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Sex Differences in Human Brain Structure at Birth. 人类出生时大脑结构的性别差异。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-17 DOI: 10.1186/s13293-024-00657-5
Yumnah T Khan, Alex Tsompanidis, Marcin A Radecki, Lena Dorfschmidt, Topun Austin, John Suckling, Carrie Allison, Meng-Chuan Lai, Richard A I Bethlehem, Simon Baron-Cohen

Background: Sex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain.

Methods: Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0-28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development.

Results: On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts).

Conclusions: Our findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain.

背景:人类大脑解剖学中的性别差异已被充分证明,但对早期发育过程的研究仍显不足。新生儿期是大脑发育的关键阶段,可为了解产前和产后早期因素在形成大脑性别差异方面所起的作用提供重要信息。方法:在此,我们利用正在开展的人类连接组项目的数据,评估了 514 名 0-28 天大的新生儿(236 名出生时指定的女性和 278 名出生时指定的男性)在整体和区域脑容量方面的平均性别差异。我们还评估了性别与年龄的相互作用,以研究出生后早期大脑发育的性别差异:结果:平均而言,即使控制了出生体重,男性的颅内体积和大脑总体积也明显更大。在控制了大脑总体积后,女性的皮层灰质总体积明显更大,而男性的白质总体积更大。在控制了区域比较中的脑总量后,女性胼胝体的白质体积明显增加,双侧海马旁回(后部)、左扣带回前部、双侧顶叶和左尾状核的灰质体积增加。男性右侧颞内侧和颞下回(后部)以及右侧丘脑下核的灰质体积明显增加。效应大小从区域比较的小到整体比较的大不等。左侧扣带回前部和左侧颞上回(后部)存在显著的性别-年龄交互作用:我们的研究结果表明,大脑结构的性别差异在出生时就已经存在,并在出生后早期发育过程中保持相对稳定,这凸显了产前因素在大脑性别差异形成过程中的重要作用。
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引用次数: 0
Sex differences in prelimbic cortex calcium dynamics during stress and fear learning. 压力和恐惧学习过程中前缘皮层钙动态的性别差异
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-16 DOI: 10.1186/s13293-024-00653-9
Ignacio Marin-Blasco, Giorgia Vanzo, Joaquin Rusco-Portabella, Lucas Perez-Molina, Leire Romero, Antonio Florido, Raul Andero

In recent years, research has progressively increased the importance of considering sex differences in stress and fear memory studies. Many studies have traditionally focused on male subjects, potentially overlooking critical differences with females. Emerging evidence suggests that males and females can exhibit distinct behavioral and neurophysiological responses to stress and fear conditioning. These differences may be attributable to variations in hormone levels, brain structure, and neural circuitry, particularly in regions such as the prefrontal cortex (PFC). In the present study, we explored sex differences in prelimbic cortex (PL) calcium activity in animals submitted to immobilization stress (IMO), fear conditioning (FC), and fear extinction (FE). While no significant sex differences were found in behavioral responses, we did observe differences in several PL calcium activity parameters. To determine whether these results were related to behaviors beyond stress and fear memory, we conducted correlation studies between the movement of the animals and PL activity during IMO and freezing behavior during FC and FE. Our findings revealed a clear correlation between PL calcium activity with movement during stress exposure and freezing behavior, with no sex differences observed in these correlations. These results suggest a significant role for the PL in movement and locomotion, in addition to its involvement in fear-related processes. The inclusion of both female and male subjects is crucial for studies like this to fully understand the role of the PFC and other brain areas in stress and fear responses. Recognizing sex differences enhances our comprehension of brain function and can lead to more personalized and effective approaches in the study and treatment of stress and fear-related conditions.

近年来,研究逐渐增加了在压力和恐惧记忆研究中考虑性别差异的重要性。传统上,许多研究都以男性受试者为研究对象,可能忽略了与女性的关键差异。新的证据表明,男性和女性对压力和恐惧条件反射会表现出不同的行为和神经生理反应。这些差异可能归因于激素水平、大脑结构和神经回路的变化,尤其是前额叶皮层(PFC)等区域的变化。在本研究中,我们探讨了动物在接受固定应激(IMO)、恐惧条件反射(FC)和恐惧消退(FE)后边缘前皮层(PL)钙活动的性别差异。虽然在行为反应方面没有发现明显的性别差异,但我们确实观察到了几种前边缘皮层钙活动参数的差异。为了确定这些结果是否与应激和恐惧记忆以外的行为有关,我们对 IMO 期间动物的运动和 PL 活性以及 FC 和 FE 期间的冻结行为进行了相关性研究。我们的研究结果表明,PL钙活性与应激暴露时的运动和冻结行为之间存在明显的相关性,而且在这些相关性中没有观察到性别差异。这些结果表明,除了参与恐惧相关过程外,钙离子在运动和运动中也扮演着重要角色。要想充分了解前脑功能区和其他脑区在压力和恐惧反应中的作用,同时纳入女性和男性受试者对于此类研究至关重要。认识到性别差异会增强我们对大脑功能的理解,并能在研究和治疗压力和恐惧相关疾病时采用更加个性化和有效的方法。
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引用次数: 0
Isolated during adolescence: long-term impact on social behavior, pain sensitivity, and the oxytocin system in male and female rats. 青春期隔离:对雌雄大鼠社交行为、疼痛敏感性和催产素系统的长期影响。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-15 DOI: 10.1186/s13293-024-00655-7
Akseli P Graf, Anita C Hansson, Rainer Spanagel

Background: Adolescent social isolation (ASI) has profound long-term effects on behavioral and neural development. Despite this, the specific long-term impact of ASI during different adolescent stages and across sexes remain underexplored.

Methods: Our study addresses this gap by examining the effects of early- and late- adolescent social isolation on both male and female rats. Rats were either isolated (or group-housed) starting from PD 21 (early) or PD 42 (late) for three weeks and then rehoused into groups. In adulthood (PD 90), rats underwent a battery of tests: elevated plus-maze, open field, novel object recognition, social interaction and social recognition memory and hotplate tests. Finally, we analyzed oxytocin receptor binding in several regions in the brains of a second cohort of rats.

Results: Both, male and female rats from the late adolescent social isolation (LASI) groups spent significantly less time interacting in the social interaction test. Additionally, we observed a general decrease in social recognition memory regardless of sex. Both male ASI groups demonstrated heightened thermal pain sensitivity, while the opposite was observed in early adolescent social isolation (EASI) female rats. In the brain, we observed changes in oxytocin receptor (OTR) binding in the paraventricular nucleus of the hypothalamus (PVN) and paraventricular nucleus of the thalamus (PVT) and central amygdala (CeA) with the largest changes in EASI and LASI female rats.

Conclusion: Our model demonstrates long-lasting alterations on behavior and oxytocin receptor binding levels following ASI providing insights into the long-term effects of ASI in a time- and sex-specific manner.

背景:青少年社会隔离(ASI)会对行为和神经发育产生深远的长期影响。尽管如此,不同青春期阶段和不同性别的青少年社会隔离的具体长期影响仍未得到充分探索:我们的研究通过考察青春期早期和晚期社会隔离对雄性和雌性大鼠的影响来填补这一空白。大鼠从青春期21(早期)或42(晚期)开始被隔离(或群居)三周,然后重新群居。在成年期(PD 90),大鼠接受了一系列测试:高架迷宫、开阔地、新物体识别、社会互动和社会识别记忆以及热板测试。最后,我们分析了第二批大鼠大脑中多个区域的催产素受体结合情况:结果:青春期晚期社会隔离(LASI)组的雄性和雌性大鼠在社会互动测试中的互动时间都明显减少。此外,我们还观察到,无论性别如何,大鼠的社会识别记忆力普遍下降。两组雄性 ASI 大鼠的热痛敏感性都有所提高,而青春期早期社会隔离(EASI)雌性大鼠的情况则恰恰相反。在大脑中,我们观察到下丘脑室旁核(PVN)、丘脑室旁核(PVT)和杏仁核中央(CeA)的催产素受体(OTR)结合发生了变化,其中EASI和LASI雌性大鼠的变化最大:我们的模型显示了 ASI 对大鼠行为和催产素受体结合水平的持久改变,这有助于深入了解 ASI 在时间和性别上的特异性长期影响。
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引用次数: 0
Integration of long-read sequencing, DNA methylation and gene expression reveals heterogeneity in Y chromosome segment lengths in phenotypic males with 46,XX testicular disorder/difference of sex development. 长线程测序、DNA甲基化和基因表达的整合揭示了46,XX睾丸疾病/性别发育差异表型男性Y染色体片段长度的异质性。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-08 DOI: 10.1186/s13293-024-00654-8
Agnethe Berglund, Emma B Johannsen, Anne Skakkebæk, Simon Chang, Julia Rohayem, Sandra Laurentino, Arne Hørlyck, Simon O Drue, Ebbe Norskov Bak, Jens Fedder, Frank Tüttelmann, Jörg Gromoll, Jesper Just, Claus H Gravholt

Background: 46,XX testicular disorder/difference of sex development (46,XX DSD) is a rare congenital condition, characterized by a combination of the typical female sex chromosome constitution, 46,XX, and a variable male phenotype. In the majority of individuals with 46,XX DSD, a Y chromosome segment containing the sex-determining region gene (SRY) has been translocated to the paternal X chromosome. However, the precise genomic content of the translocated segment and the genome-wide effects remain elusive.

Methods: We performed long-read DNA sequencing, RNA sequencing and DNA methylation analyses on blood samples from 46,XX DSD (n = 11), male controls (46,XY; variable cohort sizes) and female controls (46,XX; variable cohort sizes), in addition to RNA sequencing and DNA methylation analysis on blood samples from males with Klinefelter syndrome (47,XXY, n = 22). We also performed clinical measurements on all 46,XX DSD and a subset of 46,XY (n = 10).

Results: We identified variation in the translocated Y chromosome segments, enabling subcategorization into 46,XX DSD (1) lacking Y chromosome material (n = 1), (2) with short Yp arms (breakpoint at 2.7-2.8 Mb, n = 2), (3) with medium Yp arms (breakpoint at 7.3 Mb, n = 1), and (4) with long Yp arms (n = 7), including deletions of AMELY, TBLY1 and in some cases PRKY. We also identified variable expression of the X-Y homologues PRKY and PRKX. The Y-chromosomal transcriptome and methylome reflected the Y chromosome segment lengths, while changes to autosomal and X-chromosomal regions indicated global effects. Furthermore, transcriptional changes tentatively correlated with phenotypic traits of 46,XX DSD, including reduced height, lean mass and testicular size.

Conclusion: This study refines our understanding of the genetic composition in 46,XX DSD, describing the translocated Y chromosome segment in more detail than previously and linking variability herein to genome-wide changes in the transcriptome and methylome.

背景:46,XX睾丸发育障碍/性别发育差异(46,XX DSD)是一种罕见的先天性疾病,其特征是典型的女性性染色体结构(46,XX)和可变的男性表型的结合。在大多数 46,XX DSD 患者中,含有性别决定区基因(SRY)的 Y 染色体片段被易位到父方的 X 染色体上。然而,该易位片段的精确基因组内容及其对全基因组的影响仍然难以捉摸:我们对 46,XX DSD(n = 11)、男性对照组(46,XY;队列大小不一)和女性对照组(46,XX;队列大小不一)的血液样本进行了长线程 DNA 测序、RNA 测序和 DNA 甲基化分析,此外还对 Klinefelter 综合征(47,XXY,n = 22)男性患者的血液样本进行了 RNA 测序和 DNA 甲基化分析。我们还对所有 46,XX DSD 和 46,XY 子集(n = 10)进行了临床测量:结果:我们确定了易位 Y 染色体片段的变异,从而将 46,XX DSD 分成以下几类:(1)缺乏 Y 染色体材料(n = 1);(2)短 Yp 臂(断点在 2.7-2.8 Mb,n = 2);(3)中等 Yp 臂(断点在 7.3 Mb,n = 1);(4)长 Yp 臂(n = 7),包括 AMELY、TBLY1 和某些 PRKY 的缺失。我们还发现了 X-Y 同源物 PRKY 和 PRKX 的可变表达。Y 染色体转录组和甲基组反映了 Y 染色体片段的长度,而常染色体和 X 染色体区域的变化则显示了整体效应。此外,转录变化还与 46,XX DSD 的表型特征(包括身高、瘦体重和睾丸大小的减少)初步相关:这项研究完善了我们对 46,XX DSD 遗传组成的认识,比以前更详细地描述了易位的 Y 染色体片段,并将其中的变异与转录组和甲基组的全基因组变化联系起来。
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引用次数: 0
Female-bias in systemic lupus erythematosus: How much is the X chromosome to blame? 系统性红斑狼疮的女性偏爱:X染色体的责任有多大?
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-07 DOI: 10.1186/s13293-024-00650-y
Adriana A Vieira, Inês Almada-Correia, Joana Inácio, Patrícia Costa-Reis, S T da Rocha

Systemic lupus erythematosus (SLE or lupus) is an immune-mediated disease associated with substantial medical burden. Notably, lupus exhibits a striking female bias, with women having significantly higher susceptibility compared to men, up to 14-fold higher in some ethnicities. Supernumerary X chromosome syndromes, like Klinefelter (XXY) and Triple X syndrome (XXX), also present higher SLE prevalence, whereas Turner syndrome (XO) displays lower prevalence. Taken together, SLE prevalence in different X chromosome dosage sceneries denotes a relationship between the number of X chromosomes and the risk of developing lupus. The dosage of X-linked genes, many of which play roles in the immune system, is compensated between males and females through the inactivation of one of the two X chromosomes in female cells. X-chromosome inactivation (XCI) initiates early in development with a random selection of which X chromosome to inactivate, a choice that is then epigenetically maintained in the daughter cells. This process is regulated by the X-Inactive-Specific Transcript (XIST), encoding for a long non-coding RNA, exclusively expressed from the inactive X chromosome (Xi). XIST interacts with various RNA binding proteins and chromatin modifiers to form a ribonucleoprotein (RNP) complex responsible for the transcriptional silencing and heterochromatinization of the Xi. This ensures stable silencing of most genes on the X chromosome, with only a few genes able to escape this process. Recent findings suggest that the molecular components involved in XCI, or their dysregulation, contribute to the pathogenesis of lupus. Indeed, nonrandom XCI, elevated gene escape from XCI, and the autoimmune potential of the XIST RNP complex have been suggested to contribute to auto-immune diseases, such as lupus. This review examines these current hypotheses concerning how this dosage compensation mechanism might impact the development of lupus, shedding light on potential mechanisms underlying the pathogenesis of the disease.

系统性红斑狼疮(SLE 或狼疮)是一种由免疫介导的疾病,给患者带来沉重的医疗负担。值得注意的是,狼疮有明显的女性偏向,女性的易感性明显高于男性,在某些种族中,女性的易感性可高达男性的14倍。X 染色体超常综合征,如 Klinefelter(XXY)和三X 综合征(XXX),其系统性红斑狼疮发病率也较高,而特纳综合征(XO)的发病率则较低。总之,不同 X 染色体剂量情况下系统性红斑狼疮的发病率表明,X 染色体的数量与患狼疮的风险之间存在一定的关系。许多在免疫系统中发挥作用的 X 连锁基因的剂量是通过女性细胞中两条 X 染色体中的一条失活来在男性和女性之间进行补偿的。X 染色体失活(XCI)始于发育早期,随机选择要失活的 X 染色体,然后在子细胞中通过表观遗传学保持这一选择。这一过程受 X 非活性特异性转录本(XIST)的调控,该转录本编码一种非编码长 RNA,仅由非活性 X 染色体(Xi)表达。XIST 与各种 RNA 结合蛋白和染色质修饰因子相互作用,形成一个核糖核蛋白(RNP)复合物,负责 Xi 的转录沉默和异染色质化。这确保了 X 染色体上大多数基因的稳定沉默,只有少数基因能够逃脱这一过程。最近的研究结果表明,参与 XCI 的分子成分或它们的失调有助于红斑狼疮的发病机制。事实上,非随机 XCI、基因从 XCI 中逃逸的程度升高以及 XIST RNP 复合物的自身免疫潜能都被认为是红斑狼疮等自身免疫性疾病的诱因。这篇综述探讨了目前关于剂量补偿机制如何影响红斑狼疮发病的假设,揭示了该病发病机制的潜在机制。
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引用次数: 0
Sex differences in symptoms following the administration of BNT162b2 mRNA COVID-19 vaccine in children below 5 years of age in Germany (CoVacU5): a retrospective cohort study. 德国 5 岁以下儿童接种 BNT162b2 mRNA COVID-19 疫苗(CoVacU5)后症状的性别差异:一项回顾性队列研究。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-26 DOI: 10.1186/s13293-024-00651-x
Jeanne Moor, Nicole Toepfner, Wolfgang C G von Meißner, Reinhard Berner, Matthias B Moor, Karolina Kublickiene, Christoph Strumann, Cho-Ming Chao

Background: Sex differences exist not only in the efficacy but also in adverse event rates of many vaccines. Here we compared the safety of BNT162b2 vaccine administered off-label in female and male children younger than 5 years in Germany.

Methods: This is a retrospective cohort study, in which we performed a post-hoc analysis of a dataset collected through an authentication-based survey of individuals having registered children aged 0-<5 years for vaccination against SARS-CoV-2 in six private practices and/or two lay person-initiated vaccination campaigns. We analyzed the safety profiles of the first 3 doses of 3-10 µg BNT162b2. Primary outcome was comparison in frequencies of 4 common post-vaccination symptom categories such as local, general, musculoskeletal symptoms and fever. Data were analyzed according to sex in bivariate analyses and regression models adjusting for age, weight, and dosage. Interaction between sex and BNT162b2 dosage was assessed. An active-comparator analysis was applied to compare post-vaccination symptoms after BNT162b2 versus non-SARS-CoV-2 vaccines.

Results: The dataset for the present analysis consisted of 7801 participants including 3842 females (49%) and 3977 males (51%) with an age of 3 years (median, interquartile: 2 years). Among individuals receiving 3 µg BNT162b2, no sex differences were noted, but after a first dose of 5-10 µg BNT162b2, local injection-site symptoms were more prevalent in girls compared to boys. In logistic regression, female sex was associated with higher odds of local symptoms, odds ratio (OR) of 1.33 (95% confidence interval [CI]: 1.15-1.55, p < 0.05) and general symptoms with OR 1.21 (95% CI: 1.01-1.44, p < 0.05). Following non-BNT162b2 childhood vaccinations, female sex was associated with a lower odds of post-vaccination musculoskeletal symptoms (OR: 0.29, 95% CI: 0.11-0.82, p < 0.05). An active comparator analysis between BNT162b2 and non-SARS-CoV-2 vaccinations revealed that female sex positively influenced the association between BNT162b2 vaccine type and musculoskeletal symptoms.

Conclusions: Sex differences exist in post-vaccination symptoms after BNT162b2 administration even in young children. These are of importance for the conception of approval studies, for post-vaccination monitoring and for future vaccination strategies (German Clinical Trials Register ID: DRKS00028759).

背景:许多疫苗不仅在效力上存在性别差异,在不良反应率上也是如此。在此,我们比较了德国 5 岁以下男女儿童在标签外接种 BNT162b2 疫苗的安全性:这是一项回顾性队列研究,我们对通过认证调查收集的数据集进行了事后分析,调查对象是登记有 0 岁儿童的个人:本次分析的数据集包括 7801 名参与者,其中女性 3842 名(占 49%),男性 3977 名(占 51%),年龄为 3 岁(中位数,四分位数之间为 2 岁)。在接受 3 µg BNT162b2 治疗的患者中,没有发现性别差异,但在首次接受 5-10 µg BNT162b2 治疗后,女孩出现注射部位局部症状的比例高于男孩。在逻辑回归中,女性出现局部症状的几率更高,几率比(OR)为 1.33(95% 置信区间 [CI]:1.15-1.55,P<0.05):1.33(95% 置信区间 [CI]:1.15-1.55,P 结论:接种疫苗后存在性别差异:即使是幼儿,接种 BNT162b2 后的症状也存在性别差异。这对审批研究的构思、疫苗接种后的监测以及未来的疫苗接种策略都具有重要意义(德国临床试验注册编号:DRKS00028759)。
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引用次数: 0
Sex-dependent effects of acute stress and alcohol exposure during adolescence on mRNA expression of brain signaling systems involved in reward and stress responses in young adult rats. 青春期急性应激和酒精暴露对年轻成年大鼠大脑奖赏和应激反应信号系统 mRNA 表达的性别依赖性影响
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-26 DOI: 10.1186/s13293-024-00649-5
Carlotta Gobbi, Laura Sánchez-Marín, María Flores-López, Dina Medina-Vera, Francisco Javier Pavón-Morón, Fernando Rodríguez de Fonseca, Antonia Serrano

Background: Adolescent stress and alcohol exposure increase the risk of maladaptive behaviors and mental disorders in adulthood, with distinct sex-specific differences. Understanding the mechanisms underlying these early events is crucial for developing targeted prevention and treatment strategies.

Methods: Male and female Wistar rats were exposed to acute restraint stress and intermittent alcohol during adolescence. We assessed lasting effects on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, and mRNA expression of genes related to corticotropin releasing hormone (CRH), neuropeptide Y (NPY), corticoid, opioid, and arginine vasopressin systems in the amygdala and hypothalamus.

Results: The main findings are as follows: (1) blood alcohol concentrations (BAC) increased after the final alcohol administration, but stressed males had lower BAC than non-stressed males; (2) Males gained significantly more weight than females; (3) Stressed females showed higher ACTH levels than non-stressed females, with no changes in males; (4) Stress increased CORT levels in males, while stressed, alcohol-treated females had lower CORT levels than non-stressed females; (5) CRH: Females had lower Crhr1 levels in the amygdala, while alcohol reduced Crhr2 levels in males but not females. Significant interactions among sex, stress, and alcohol were found in the hypothalamus, with distinct patterns between sexes; (6) NPY: In the amygdala, stress reduced Npy and Npy1r levels in males but increased them in females. Alcohol decreased Npy2r levels in males, with varied effects in females. Similar sex-specific patterns were observed in the hypothalamus; (7) Corticoid system: Stress and alcohol had complex, sex-dependent effects on Pomc, Nr3c1, and Nr3c2 in both brain regions; (8) Opioid receptors: Stress and alcohol blunted the elevated expression of Oprm1, Oprd1, and Oprk1 in the amygdala of males and the hypothalamus of females; (8) Vasopressin: Stress and alcohol interacted significantly to affect Avp and Avpr1a expression in the amygdala, with stronger effects in females. In the hypothalamus, alcohol increased Avp levels in females.

Conclusions: This study demonstrates that adolescent acute stress and alcohol exposure induce lasting, sex-specific alterations in systems involved in reward and stress responses. These findings emphasize the importance of considering sex differences in the prevention and management of HPA dysfunction and psychiatric disorders.

背景:青少年时期的压力和酗酒会增加成年后出现适应不良行为和精神障碍的风险,并具有明显的性别差异。了解这些早期事件的内在机制对于制定有针对性的预防和治疗策略至关重要:方法:雄性和雌性 Wistar 大鼠在青春期受到急性束缚应激和间歇性酒精的影响。我们评估了对血浆皮质酮(CORT)和促肾上腺皮质激素(ACTH)水平以及杏仁核和下丘脑中促肾上腺皮质激素释放激素(CRH)、神经肽 Y(NPY)、类皮质激素、阿片类和精氨酸加压素系统相关基因 mRNA 表达的持久影响:主要研究结果如下(结果:主要发现如下:(1) 血液中酒精浓度(BAC)在最后一次给药后升高,但应激男性的 BAC 水平低于非应激男性;(2) 男性体重增加明显多于女性;(3) 应激女性的促肾上腺皮质激素(ACTH)水平高于非应激女性,男性无变化;(4) 应激增加了男性的促肾上腺皮质激素(CORT)水平,而应激、酒精处理的女性的促肾上腺皮质激素(CORT)水平低于非应激女性;(5) CRH:杏仁核中女性的 Crhr1 水平较低,而酒精会降低男性的 Crhr2 水平,但不会降低女性的 Crhr2 水平。在下丘脑中发现了性别、压力和酒精之间的显著交互作用,不同性别之间有不同的模式;(6)NPY:在杏仁核中,压力降低了男性的 Npy 和 Npy1r 水平,但增加了女性的 Npy 和 Npy1r 水平。酒精会降低男性的 Npy2r 水平,但对女性的影响各不相同。在下丘脑中也观察到类似的性别特异性模式;(7)皮质类固醇系统:压力和酒精对两个脑区的 Pomc、Nr3c1 和 Nr3c2 都有复杂的性别依赖性影响;(8)阿片受体:压力和酒精削弱了男性杏仁核和女性下丘脑中 Oprm1、Oprd1 和 Oprk1 的表达;(8)血管加压素:压力和酒精对杏仁核中 Avp 和 Avpr1a 的表达有明显的交互作用,对女性的影响更大。在下丘脑中,酒精会增加女性的 Avp 水平:本研究表明,青少年急性应激反应和酒精暴露会诱导奖赏和应激反应系统发生持久的、有性别特异性的改变。这些发现强调了在预防和处理 HPA 功能障碍和精神疾病时考虑性别差异的重要性。
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引用次数: 0
Application and insights of targeted next-generation sequencing in a large cohort of 46,XY disorders of sex development in Chinese 定向新一代测序在中国 46,XY 性别发育障碍大样本中的应用和启示
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-16 DOI: 10.1186/s13293-024-00648-6
Hongyu Chen, Guangjie Chen, Fengxia Li, Yong Huang, Linfeng Zhu, Yijun Zhao, Ziyi Jiang, Xiang Yan, Lan Yu
46,XY disorders of sex development (46,XY DSD) are characterized by incomplete masculinization of genitalia with reduced androgenization. Accurate clinical management remains challenging, especially based solely on physical examination. Targeted next-generation sequencing (NGS) with known pathogenic genes provides a powerful tool for diagnosis efficiency. This study aims to identify the prevalent genetic variants by targeted NGS technology and investigate the diagnostic rate in a large cohort of 46,XY DSD patients, with most of them presenting atypical phenotypes. Two different DSD panels were developed for sequencing purposes, targeting a cohort of 402 patients diagnosed with 46,XY DSD, who were recruited from the Department of Urology at Children’s Hospital, Zhejiang University School of Medicine (Hangzhou, China). The detailed clinical characteristics were evaluated, and peripheral blood was collected for targeted panels to find the patients’ variants. The clinical significance of these variants was annotated according to American College of Medical Genetics and Genomics (ACMG) guidelines. A total of 108 variants across 42 genes were found in 107 patients, including 46 pathogenic or likely pathogenic variants, with 45.7%(21/46) being novel. Among these genes, SRD5A2, AR, FGFR1, LHCGR, NR5A1, CHD7 were the most frequently observed. Besides, we also detected some uncommon causative genes like SOS1, and GNAS. Oligogenic variants were also identified in 9 patients, including several combinations PROKR2/FGFR1/CYP11B1, PROKR2/ATRX, PROKR2/AR, FGFR1/LHCGR/POR, FGFR1/NR5A1, GATA4/NR5A1, WNT4/AR, MAP3K1/FOXL2, WNT4/AR, and SOS1/FOXL2. The overall genetic diagnostic rate was 11.2%(45/402), with an additional 15.4% (62/402) having variants of uncertain significance. Additionally, trio/duo patients had a higher genetic diagnostic rate (13.4%) compared to singletons (8.6%), with a higher proportion of singletons (15.1%) presenting variants of uncertain significance. In conclusion, targeted gene panels identified pathogenic variants in a Chinese 46,XY DSD cohort, expanding the genetic understanding and providing evidence for known pathogenic genes’ involvement. 46,XY disorders of sex development (46,XY DSD) are conditions where individuals don’t fully develop male genitalia due to reduced androgen hormones. Diagnosing these conditions based only on physical exams is difficult. This study used advanced genetic testing called targeted next-generation sequencing (NGS) to identify common genetic variations in a large group of 46,XY DSD patients, many of whom had unusual symptoms. We examined 402 patients with DSD and a 46,XY karyotype, focusing on 142 candidate genes related to sex development. We found genetic variations in 107 patients, including 45 that were likely responsible for their condition. Some of these variations were new discoveries. The most commonly affected genes were SRD5A2, AR, FGFR1, LHCGR, NR5A1, CHD7. We also found that some patients had va
46,XY性发育障碍(46,XY DSD)的特点是生殖器不完全男性化,雄激素分泌减少。准确的临床管理仍然具有挑战性,尤其是仅凭体格检查。已知致病基因的靶向新一代测序(NGS)为提高诊断效率提供了有力工具。本研究旨在通过靶向 NGS 技术鉴定普遍存在的基因变异,并调查一大批 46,XY DSD 患者的诊断率。为了测序目的,我们开发了两种不同的 DSD 面板,目标人群是浙江大学医学院附属儿童医院(中国杭州)泌尿外科的 402 名确诊为 46,XY DSD 的患者。研究人员对这些患者的详细临床特征进行了评估,并采集了他们的外周血进行靶向分析,以发现他们的变异基因。根据美国医学遗传学和基因组学学院(ACMG)指南,对这些变异的临床意义进行了注释。在107名患者的42个基因中共发现108个变异,包括46个致病或可能致病的变异,其中45.7%(21/46)为新变异。在这些基因中,SRD5A2、AR、FGFR1、LHCGR、NR5A1、CHD7是最常见的变异。此外,我们还发现了一些不常见的致病基因,如 SOS1 和 GNAS。我们还在 9 例患者中发现了寡基因变异,包括 PROKR2/FGFR1/CYP11B1、PROKR2/ATRX、PROKR2/AR、FGFR1/LHCGR/POR、FGFR1/NR5A1、GATA4/NR5A1、WNT4/AR、MAP3K1/FOXL2、WNT4/AR 和 SOS1/FOXL2。总体基因诊断率为 11.2%(45/402),另有 15.4%(62/402)的变异意义不确定。此外,三人/二人患者的基因诊断率(13.4%)高于单人患者(8.6%),单人患者中出现意义不确定变异的比例更高(15.1%)。总之,在中国 46,XY DSD 群体中,有针对性的基因面板鉴定出了致病变异,拓展了对遗传学的理解,并为已知致病基因的参与提供了证据。46,XY性发育障碍(46,XY DSD)是指由于雄性激素减少导致男性生殖器发育不完全。仅靠体格检查很难诊断出这些疾病。这项研究采用了先进的基因检测方法,即定向下一代测序(NGS),在一大群46,XY DSD患者中确定常见的基因变异,其中很多人都有不寻常的症状。我们研究了 402 名患有 DSD 且核型为 46,XY 的患者,重点研究了 142 个与性发育相关的候选基因。我们在 107 名患者中发现了基因变异,其中 45 个基因变异很可能是导致他们患病的原因。其中一些变异是新发现的。最常受影响的基因是 SRD5A2、AR、FGFR1、LHCGR、NR5A1 和 CHD7。我们还发现,一些患者的多个基因都存在变异,这表明遗传原因很复杂。总体而言,我们通过基因检测确诊了 11.2% 的患者,另有 15.4% 的患者结果不确定。与单独检测的患者相比,三人或两人(与父母一起)检测的患者诊断率更高。这项研究有助于我们进一步了解中国人群中 46,XY DSD 的遗传因素。该研究设计了两个基因片段,分别由142个和271个与性发育相关的候选基因组成,对402名46,XY DSD患者进行测序。在107名患者中发现了42个基因中的108个变异,其中46个被归类为致病或可能致病,包括几个新变异。SRD5A2、AR、FGFR1、LHCGR、NR5A1、CHD7 是最常见的变异基因。总体基因诊断率为11.2%,另有15.4%的患者存在意义不确定的变异,9名患者检测到寡源性变异,这表明46,XY DSD存在复杂的基因相互作用。与单基因患者(8.6%)相比,三基因/双基因患者的基因诊断率更高(13.4%),这凸显了父母基因数据的重要性。表型变异和潜在的遗传异质性凸显了46,XY DSD的复杂性,强调了进一步研究和多中心合作的必要性。
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引用次数: 0
Sex-specific molecular signature of mouse podocytes in homeostasis and in response to pharmacological challenge with rapamycin 小鼠荚膜细胞在体内平衡和雷帕霉素药理作用下的性别特异性分子特征
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-15 DOI: 10.1186/s13293-024-00647-7
Ola Al-Diab, Christin Sünkel, Eric Blanc, Rusan Ali Catar, Muhammad Imtiaz Ashraf, Hongfan Zhao, Pinchao Wang, Markus M. Rinschen, Raphaela Fritsche-Guenther, Florian Grahammer, Sebastian Bachmann, Dieter Beule, Jennifer A. Kirwan, Nikolaus Rajewsky, Tobias B. Huber, Dennis Gürgen, Angelika Kusch
Sex differences exist in the prevalence and progression of major glomerular diseases. Podocytes are the essential cell-type in the kidney which maintain the physiological blood-urine barrier, and pathological changes in podocyte homeostasis are critical accelerators of impairment of kidney function. However, sex-specific molecular signatures of podocytes under physiological and stress conditions remain unknown. This work aimed at identifying sexual dimorphic molecular signatures of podocytes under physiological condition and pharmacologically challenged homeostasis with mechanistic target of rapamycin (mTOR) inhibition. mTOR is a crucial regulator involved in a variety of physiological and pathological stress responses in the kidney and inhibition of this pathway may therefore serve as a general stress challenger to get fundamental insights into sex differences in podocytes. The genomic ROSAmT/mG-NPHS2 Cre mouse model was used which allows obtaining highly pure podocyte fractions for cell-specific molecular analyses, and vehicle or pharmacologic treatment with the mTOR inhibitor rapamycin was performed for 3 weeks. Subsequently, deep RNA sequencing and proteomics were performed of the isolated podocytes to identify intrinsic sex differences. Studies were supplemented with metabolomics from kidney cortex tissues. Although kidney function and morphology remained normal in all experimental groups, RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways. Interestingly, rapamycin abolished prominent sex-specific clustering of podocyte gene expression and induced major changes only in male transcriptome. Several sex-biased transcription factors could be identified as possible upstream regulators of these sexually dimorphic responses. Concordant to transcriptomics, metabolomic changes were more prominent in males. Remarkably, high number of previously reported kidney disease genes showed intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. Our results highlight remarkable intrinsic sex-differences and sex-specific response patterns towards pharmacological challenged podocyte homeostasis which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. This work provides rationale and an in-depth database for novel targets to be tested in specific kidney disease models to advance with sex-specific treatment strategies. The global burden of chronic kidney diseases is rapidly increasing and is projected to become the fifth most common cause of years of life lost worldwide by 2040. Sexual dimorphism in kidney diseases and transplantation is well known, yet sex-specific therapeutic strategies are still missing. One reason is the lack of knowledge due to the lack of inclusion of sex as a biological variable in study d
主要肾小球疾病的发病率和进展存在性别差异。荚膜细胞是肾脏中维持生理血尿屏障的重要细胞类型,荚膜细胞稳态的病理变化是肾功能受损的关键加速因素。然而,荚膜细胞在生理和应激条件下的性别特异性分子特征仍然未知。mTOR是参与肾脏各种生理和病理应激反应的关键调节因子,因此抑制该通路可作为一种通用的应激挑战因子,从根本上揭示荚膜细胞的性别差异。采用基因组ROSAmT/mG-NPHS2 Cre小鼠模型可获得高纯度的荚膜细胞碎片,用于细胞特异性分子分析。随后,对分离的荚膜细胞进行了深度 RNA 测序和蛋白质组学分析,以确定内在的性别差异。研究还辅以肾皮质组织的代谢组学。虽然所有实验组的肾功能和形态都保持正常,但 RNA 测序、蛋白质组学和代谢组学发现,线粒体、翻译和结构转录本的表达水平、蛋白质丰度和代谢途径的调控都存在强烈的内在性别差异。有趣的是,雷帕霉素消除了荚膜细胞基因表达的突出性别特异性集群,只诱导男性转录组发生重大变化。几种有性别偏见的转录因子可能是这些性别二态反应的上游调节因子。与转录组学一致,代谢组学的变化在雄性中更为显著。值得注意的是,大量以前报道过的肾脏疾病基因显示了内在的性别二态性和/或对mTOR抑制的不同反应模式。我们的研究结果突显了显著的内在性别差异和对药物挑战荚膜细胞稳态的特异性反应模式,这可能从根本上导致肾脏疾病易感性和进展的性别差异。这项工作为在特定肾病模型中测试新靶点提供了理论依据和深入的数据库,以推进性别特异性治疗策略。慢性肾脏疾病给全球造成的负担正在迅速增加,预计到 2040 年将成为导致全球寿命损失的第五大常见病因。肾脏疾病和移植中的性别二形性已广为人知,但仍缺乏针对不同性别的治疗策略。原因之一是在研究设计中没有将性别作为一个生物变量纳入其中,从而导致知识的匮乏。这项研究旨在鉴定肾小球滤过屏障的守门人--男性和女性荚膜细胞的分子特征。与心肌细胞一样,荚膜细胞也是终末分化的细胞,极易受到病理挑战的影响。荚膜细胞是肾脏维持生理血尿屏障的决定性细胞类型,其平衡紊乱会严重加速肾功能损伤。在基因组小鼠模型的帮助下,研究人员从接受或未接受雷帕霉素机制靶标(mTOR)信号通路药物挑战的雌雄小鼠体内获得了高度纯化的荚膜细胞。深度 RNA 测序、蛋白质组学和代谢组学发现,线粒体、翻译和结构转录本的表达水平、蛋白质丰度和代谢通路的调控存在强烈的内在性别差异,这可能从根本上导致肾脏疾病易感性和进展的性别差异。值得注意的是,之前报道的大量肾病基因显示出迄今未知的内在性双态性和/或对 mTOR 抑制的不同反应模式。我们的工作提供了一个深入的数据库,用于在肾脏疾病模型中测试新的靶点,以推进性别特异性治疗策略。
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引用次数: 0
Correction: MetaFun: unveiling sex-based differences in multiple transcriptomic studies through comprehensive functional meta-analysis 更正:MetaFun:通过综合功能荟萃分析揭示多项转录组研究中的性别差异
IF 7.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-12 DOI: 10.1186/s13293-024-00646-8
Pablo Malmierca-Merlo, Rubén Sánchez-Garcia, Rubén Grillo-Risco, Irene Pérez-Díez, José F. Català-Senent, María de la Iglesia-Vayá, Marta R. Hidalgo, Francisco Garcia-Garcia
<p><b>Correction: Biol Sex Differ 15</b>,<b> 66 (2024)</b></p><p><b>https://doi.org/10.1186/s13293-024-00640-0</b></p><p>Following publication of the original article [1], the authors reported an error in the funding statement.</p><p>The original article [1] has been corrected.</p><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>Malmierca-Merlo P, Sánchez-Garcia R, Grillo-Risco R et al. MetaFun: unveiling sex-based differences in multiple transcriptomic studies through comprehensive functional meta-analysis. Biol Sex Differ. 2024;15:66. https://doi.org/10.1186/s13293-024-00640-0</p></li></ol><p>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Computational Biomedicine Laboratory, Principe Felipe Research Center (CIPF), Eduardo Primo Yúfera Street, 3, Valencia, 46012, Spain</p><p>Pablo Malmierca-Merlo, Rubén Sánchez-Garcia, Rubén Grillo-Risco, Irene Pérez-Díez, José F. Català-Senent, Marta R. Hidalgo & Francisco Garcia-Garcia</p></li><li><p>Biomedical Imaging Unit FISABIOCIPF, Fundación Para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana, Valencia, 46012, Spain</p><p>Irene Pérez-Díez & María de la Iglesia-Vayá</p></li><li><p>Department of Mathematics, Faculty of Mathematics, University of Valencia (UV), BurjassotValencia, 46100, Spain</p><p>Marta R. Hidalgo</p></li></ol><span>Authors</span><ol><li><span>Pablo Malmierca-Merlo</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rubén Sánchez-Garcia</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rubén Grillo-Risco</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Irene Pérez-Díez</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>José F. Català-Senent</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>María de la Iglesia-Vayá</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Marta R. Hidalgo</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Francisco Garcia-Garcia</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding authors</h3><p>Correspondence to Marta R. Hidalgo or Francisco Garcia-Garcia.</p><h3>Publisher
更正:Biol Sex Differ 15, 66 (2024)https://doi.org/10.1186/s13293-024-00640-0Following 原文[1]发表时,作者报告了资助声明中的一处错误。原文[1]已更正。Malmierca-Merlo P, Sánchez-Garcia R, Grillo-Risco R et al. MetaFun: 通过综合功能荟萃分析揭示多项转录组研究中的性别差异。Biol Sex Differ.2024;15:66。https://doi.org/10.1186/s13293-024-00640-0Download 参考文献作者及单位Principe Felipe 研究中心(CIPF)计算生物医学实验室,Eduardo Primo Yúfera Street, 3, Valencia, 46012, SpainPablo Malmierca-Merlo, Rubén Sánchez-Garcia, Rubén Grillo-Risco, Irene Pérez-Díez, José F. Català-Senent, Marta R. Hidalgo & Francisco Garillo-Risco.Hidalgo & Francisco Garcia-GarciaBiomedical Imaging Unit FISABIOCIPF, Fundación Para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana, Valencia, 46012, SpainIrene Pérez-Díez & María de la Iglesia-VayáDepartment of Mathematics, Faculty of Mathematics, University of Valencia (UV), BurjassotValencia, 46100, SpainMarta R.Hidalgo作者Pablo Malmierca-Merlo查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Rubén Sánchez-Garcia 查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Rubén Grillo-Risco查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Irene Pérez-Díez 查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者José F.Català-Senent查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者María de la Iglesia-Vayá查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Marta R. Hidalgo查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Francisco Garcia-Garcia查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者通信作者Marta R. Hidalgo或Francisco Garcia-Garcia。出版者注释Springer Nature对出版地图中的管辖权主张和机构隶属关系保持中立。原文的在线版本可在以下网址找到:https://doi.org/10.1186/s13293-024-00640-0.Open Access 本文采用知识共享署名 4.0 国际许可协议进行许可,该协议允许以任何媒介或格式使用、共享、改编、分发和复制,只要您适当注明原作者和来源,提供知识共享许可协议的链接,并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中,除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中,且您打算使用的材料不符合法律规定或超出许可使用范围,您需要直接从版权所有者处获得许可。要查看该许可的副本,请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明,否则知识共享公共领域专用免责声明(http://creativecommons.org/publicdomain/zero/1.0/)适用于本文提供的数据。转载与许可引用本文Malmierca-Merlo, P., Sánchez-Garcia, R., Grillo-Risco, R. et al. Correction:MetaFun:通过综合功能荟萃分析揭示多项转录组研究中的性别差异。Biol Sex Differ 15, 71 (2024). https://doi.org/10.1186/s13293-024-00646-8Download citationPublished: 12 September 2024DOI: https://doi.org/10.1186/s13293-024-00646-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative
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Biology of Sex Differences
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