predicting favorable interactions between BPA and several candidate RNA-binding proteins (RBPs), including CPEB1, RALYL, HNRNPDL, and ACO1. Our findings support a model in which BPA may perturb RBP-associated splicing regulation, including altered splicing of chromatin regulators such as Ccar1 in males. These molecular and cellular findings were accompanied by sex-stratified differences in neuronal viability and synaptic puncta measurements. BPA exposure was associated with an increased MTS viability signal in male primary cerebellar neurons, together with significant reductions in Psd95 and Syn1 puncta density, whereas female neurons showed significantly increased synaptic puncta colocalization together with reduced viability.</p><p><strong>Conclusions: </strong>In this study, we propose that prenatal BPA may be relevant to ASD-related neurodevelopmental pathways through sex-dependent changes in RBP-associated alternative splicing, including altered splicing of Ccar1 in males, together with distinct cellular outcomes. Together, these findings identify the developing cerebellum as a sensitive target of prenatal BPA exposure and highlight alternative splicing as a candidate pathway relevant to ASD biology.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300740","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":"Exploring sex-specific causal links between thousands of proteins and lipid metabolism using the UK Biobank Pharma Proteomics Project data.","authors":"Daniela Zanetti, Mine Koprulu, Federica Grosso, Daria V Zhernakova, Francesca Crobu, Serena Sanna","doi":"10.1186/s13293-026-00934-5","DOIUrl":"10.1186/s13293-026-00934-5","url":null,"abstract":"<p><p>Lipid traits are known to be sex-differential, but the underlying molecular players are largely unknown. Herein, we aim to highlight differential molecular signatures in lipid metabolism between males and females by identifying proteins that are causally linked to lipids in a sex-specific or sex-differentiated manner. Since protein levels are downstream products of gene expression, proteomics data can be crucial to understand etiology of sex-differences in lipids metabolism.We used sex-specific pQTL summary statistics for 2,923 circulating proteins measured in the UK Biobank Pharma Proteomics Project, along with sex-specific summary statistics of lipids from the Global Lipids Genetics Consortium. We combined these using two-sample Mendelian Randomization analyses and applied stringent multiple testing p-values correction and sensitivity analyses.We identified several sex-specific significant causal links between protein levels and lipid phenotypes: 83 were exclusive to females and 82 to males, 46% of which would not have been identified using combined-sex GWASs. The estimated causal effect was instead significant in both sexes but substantially different in size for 39 causal relationships (p < 0.05). Intriguingly, several of these proteins were previously shown to be involved in inflammation and cardiometabolic diseases, such as Apolipoprotein(a) and lipoprotein lipase. Furthermore, two sex-specific proteins - LEPR and LPA - are molecular targets of emerging cardiometabolic therapies, highlighting the need for future investigations to determine whether these protein-level differences translate into sex-specific efficacy or safety in clinical trials and routine treatments.The discovery of these sex-differences can provide important etiological insights into the management of lipid metabolism. Such knowledge may in turn improve the predictive use of sex-specific pQTLs and point to new therapeutic gender specific strategies to prevent cardiovascular disease.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263150","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":"Circulating nitric oxide pathway metabolites in heart failure with preserved ejection fraction: a sex-stratified cross-sectional analysis.","authors":"Sophia Marie-Theres Dinges, Edzard Schwedhelm, Flavia Baldassarri, Bernhard Haller, Andreas B Gevaert, Rainer Böger, Ephraim B Winzer, Frank Edelmann, Ulrik Wisløff, Volker Adams, Burkert Pieske, Emeline M Van Craenenbroeck, Martin Halle, Susanna M Hofmann, Stephan Mueller-Stegner","doi":"10.1186/s13293-026-00940-7","DOIUrl":"10.1186/s13293-026-00940-7","url":null,"abstract":"<p><strong>Background: </strong>Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women, who often present with earlier onset and greater severity of vascular and endothelial dysfunction. Nitric oxide (NO) is a key contributor to vascular health, and several NO-related metabolites are associated with cardiovascular outcomes. However, it remains unknown whether differences in circulating NO-related metabolite concentrations exist between men and women with HFpEF.</p><p><strong>Methods: </strong>In this cross-sectional analysis of a multicentre randomized controlled intervention trial (OptimEx-Clin), plasma concentrations of NO-related amino acids (L-arginine, L-homoarginine (hArg), L-ornithine, L-lysine, L-citrulline), asymmetric and symmetric dimethylarginines (ADMA, SDMA), and functional metabolite ratios were assessed in 171 patients with HFpEF. Analyses were stratified by sex and age, and further adjusted for relevant clinical covariates using multivariable regression models. A principal component analysis (PCA) was performed to explore sex-related metabolite patterns.</p><p><strong>Results: </strong>The comparison of NO-related metabolites in 58 men and 113 women with HFpEF showed significant sex differences for SDMA (β-coefficient [95% CI]; -0.11 [-0.20 to -0.03] µmol/L, p = 0.010) and hArg (-0.24 [-0.46 to -0.01] µmol/L, p = 0.043) in unadjusted models; both with lower concentrations in women. While the association with hArg was attenuated after multivariable adjustment, higher SDMA concentrations in men were observed in five out of six tested models. No other significant sex differences were observed neither in single metabolites nor in composite metabolite ratios. The PCA of all measured metabolites did not demonstrate a clear separation between women and men in the overall metabolite profile.</p><p><strong>Conclusions: </strong>In HFpEF, sex-related differences in circulating NO-related metabolites were limited and metabolite-specific, with SDMA showing the most consistent sex-associated difference with higher concentrations in men. The substantial overlap of metabolic profiles between women and men showed no distinct patterns of circulating metabolites linked to endothelial function in patients with HFpEF.</p><p><strong>Registry: </strong>ClinicalTrials.gov, TRN: NCT02078947.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13270708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257252","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":"Functional and transcriptomic insights into 46,XY disorders of sex development associated with NR5A1 gene variants.","authors":"Qingxu Liu, Shaolian Zang, Yan Li, Xiaoqin Yin, Pin Li","doi":"10.1186/s13293-026-00939-0","DOIUrl":"10.1186/s13293-026-00939-0","url":null,"abstract":"<p><strong>Background: </strong>NR5A1 encodes a transcription factor essential for adrenal and gonadal development. Gene variants are a known cause of heterogeneous 46,XY disorders of sex development (DSD), but the mechanisms underlying the phenotypic variability remain unclear. We investigated how different NR5A1 variants affect downstream gene regulation and contribute to DSD pathogenesis.</p><p><strong>Methods: </strong>We analyzed four naturally occurring NR5A1 variants identified in patients with 46,XY DSD-two novel (p.Cys65Ser, p.His310Arg) and two previously reported (p.Cys30Ser, p.Gln329*). We performed protein and transcriptomic analyses to characterize variant effects and identify dysregulated and candidate target genes, validated by qPCR and luciferase assays. Transcriptomic and CUT&Tag analyses focused on the p.Gln329* truncating variant.</p><p><strong>Results: </strong>All four variants occurred at conserved residues and resulted in reduced NR5A1 protein expression and impaired nuclear localization upon transfection in HEK293T cells. Transcriptomic analysis using the p.Gln329* variant revealed broad downregulation of genes involved in steroidogenesis, including CYP11A1, STAR, and CYP17A1. Notably, AMHR2 and STARD8 were significantly downregulated and showed reduced CUT&Tag signal in variant-transfected cells. Promoter assays confirmed that all variants diminished CYP11A1 and AMHR2 promoter activity. Only the p.Gln329* variant affected STARD8 promoter activity.</p><p><strong>Conclusions: </strong>These findings indicate that NR5A1 variants impair protein expression and localization, leading to transcriptional dysregulation of genes involved in steroid hormone biosynthesis and sexual development. Based on analysis of the p.Gln329* truncating variant, AMHR2 and STARD8 are strong candidate novel downstream targets of NR5A1, offering further insight into the mechanisms driving 46,XY DSD.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203663","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":"Social determinants of health and sex differences: insights from NIH Specialized Centers of Research Excellence (SCORE).","authors":"Sherry A McKee, Lin Chang, Izzuddin M Aris","doi":"10.1186/s13293-026-00936-3","DOIUrl":"10.1186/s13293-026-00936-3","url":null,"abstract":"","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13245042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203682","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}