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Menstrual cycle modulates the effect of BDNF Val66Met variant on category learning. 月经周期调节BDNF Val66Met变异对类别学习的影响。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-03-01 DOI: 10.1186/s13293-026-00856-2
Mateja Perović, Jianqi Hou, Michael L Mack

Background: Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition.

Methods: We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol).

Results: While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol.

Conclusions: The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition.

背景:脑源性神经营养因子(BDNF)和卵巢激素都是强大的神经调节剂,但它们对人类认知影响的证据仍然是混合的。由于先前的工作是孤立地研究它们,检查它们的相互作用为解释它们对认知的影响提供了一个关键的经验机会。方法:我们对参与者进行BDNF Val66Met单核苷酸多态性基因分型,该基因与活性依赖性BDNF分泌效率低下和海马功能改变有关,并在月经周期的两个时间点(卵泡早期(以卵巢激素水平低为特征)和卵泡晚期(以高雌二醇为特征)检查他们在复杂学习任务中的表现。结果:虽然met携带者在卵泡早期时间点表现出优势,但val纯合子在卵泡晚期时间点表现出优势。此外,met携带者的影响主要是由于对雌二醇绝对水平和水平变化的敏感性增加。结论:目前的研究结果提供了BDNF Val66Met与月经周期相互作用来预测认知的第一个证据,展示了细微的基因型和激素特异性结果,并强调了研究相互作用的生物系统对人类认知的影响的重要性。
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引用次数: 0
Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications. 钾调节的性别差异:证据、分子机制和临床意义。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-03-01 DOI: 10.1186/s13293-026-00862-4
Lama Al-Qusairi

Men and women exhibit well-established differences in electrolyte regulation, susceptibility to hypertension, kidney disease prevalence, and response to therapies for cardiovascular and renal disorders. Among these, plasma potassium regulation emerges as a key area of sex-specific divergence. Clinical and experimental studies consistently show that women are more susceptible to hypokalemia, while men are more prone to hyperkalemia, a pattern most evident during physiological or pathological stressors such as specific dietary patterns, exercise, medication use, and diseases like chronic kidney disease or cardiorenal syndrome. In this review, we synthesize current evidence from both human and animal studies on sex differences in potassium homeostasis and discuss their clinical implications. We also explore the physiological and molecular mechanisms underlying these differences, and highlight critical knowledge gaps. Advancing our understanding of these biological differences and their underlying mechanisms is essential to move beyond one-size-fits-all nutritional recommendations and disease management strategies.

男性和女性在电解质调节、对高血压的易感性、肾脏疾病的患病率以及对心血管和肾脏疾病治疗的反应方面表现出明显的差异。其中,血浆钾调节是性别差异的一个关键领域。临床和实验研究一致表明,女性更容易患低钾血症,而男性更容易患高钾血症,这种模式在生理或病理压力因素(如特定的饮食模式、运动、药物使用和慢性肾病或心肾综合征等疾病)中最为明显。在这篇综述中,我们综合了目前人类和动物研究中关于钾稳态性别差异的证据,并讨论了它们的临床意义。我们还探讨了这些差异背后的生理和分子机制,并强调了关键的知识差距。推进我们对这些生物学差异及其潜在机制的理解,对于超越一刀切的营养建议和疾病管理策略至关重要。
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引用次数: 0
Hepatocyte growth factor may contribute to male protection against pulmonary arterial hypertension. 肝细胞生长因子可能有助于男性预防肺动脉高压。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-03-01 DOI: 10.1186/s13293-026-00852-6
Lejla Medzikovic, Grégoire Ruffenach, Ateyeh Dehghanitafti, Brenda Wong, Ashley Ryder, Mohammad Reza Hatamnejad, Wasila Sun, Leana Esdin, Joshua Eghbali, Adam Brownstein, Asif Razee, Soban Umar, Jason Hong, Mansoureh Eghbali

Background: Pulmonary arterial hypertension (PAH) presents as increased pressure in the pulmonary arteries (PA) leading to cardiac right ventricular (RV) failure and death. Pulmonary arterial (PA) remodeling characterized by enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) and fibroblasts (PAFB) underlies PAH. There are currently no cures and PAH mortality remains high. PAH has a striking female-predominant incidence - 4:1 ratio - indicating that males may have a protective factor. However, to date only a few sex-biased factors in PAH have been investigated.

Methods: Analyses were performed on a publicly available microarray dataset (GSE117261), comprising human lung tissues from PAH patients and healthy controls, as well as publicly available single-cell lung atlases of humans and mice. Lung tissue, plasma, PASMC and PAFB were collected from male and female PAH patients. Cell proliferation was assessed after recombinant HGF protein stimulation. PH was induced in male and female rats by monocrotaline (MCT). Lung-specific knockdown was performed by intratracheal siRNA instillation the first two weeks after MCT injection. PA and RV function were assessed by echocardiography, RV systolic pressure by catheterization, and PA remodeling by histology.

Results: HGF was only upregulated in lungs of male PAH patients compared to male control lungs, but not in female PAH patients vs. female controls. Elevated plasma HGF correlated with favorable clinical characteristics only in male PAH patients. HGF is highly expressed in vascular SMC and FB in the lung and recombinant HGF inhibited PASMC and PAFB proliferation to a greater extent in cells isolated from male PAH patients compared to female. Lung HGF expression is increased to a higher extent and longer duration at early stage of PH in male rats in MCT model vs. female rats. Finally, knockdown of HGF in the lungs in early disease stage exacerbated PH in male rats characterized by higher mortality, worsened RV and PA function as well as enhanced PA medial thickening and adventitial fibrosis.

Conclusions: Lung HGF expression may be upregulated to counteract PAH disease progression by inhibiting proliferation of PASMC and PAFB. Elevated HGF in males might at least partially account for the lower incidence of male PAH patients.

背景:肺动脉高压(PAH)表现为肺动脉(PA)压力升高,导致心脏右心室(RV)衰竭和死亡。以肺动脉平滑肌细胞(PASMC)和成纤维细胞(PAFB)增殖增强为特征的肺动脉(PA)重塑是PAH的基础。目前还没有治愈方法,多环芳烃的死亡率仍然很高。多环芳烃的发病率以女性为主,比例为4:1,这表明男性可能有保护因素。然而,迄今为止,在多环芳烃中只有少数性别偏见因素被研究过。方法:对公开可用的微阵列数据集(GSE117261)进行分析,该数据集包括来自PAH患者和健康对照的人肺组织,以及公开可用的人和小鼠单细胞肺图谱。采集男性和女性PAH患者肺组织、血浆、PASMC和PAFB。重组HGF蛋白刺激后观察细胞增殖情况。用MCT诱导雄性和雌性大鼠PH。在MCT注射后的前两周,通过气管内注入siRNA进行肺特异性敲除。超声心动图评估左室和右室功能,导管置管评估右室收缩压,组织学评估右室重塑。结果:HGF仅在男性PAH患者的肺中与男性对照组相比上调,而在女性PAH患者的肺中与女性对照组相比没有上调。血浆HGF升高仅与男性PAH患者的有利临床特征相关。HGF在肺血管SMC和FB中高表达,重组HGF在男性PAH患者分离的细胞中比女性更能抑制PASMC和PAFB的增殖。MCT模型雄性大鼠肺HGF表达在PH早期比雌性大鼠增加程度更高,持续时间更长。最后,疾病早期肺中HGF的下调加重了雄性大鼠的PH,其特点是死亡率更高,RV和PA功能恶化,PA内侧增厚和外膜纤维化增强。结论:肺HGF表达上调可能通过抑制PASMC和PAFB的增殖来对抗PAH的疾病进展。男性HGF升高可能至少部分解释了男性PAH患者发病率较低的原因。
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引用次数: 0
SASdb: a comprehensive database for sex-biased alternative splicing profiles in human tissues. SASdb:人类组织中性别偏倚的可选剪接谱的综合数据库。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-02-26 DOI: 10.1186/s13293-026-00861-5
Xi Chen, Yueqi Lu, You Duan, Yongfeng Bai, Weidong Ye, Sijia Chen, Hang Zhou, Heng Xu, Le Xu, Cheng Guo

Alternative splicing (AS) significantly enhances transcriptomic diversity, and its dysregulation is implicated in numerous human diseases. However, no public database systematically compiles sex-related AS events across human tissues. We developed SASdb (http://www.gdbioinfo.top/sasdb), a comprehensive database contains 2,951,059 AS events and 46,418 sex-biased alternative splicing (SAS) events, covering 22 human tissues. SASdb reveals extensive sex-specific splicing patterns, offering new insights into molecular sex differences. A case study on NSCLC-specific SAS events, absent in healthy tissues, highlights their enrichment in cancer-related pathways like autophagy, GPI-anchor biosynthesis, and AMPK/mTOR signaling. SASdb's intuitive visualization supports research in sex biology and precision medicine.

选择性剪接(AS)显著增强转录组多样性,其失调与许多人类疾病有关。然而,没有公共数据库系统地汇编跨人体组织的与性别相关的AS事件。我们开发了SASdb (http://www.gdbioinfo.top/sasdb),这是一个综合数据库,包含2,951,059个AS事件和46,418个性别偏倚的选择性剪接(SAS)事件,涵盖22个人体组织。SASdb揭示了广泛的性别特异性剪接模式,为分子性别差异提供了新的见解。一项关于非小细胞肺癌特异性SAS事件的案例研究,在健康组织中缺失,强调了它们在自噬、gpi锚定生物合成和AMPK/mTOR信号传导等癌症相关途径中的富集。SASdb的直观可视化支持性别生物学和精准医学的研究。
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引用次数: 0
Estradiol treatment induces both shared and unique gene regulation and networks in adipose cell types of gonadectomized obese XX and XY mice. 雌二醇治疗诱导了性腺去角质的肥胖XX和XY小鼠脂肪细胞类型的共享和独特的基因调控和网络。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-02-23 DOI: 10.1186/s13293-026-00859-z
Yutian Zhao, Ruoshui Liu, Jonathan P Ng, Sophia Yu, In Sook Ahn, Graciel Diamante, Guanglin Zhang, Ariel Thorson, Kelsey P Schaefers, John M Stafford, Xia Yang
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引用次数: 0
Nationwide analysis on sex differences in diagnosis, treatment and survival of rectal cancer. 全国范围内直肠癌诊断、治疗和生存的性别差异分析。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-02-22 DOI: 10.1186/s13293-026-00863-3
D M Mens, V M T van Verschuer, J M van Rees, R R J Coebergh van den Braak, C Verhoef, D E Hilling

Objective: Limited literature is available comparing sexes in rectal cancer. This nationwide study using real-world data was performed to evaluate sex-based differences in diagnosis, treatment and survival outcomes in rectal cancer.

Methods: Data from the Netherlands Cancer Registry were analyzed for patients diagnosed with rectal adenocarcinoma between 2015 and 2019. Patient and tumor characteristics, treatment strategies, response to neoadjuvant therapy, and survival outcomes were compared between sexes.

Results: The cohort consisted of 22251 patients (37.1% women, 62.9% men). Women more frequently presented with cT4 tumors (16% vs. 11%, P < 0.001) but no differences were observed in nodal status, distant metastases, use of neoadjuvant (chemo) radiotherapy and radicality in resections between sexes. In the total study population, 5-year survival did not differ significantly (63.6% in women vs. 61.6% in men, P=0.23). However, in surgically treated patients, survival was higher in women (77.4% vs. 75.0%, P=0.019). Female sex was an independent predictor for survival in surgically treated patients (HR 0.90; 95% CI 0.82-0.98). In the subgroup of patients who were asymptomatic at the time of diagnosis [n=1320], there were no sex-based differences in presentation, treatment, or survival (5-year overall survival: 78.8% vs. 80.4%, P=0.45).

Conclusion: Sex-based differences exist in rectal cancer presentation and outcome. Women are more likely to present a more advanced T-stage. Despite this, women have a better overall survival after surgical treatment. In contrast, men and women undergoing treatment for asymptomatic rectal cancer have comparable outcomes.

目的:比较直肠癌性别的文献有限。这项使用真实世界数据的全国性研究旨在评估基于性别的直肠癌诊断、治疗和生存结果的差异。方法:分析荷兰癌症登记处2015年至2019年诊断为直肠腺癌的患者的数据。患者和肿瘤特征、治疗策略、对新辅助治疗的反应和生存结果在性别之间进行了比较。结果:该队列包括22251例患者(女性37.1%,男性62.9%)。女性更常出现cT4肿瘤(16% vs. 11%)。结论:直肠癌的表现和预后存在性别差异。女性更有可能出现更晚期的t期。尽管如此,女性在手术治疗后总体生存率更高。相比之下,接受无症状直肠癌治疗的男性和女性有相当的结果。
{"title":"Nationwide analysis on sex differences in diagnosis, treatment and survival of rectal cancer.","authors":"D M Mens, V M T van Verschuer, J M van Rees, R R J Coebergh van den Braak, C Verhoef, D E Hilling","doi":"10.1186/s13293-026-00863-3","DOIUrl":"https://doi.org/10.1186/s13293-026-00863-3","url":null,"abstract":"<p><strong>Objective: </strong>Limited literature is available comparing sexes in rectal cancer. This nationwide study using real-world data was performed to evaluate sex-based differences in diagnosis, treatment and survival outcomes in rectal cancer.</p><p><strong>Methods: </strong>Data from the Netherlands Cancer Registry were analyzed for patients diagnosed with rectal adenocarcinoma between 2015 and 2019. Patient and tumor characteristics, treatment strategies, response to neoadjuvant therapy, and survival outcomes were compared between sexes.</p><p><strong>Results: </strong>The cohort consisted of 22251 patients (37.1% women, 62.9% men). Women more frequently presented with cT4 tumors (16% vs. 11%, P < 0.001) but no differences were observed in nodal status, distant metastases, use of neoadjuvant (chemo) radiotherapy and radicality in resections between sexes. In the total study population, 5-year survival did not differ significantly (63.6% in women vs. 61.6% in men, P=0.23). However, in surgically treated patients, survival was higher in women (77.4% vs. 75.0%, P=0.019). Female sex was an independent predictor for survival in surgically treated patients (HR 0.90; 95% CI 0.82-0.98). In the subgroup of patients who were asymptomatic at the time of diagnosis [n=1320], there were no sex-based differences in presentation, treatment, or survival (5-year overall survival: 78.8% vs. 80.4%, P=0.45).</p><p><strong>Conclusion: </strong>Sex-based differences exist in rectal cancer presentation and outcome. Women are more likely to present a more advanced T-stage. Despite this, women have a better overall survival after surgical treatment. In contrast, men and women undergoing treatment for asymptomatic rectal cancer have comparable outcomes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269815","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}
引用次数: 0
Sry-modified laboratory rat lines to study sex-chromosome effects underlying sex differences in physiology and disease: four core genotypes and more. sry修饰的实验室大鼠系研究生理和疾病性别差异背后的性染色体效应:四种核心基因型及更多。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-02-21 DOI: 10.1186/s13293-026-00837-5
Arthur P Arnold, Xuqi Chen, Michael N Grzybowski, Janelle M Ryan, Dale R Sengelaub, Tara Mohanroy, V Andree Furlan, Helen R Schmidtke, Jeremy W Prokop, Monika Tutaj, Julia L Ciosek, Theodore S Kalbfleisch, Liza O'Donnell, William Grisham, Shanie Landen, Lynn Malloy, Akiko Takizawa, Kai Li, Hayk Barseghyan, Carrie B Wiese, Laurent Vergnes, Karen Reue, Jonathan Wanagat, Helen Skaletsky, David C Page, Vincent R Harley, Melinda R Dwinell, Aron M Geurts

Background: Previous research on Four Core Genotypes and XY* mice has been instrumental in establishing important effects of sex-chromosome complement that cause sex differences in physiology and disease. We have generated rat models using similar modifications of the testis-determining gene Sry, to produce XX and XY rats with the same type of gonad, as well as XO, XXY and XYY rats with varying gonads. The models permit discovery of novel sex-chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype, and test for effects of different numbers of X or Y chromosomes.

Methods: XY rats were created with an autosomal transgene of Sry, producing XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females. Interbreeding of these lines produced rats with interesting combinations of sex chromosomes and gonads: XO, XX, XY, XXY rats with ovaries; and XO, XX, XY, XXY, and XYY rats with testes. These groups can be compared to detect sex differences caused by sex-chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Other comparisons detect the effects of X or Y chromosome number (in gonadal females: XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY; in gonadal males: XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XX, XO vs. XY).

Results: We measured numerous phenotypes to characterize these models, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Phenotypes previously known to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development.

Conclusion: The results establish powerful new models to discriminate sex-chromosome and gonadal hormone effects that cause sex differences in rat physiology and disease.

背景:以往对四种核心基因型和XY*小鼠的研究有助于确立性染色体补体在生理和疾病中引起性别差异的重要作用。我们对睾丸决定基因Sry进行了类似的修饰,产生了具有相同性腺类型的XX和XY大鼠,以及具有不同性腺类型的XO、XXY和XYY大鼠。这些模型允许发现新的性染色体效应(XX vs. XY),这些效应导致了任何大鼠表型的性别差异,并测试了不同数量的X或Y染色体的影响。方法:用常染色体基因Sry克隆XY大鼠,产生具有睾丸的XX和XY后代。在其他大鼠中,使用CRISPR-Cas9技术去除启动睾丸分化的Y染色体因子,产生可生育的XY性腺雌性。这些系杂交产生的大鼠具有有趣的性染色体和性腺组合:XO、XX、XY、XXY大鼠有卵巢;睾丸大鼠XO、XX、XY、XXY、XYY。这些组可以进行比较,以检测由性染色体补体(XX vs XY)和/或性腺激素(有睾丸的大鼠vs有卵巢的大鼠)引起的性别差异。其他比较检测X或Y染色体数目的影响(在生殖期女性中:XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY;在生殖期男性中:XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XX, XO vs. XY)。结果:我们测量了许多表型来表征这些模型,包括性腺组织学、繁殖性能、肛门生殖器距离、生殖激素水平、身体和器官重量以及中枢神经系统性别二态性。血清睾酮水平在成年XX和XY性腺男性中是相当的。我们发现,在具有相同性腺类型的XX大鼠和XY大鼠中,先前已知的通过性腺激素作用进行性别分化的表型是相似的,这表明具有相同性腺类型的XX大鼠和XY大鼠在不同发育阶段的性腺激素水平相当。结论:该结果为鉴别大鼠生理和疾病中性别差异的性染色体和性腺激素效应建立了强有力的新模型。
{"title":"Sry-modified laboratory rat lines to study sex-chromosome effects underlying sex differences in physiology and disease: four core genotypes and more.","authors":"Arthur P Arnold, Xuqi Chen, Michael N Grzybowski, Janelle M Ryan, Dale R Sengelaub, Tara Mohanroy, V Andree Furlan, Helen R Schmidtke, Jeremy W Prokop, Monika Tutaj, Julia L Ciosek, Theodore S Kalbfleisch, Liza O'Donnell, William Grisham, Shanie Landen, Lynn Malloy, Akiko Takizawa, Kai Li, Hayk Barseghyan, Carrie B Wiese, Laurent Vergnes, Karen Reue, Jonathan Wanagat, Helen Skaletsky, David C Page, Vincent R Harley, Melinda R Dwinell, Aron M Geurts","doi":"10.1186/s13293-026-00837-5","DOIUrl":"10.1186/s13293-026-00837-5","url":null,"abstract":"<p><strong>Background: </strong>Previous research on Four Core Genotypes and XY* mice has been instrumental in establishing important effects of sex-chromosome complement that cause sex differences in physiology and disease. We have generated rat models using similar modifications of the testis-determining gene Sry, to produce XX and XY rats with the same type of gonad, as well as XO, XXY and XYY rats with varying gonads. The models permit discovery of novel sex-chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype, and test for effects of different numbers of X or Y chromosomes.</p><p><strong>Methods: </strong>XY rats were created with an autosomal transgene of Sry, producing XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females. Interbreeding of these lines produced rats with interesting combinations of sex chromosomes and gonads: XO, XX, XY, XXY rats with ovaries; and XO, XX, XY, XXY, and XYY rats with testes. These groups can be compared to detect sex differences caused by sex-chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Other comparisons detect the effects of X or Y chromosome number (in gonadal females: XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY; in gonadal males: XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XX, XO vs. XY).</p><p><strong>Results: </strong>We measured numerous phenotypes to characterize these models, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Phenotypes previously known to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development.</p><p><strong>Conclusion: </strong>The results establish powerful new models to discriminate sex-chromosome and gonadal hormone effects that cause sex differences in rat physiology and disease.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776001","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}
引用次数: 0
Sex-specific hypothalamic PVN transcriptomic signatures of blood pressure autonomic regulation and neuroinflammation in hypertension. 高血压患者血压自主调节和神经炎症的性别特异性下丘脑PVN转录组特征。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-02-21 DOI: 10.1186/s13293-026-00855-3
V J Duque, J V Nani, M Jovanovic, M Lozić, O Šarenac, A G Pauža, D M Murphy, N Z Japundžić-Žigon, A S Mecawi

Introduction: Hypertension is a multifactorial condition of unknown cause that affects more than 1.28 billion adults worldwide and impacts the sexes differently. The hypothalamic paraventricular nucleus (PVN) plays a central role in blood pressure (BP) regulation by modulating sympathetic tone and releasing neuropeptides that affect the cardiovascular function. In this study, we investigated the transcriptomic profile of the PVN in hypertensive strains and across sexes, aiming to identify novel sex-specific molecular pathways involved in the regulation of BP.

Methods: To accomplish this goal, we sequenced RNA from the PVNs of normotensive Wistar rats and Spontaneously Hypertensive Rats (SHR), both male and female. We also performed a cardiovascular assessment based on blood pressure (BP) measurements and their variability.

Results: Cardiovascular assessment revealed higher SBP in SHRs than in Wistar rats; while males exhibited greater autonomic regulation associated with vasomotor and neurohumoral mechanisms, while females maintained comparable SBP levels primarily through an increase in heart rate, reflecting distinct autonomic adaptations. Hypertension also impacted gene expression, with influences from both the hypertensive state and sex. Compared with female SHRs, male SHRs presented a marked increase in differentially expressed genes (DEGs). Key upregulated genes in males, including Brain-Derived Neurotrophic Factor (Bdnf) and Hypocretin (Hcrt), have already been linked to elevated BP, and Angiotensin II Receptor Type 1 (Agtr1a) is possibly associated with increased SBP-VLF variability, which serves as an indirect measure of enhanced sympathetic tone. In contrast, the female transcriptomic signature was characterized by the upregulation of anti-inflammatory pathways, with upregulation of NLR Family CARD Domain Containing 3 (Nlrc3) and Paired Ig-like Receptor B (Pirb), and downregulation of Absent in Melanoma 2 (Aim2), and S100 Calcium Binding Protein B (S100b). Notably, genes associated with neuroinflammation, such as the downregulation of Annexin A1 (Anxa1) and the upregulation of Solute Carrier Family 11 Member 1 (Slc11a1), were consistently altered in both sexes.

Conclusion: These results provide new insights into the cardiovascular and molecular basis of sex differences in hypertension, suggesting distinct neurohumoral autonomic profile in males, whereas in females a greater anti-inflammatory component. These findings offer a valuable framework for developing future sex-specific therapeutic strategies.

导读:高血压是一种病因不明的多因素疾病,影响全球超过12.8亿成年人,且影响性别不同。下丘脑室旁核(PVN)通过调节交感神经张力和释放影响心血管功能的神经肽,在调节血压(BP)中发挥核心作用。在这项研究中,我们研究了高血压品系和性别间PVN的转录组学特征,旨在发现参与BP调节的新的性别特异性分子途径。方法:为了实现这一目标,我们对正常血压Wistar大鼠和自发性高血压大鼠(SHR)的pvn进行了RNA测序。我们还进行了基于血压(BP)测量及其变异性的心血管评估。结果:心血管功能评估显示shs的收缩压高于Wistar大鼠;而男性表现出与血管舒缩和神经体液机制相关的更大的自主调节,而女性主要通过心率的增加来维持类似的收缩压水平,反映出独特的自主适应。高血压也影响基因表达,受高血压状态和性别的影响。与雌性SHRs相比,雄性SHRs的差异表达基因(DEGs)显著增加。男性中的关键上调基因,包括脑源性神经营养因子(Bdnf)和下丘脑分泌素(Hcrt),已经与血压升高有关,血管紧张素II受体1型(Agtr1a)可能与SBP-VLF变异性增加有关,这是交感神经张力增强的间接测量指标。相比之下,女性的转录组特征表现为抗炎途径上调,NLR家族CARD Domain Containing 3 (Nlrc3)和配对的igg样受体B (Pirb)上调,黑色素瘤2 (Aim2)和S100钙结合蛋白B (S100b)下调。值得注意的是,与神经炎症相关的基因,如膜联蛋白A1 (Anxa1)的下调和溶质载体家族11成员1 (Slc11a1)的上调,在两性中都发生了一致的改变。结论:这些结果为高血压性别差异的心血管和分子基础提供了新的见解,表明男性有不同的神经体液自主谱,而女性有更大的抗炎成分。这些发现为未来发展针对性别的治疗策略提供了一个有价值的框架。
{"title":"Sex-specific hypothalamic PVN transcriptomic signatures of blood pressure autonomic regulation and neuroinflammation in hypertension.","authors":"V J Duque, J V Nani, M Jovanovic, M Lozić, O Šarenac, A G Pauža, D M Murphy, N Z Japundžić-Žigon, A S Mecawi","doi":"10.1186/s13293-026-00855-3","DOIUrl":"10.1186/s13293-026-00855-3","url":null,"abstract":"<p><strong>Introduction: </strong>Hypertension is a multifactorial condition of unknown cause that affects more than 1.28 billion adults worldwide and impacts the sexes differently. The hypothalamic paraventricular nucleus (PVN) plays a central role in blood pressure (BP) regulation by modulating sympathetic tone and releasing neuropeptides that affect the cardiovascular function. In this study, we investigated the transcriptomic profile of the PVN in hypertensive strains and across sexes, aiming to identify novel sex-specific molecular pathways involved in the regulation of BP.</p><p><strong>Methods: </strong>To accomplish this goal, we sequenced RNA from the PVNs of normotensive Wistar rats and Spontaneously Hypertensive Rats (SHR), both male and female. We also performed a cardiovascular assessment based on blood pressure (BP) measurements and their variability.</p><p><strong>Results: </strong>Cardiovascular assessment revealed higher SBP in SHRs than in Wistar rats; while males exhibited greater autonomic regulation associated with vasomotor and neurohumoral mechanisms, while females maintained comparable SBP levels primarily through an increase in heart rate, reflecting distinct autonomic adaptations. Hypertension also impacted gene expression, with influences from both the hypertensive state and sex. Compared with female SHRs, male SHRs presented a marked increase in differentially expressed genes (DEGs). Key upregulated genes in males, including Brain-Derived Neurotrophic Factor (Bdnf) and Hypocretin (Hcrt), have already been linked to elevated BP, and Angiotensin II Receptor Type 1 (Agtr1a) is possibly associated with increased SBP-VLF variability, which serves as an indirect measure of enhanced sympathetic tone. In contrast, the female transcriptomic signature was characterized by the upregulation of anti-inflammatory pathways, with upregulation of NLR Family CARD Domain Containing 3 (Nlrc3) and Paired Ig-like Receptor B (Pirb), and downregulation of Absent in Melanoma 2 (Aim2), and S100 Calcium Binding Protein B (S100b). Notably, genes associated with neuroinflammation, such as the downregulation of Annexin A1 (Anxa1) and the upregulation of Solute Carrier Family 11 Member 1 (Slc11a1), were consistently altered in both sexes.</p><p><strong>Conclusion: </strong>These results provide new insights into the cardiovascular and molecular basis of sex differences in hypertension, suggesting distinct neurohumoral autonomic profile in males, whereas in females a greater anti-inflammatory component. These findings offer a valuable framework for developing future sex-specific therapeutic strategies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12964816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776050","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}
引用次数: 0
Walking to protect against cognitive decline: the role of APOE genotype and sex. 步行预防认知能力下降:APOE基因型和性别的作用。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-02-21 DOI: 10.1186/s13293-026-00860-6
Joel S Burma, Caterina Rosano, John R Best, Eleanor M Simonsick, Teresa Liu-Ambrose, Cindy K Barha

Background: The apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease; however, risk varies by sex and lifestyle. Regular physical activity is known to mitigate cognitive decline; whether the degree of benefit differs by APOE genotype, sex, and race remains unknown.

Methods: Analyses utilized data from 2,985 participants in the Health, Aging, and Body Composition (HABC) cohort, comprising community-dwelling black and white older adults followed for 10 years. Cognitive performance was assessed multiple times across the 10 years using the Digit Symbol Substitution Test (DSST) for executive functions and processing speed and the Modified Mini-Mental State Examination (3MS) for global cognition. APOE genotypes were categorized into ε2, ε3, and ε4 groups. Annual self-reported walking time was used to quantify physical activity. Linear mixed models and latent growth curve modeling examined the interactions between APOE genotype, sex, and walking on cognitive trajectories with adjustments for race, study location, health score, age, education attained, and body mass index.

Results: APOE ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared to ε3 carriers, irrespective of sex (all β<-0.13, all p < 0.004). APOE ε2 was protective longitudinally for 3MS in females only (β = 0.15, p < 0.002). Walking showed the strongest protective effect in APOE ε4 carriers for females and males in the rate of change of DSST and 3MS scores (all β > 0.27, all p < 0.044).

Discussion: These findings underscore the importance of public messaging about the benefits of regular physical activity for retaining cognitive function especially for persons genetically at heightened risk.

背景:载脂蛋白E (APOE) ε4等位基因是迟发性阿尔茨海默病的危险因素;然而,风险因性别和生活方式而异。众所周知,有规律的体育活动可以减轻认知能力下降;是否获益程度因APOE基因型、性别和种族而异仍不得而知。方法:分析利用来自2985名健康、衰老和身体组成(HABC)队列参与者的数据,包括社区居住的黑人和白人老年人,随访10年。在10年的时间里,使用数字符号替代测试(DSST)对执行功能和处理速度进行了多次认知表现评估,并使用改进的迷你精神状态测试(3MS)对全球认知进行了评估。APOE基因型分为ε2、ε3和ε4组。每年自我报告的步行时间被用来量化身体活动。线性混合模型和潜在生长曲线模型检验了APOE基因型、性别和认知轨迹上行走之间的相互作用,并对种族、研究地点、健康评分、年龄、受教育程度和体重指数进行了调整。结果:与ε3携带者相比,APOE ε4携带者在DSST和3MS评分上的下降幅度更大,与性别无关(均β 0.27,均p)。讨论:这些发现强调了公共信息的重要性,即定期体育锻炼对保持认知功能的益处,特别是对于遗传风险较高的人。
{"title":"Walking to protect against cognitive decline: the role of APOE genotype and sex.","authors":"Joel S Burma, Caterina Rosano, John R Best, Eleanor M Simonsick, Teresa Liu-Ambrose, Cindy K Barha","doi":"10.1186/s13293-026-00860-6","DOIUrl":"https://doi.org/10.1186/s13293-026-00860-6","url":null,"abstract":"<p><strong>Background: </strong>The apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease; however, risk varies by sex and lifestyle. Regular physical activity is known to mitigate cognitive decline; whether the degree of benefit differs by APOE genotype, sex, and race remains unknown.</p><p><strong>Methods: </strong>Analyses utilized data from 2,985 participants in the Health, Aging, and Body Composition (HABC) cohort, comprising community-dwelling black and white older adults followed for 10 years. Cognitive performance was assessed multiple times across the 10 years using the Digit Symbol Substitution Test (DSST) for executive functions and processing speed and the Modified Mini-Mental State Examination (3MS) for global cognition. APOE genotypes were categorized into ε2, ε3, and ε4 groups. Annual self-reported walking time was used to quantify physical activity. Linear mixed models and latent growth curve modeling examined the interactions between APOE genotype, sex, and walking on cognitive trajectories with adjustments for race, study location, health score, age, education attained, and body mass index.</p><p><strong>Results: </strong>APOE ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared to ε3 carriers, irrespective of sex (all β<-0.13, all p < 0.004). APOE ε2 was protective longitudinally for 3MS in females only (β = 0.15, p < 0.002). Walking showed the strongest protective effect in APOE ε4 carriers for females and males in the rate of change of DSST and 3MS scores (all β > 0.27, all p < 0.044).</p><p><strong>Discussion: </strong>These findings underscore the importance of public messaging about the benefits of regular physical activity for retaining cognitive function especially for persons genetically at heightened risk.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146775963","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}
引用次数: 0
Sex chromosome-dependent epigenetic regulation underlies sex-specific H4 acetylation at the aromatase promoter in the developing mouse amygdala. 性染色体依赖性表观遗传调控是发育中的小鼠杏仁核中芳香化酶启动子的性别特异性H4乙酰化的基础。
IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2026-02-19 DOI: 10.1186/s13293-026-00854-4
C Sosa, L E Cabrera-Zapata, C D Cisternas, M A Arevalo, M J Cambiasso

Background: Sexual differentiation of the brain is a complex ontogenetic process orchestrated by genetic and hormonal influences, leading to sex‑specific physiological and behavioral traits in adulthood. In mammals, the sex chromosome complement (SCC) contributes to this process by encoding unequal genetic information in XX and XY cells. Furthermore, SCC upregulates aromatase and estrogen receptor β (ERβ) expression in amygdala neurons of XY compared to XX embryos at embryonic day (E) 14. These molecules are critically implicated in the steroid-dependent programming of neural circuits during the subsequent critical window of sexual differentiation (E17-PN10). Since epigenetic mechanisms play a key role in specific target gene expression forming a layer of gene regulation, we aimed to contribute to a better understanding of their impact on the sexual differentiation of the brain.

Methods: Four Core Genotypes mouse model was employed to study the epigenetic machinery involved in DNA methylation and histone deacetylation in different brain regions (amygdala, hypothalamus, and cortex) to elucidate the underlying epigenetic landscape at E14 by RT-qPCR. Amygdala primary neuronal cultures were then established to evaluate the epigenetic regulation of Cyp19a1 (aromatase) and Esr2 (ERβ) expression. To assess this, pharmacological inhibition of DNA methylation, using zebularine, as well as Chromatin Immunoprecipitation (ChIP-qPCR) assays were performed.

Results: Sex-specific expression of DNA methyltransferases 3a and 3b, along with histone deacetylases 2 and 8, was higher in XX than XY embryos in a region- and developmental stage- dependent manner. Pharmacological inhibition of DNA methylation did not significantly alter aromatase expression in male or female amygdala neuronal cultures under the conditions tested. However, ChIP-qPCR assays revealed a selective enrichment of Acetyl-H4 at the Cyp19a1 promoter in male cultures that was not observed in females. No significant enrichment of the examined epigenetic marks was detected at the Esr2 promoter.

Conclusions: Acetylation of histone H4 contributes to promoting the higher Cyp19a1 expression previously observed in male neurons. Our findings support a model in which SCC plays a role in the epigenetic regulation of aromatase, a key enzyme involved in hormone-driven sexual differentiation of the male brain. Furthermore, the presence of two X chromosomes shapes a distinct epigenetic landscape in the brain during early development, highlighting the influence of chromosomal sex on the neurodevelopmental programming.

背景:大脑的性别分化是一个复杂的个体发生过程,受遗传和激素的影响,导致成年期性别特异性的生理和行为特征。在哺乳动物中,性染色体补体(SCC)通过编码XX和XY细胞中的不平等遗传信息来参与这一过程。此外,与XX胚胎相比,SCC在胚胎日(E) 14上调XY杏仁核神经元中芳香化酶和雌激素受体β (ERβ)的表达。这些分子在随后的性分化关键窗口期(E17-PN10)中与神经回路的类固醇依赖性编程密切相关。由于表观遗传机制在特定靶基因表达中起着关键作用,形成了一层基因调控,我们的目的是为了更好地理解它们对大脑性别分化的影响。方法:采用4种Core基因型小鼠模型,研究不同脑区(杏仁核、下丘脑和皮层)DNA甲基化和组蛋白去乙酰化的表观遗传机制,通过RT-qPCR阐明E14期潜在的表观遗传景观。然后建立杏仁核原代神经元培养,以评估Cyp19a1(芳香化酶)和Esr2 (ERβ)表达的表观遗传调控。为了评估这一点,使用斑马碱进行了DNA甲基化的药理抑制,以及染色质免疫沉淀(ChIP-qPCR)测定。结果:DNA甲基转移酶3a和3b以及组蛋白去乙酰化酶2和8的性别特异性表达在XX胚胎中高于XY胚胎,并以区域和发育阶段依赖的方式表达。在测试条件下,DNA甲基化的药理抑制并没有显著改变雄性或雌性杏仁核神经元中芳香酶的表达。然而,ChIP-qPCR分析显示,在雄性培养物中,Cyp19a1启动子处乙酰- h4选择性富集,而在雌性培养物中未观察到。在Esr2启动子处未检测到显著的表观遗传标记富集。结论:组蛋白H4的乙酰化有助于促进先前在雄性神经元中观察到的Cyp19a1的高表达。我们的研究结果支持了SCC在芳香化酶的表观遗传调控中发挥作用的模型,芳香化酶是一种参与男性大脑激素驱动的性别分化的关键酶。此外,两条X染色体的存在在大脑早期发育过程中形成了一个独特的表观遗传景观,突出了染色体性别对神经发育程序的影响。
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Biology of Sex Differences
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