Biology of Sex Differences最新文献

{"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579829/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560403/pdf/","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":"OA","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}

{"title":"Gene × sex interactions on cognition in the Philadelphia neurodevelopmental cohort.","authors":"Josephine Mollon, Emma E M Knowles, Samuel R Mathias, Amanda Rodrigue, Ruben C Gur, Juan Manuel Peralta, Daniel J Weiner, Elise B Robinson, Armin Raznahan, Raquel E Gur, John Blangero, Laura Almasy, David C Glahn","doi":"10.1186/s13293-026-00929-2","DOIUrl":"10.1186/s13293-026-00929-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Small differences between females and males in cognitive abilities have been consistently reported, but the factors underlying these sex differences remain unclear. Social and cultural factors are thought to play a key role, but studies on this topic have been inconclusive. Examination of genetic factors may shed some light on the mechanisms underlying cognitive sex differences.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Using data from the Philadelphia Neurodevelopmental Cohort, a large, general population sample of individuals aged 8 to 21 years old (N = 4,694), we tested for sex differences in the genetic factors (i.e., Gene × Sex interactions) underlying cognitive ability. Participants completed the Penn Computerized Neurocognitive Battery, which consists of 14 tests designed to capture accuracy and speed in five domains: 1) executive function (abstraction and mental flexibility, attention, working memory), 2) episodic memory (verbal, facial, spatial), 3) complex cognition (verbal reasoning, nonverbal reasoning, spatial processing), 4) social cognition (emotion identification, emotion differentiation, age differentiation), and 5) speed (motor, sensorimotor). Composite domain scores were derived using confirmatory factor analysis, and general accuracy (g) and speed (gs) using principal component analysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Small sex differences were observed on most cognitive measures (standardized mean difference (SMD) = 0.061-0.182). Males showed significantly higher genetic variance and lower environmental variance in executive (female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.301 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.598, p = 0.001, female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.243 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.024, p = 0.007), and complex (female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.291 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.610, p = 0.001, female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.259 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.023, p = 0.006) accuracy. Females showed significantly higher genetic and lower environmental variance on complex (female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.575 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.135, p = 0.009, female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.222 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.641, p = 0.012) and social (female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.589 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;g&lt;/sub&gt; = 0.129, p = 0.009, female σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.236 v. male σ&lt;sup&gt;2&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt; = 0.672, p = 0.012) speed. Genetic correlations between females and males were not significantly different from 1 on any cognitive measure. Altogether, our results suggest that while the same genetic factors influence cognition in females and males, the magnitude of effect of these genetic factors differs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;We observed small differences between females and males on most cognitive measures, as well as sex differences in heritability on some measures. Future studies are needed to delineate how environ","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13251074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194399","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":"Maternal deprivation and adolescent alcohol exposure induce sex-dependent alterations in stress-related behavior and lipid signaling in rats.","authors":"Laura Sánchez-Marín, Adriana Castro-Zavala, María Flores-López, Ana Gavito, Raquel Reviriego, Eva M Marco, Francisco J Pavón-Morón, Fernando Rodríguez de Fonseca, Antonia Serrano","doi":"10.1186/s13293-026-00937-2","DOIUrl":"10.1186/s13293-026-00937-2","url":null,"abstract":"<p><strong>Background: </strong>Early-life stress constitutes a major risk factor for the development of neuropsychiatric and substance use disorders, exerting enduring effects on stress responsivity and emotional behavior. Maternal deprivation (MD) is a well-established model of early adversity that induces persistent neurobiological alterations. During adolescence, alcohol exposure presents an additional challenge that may interact with early-life stress, potentially influencing long-term adaptations in a sex-dependent manner. Among the systems involved, lipid signaling pathways, including the endocannabinoid system (ECS) and lysophosphatidic acid (LPA) signaling, have emerged as key regulators of stress adaptation.</p><p><strong>Methods: </strong>Male and female Wistar rats were subjected to a single 24-h MD episode on postnatal day 9 (PND9). During adolescence (PND31-55), animals received intermittent alcohol exposure (3 g/kg) or saline. Behavioral assessments included the forced swim test and elevated plus maze. Plasma levels of corticosterone, monoacylglycerols, N-acylethanolamines, LPA, and autotaxin were measured. Concurrently, mRNA expression of genes encoding ECS- and LPA-related receptors, as well as enzymes involved in the metabolism of these lipid signaling pathways, was analyzed in the medial prefrontal cortex (mPFC). Data were evaluated using three-way ANOVA with sex, MD, and adolescent alcohol exposure as factors.</p><p><strong>Results: </strong>MD induced persistent metabolic alterations and revealed sex-specific effects on alcohol pharmacokinetics, with increased blood alcohol concentrations in MD females. Behavioral analyses demonstrated sex-dependent effects, with MD increasing active coping in males and decreasing it in females, while enhancing open-arm exploration independently of adolescent alcohol exposure. Adolescent alcohol exposure increased plasma corticosterone levels. MD and sex significantly altered circulating lipid mediators, showing opposite patterns in males and females. Additionally, MD and adolescent alcohol exposure differentially modulated the expression of ECS- and LPA-related genes in the mPFC, indicating sex-dependent molecular adaptations.</p><p><strong>Conclusions: </strong>Early-life stress establishes long-lasting, sex-specific alterations in behavioral and lipid-mediated stress responses. Adolescent alcohol exposure acts as a secondary challenge, unmasking or amplifying these adaptations. The integration of peripheral lipid profiles with mPFC molecular changes highlights lipid signaling pathways as key mediators linking early adversity and adolescent experiences with long-term vulnerability to stress-related psychopathology.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13255284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197208","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 CD38 shows stronger association with incident heart failure in women despite lower levels: sex differences and kidney-function context.","authors":"Richard Mprah, Jeremiah Ong'Achwa Machuki, Prosperl Ivette Wowui, Diana Chulu, Yixuan Lei, Anastasia Wemaatu Lamawura Kanoseh, Manuella Quaye, Parfait Botolo Sakava, Simon Kumah Yalley, Joshua Nii Yemo Quarshie, Saffia Shaheen, Tao Dong, Hong Sun","doi":"10.1186/s13293-026-00924-7","DOIUrl":"10.1186/s13293-026-00924-7","url":null,"abstract":"<p><strong>Background: </strong>CD38, an NADase implicated in aging and metabolic stress, promotes cardiac dysfunction via NAD⁺ depletion. Whether circulating CD38 is associated with incident heart failure (HF), whether this association differs by sex, and how it relates to kidney-function context remain unclear.</p><p><strong>Methods: </strong>We measured plasma CD38 in 42,584 UK Biobank participants (1,659 incident HF events) and evaluated its association with HF using sequential Cox models, attenuation analyses, competing-risk models, and incremental prediction metrics. Complementary mouse studies employed chronic β-adrenergic stress (isoproterenol) to investigate sex-specific responses and test the effects of CD38 inhibition (78c), TGF-β1 inhibition (SB431542), and their combination.</p><p><strong>Results: </strong>CD38 was associated with incident HF in models adjusting for traditional risk factors (M1: HR per SD 1.25, 95% CI 1.18-1.32), with complete attenuation after eGFR adjustment. Despite higher CD38 levels in men, the association was stronger in women (M1: HR 1.39 vs. 1.17 per SD; sex interaction P = 0.004). After eGFR adjustment, the association remained positive in women (M3: HR 1.17) but became inverse in men (M3: HR 0.90). The CD38-HF association showed substantial attenuation after adjustment for NT-proBNP, ANGPT2, and IL-6, consistent with shared statistical variance with downstream biomarker burden rather than causal mediation. Fine-Gray competing-risk models (3,212 deaths without HF) produced similar results. In mice, isoproterenol induced cardiac remodeling and systolic impairment in both sexes and elicited greater metabolic and renal stress responses in females despite their higher baseline cardiac NAD⁺/ATP levels. CD38 inhibition restored cardiac NAD⁺/ATP and reduced renal stress markers, with numerically greater reductions in females, while TGF-β1 inhibition reduced fibrotic signaling. Combined inhibition produced complementary effects across metabolic and fibrotic readouts.</p><p><strong>Conclusions: </strong>Circulating CD38 is not an independent predictor of HF after accounting for kidney function and downstream biomarker burden, but appears to reflect a broader cardiometabolic-renal stress context. Despite lower circulating levels, CD38 showed a stronger association with HF in women than in men. Proof-of-concept mouse experiments showed that CD38 inhibition preserved cardiac NAD⁺/ATP and reduced renal stress markers, while TGF-β pathway inhibition reduced fibrotic signaling, providing mechanistic support for further sex-aware HF research.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161637","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}