Biology of Sex Differences最新文献

Background: Gestational environmental perturbations can induce sex-specific developmental programming, increasing offspring susceptibility to chronic diseases. While prenatal high estradiol (HE) exposure has been associated with male-biased neurodevelopmental disorders, the underlying mechanisms remain poorly understood.

Methods: Using spatial transcriptomics in a murine HE exposure model, we systematically characterized sex-divergent molecular and cellular responses in fetal brains. Through cell type identification, spatial mapping, ligand-receptor interaction analysis, and transcription factor activity assessment, we examined gene expression profile, intra-regional signaling pathway, and regulon activity variations. Additionally, we performed immunofluorescence to characterize neural progenitor cell dynamics.

Results: Our analysis revealed that maternal HE exposure differentially altered gene expression patterns between male and female fetal brain regions, with more pronounced effects on male-biased genes. Notably, HE-induced downregulation of male-biased genes was proportional to their baseline male-bias degree. We uncovered region-specific cellular responses to HE exposure and demonstrated sex-opposed alterations in intra-regional signaling pathway. Furthermore, we identified cell type- and brain region-restricted sex differences in regulon activity variations. Histological validation confirmed that maternal HE exposure specifically disrupts the proliferation-differentiation balance of neural progenitor cells in the male cerebral cortex.

Conclusions: These findings provide mechanistic insights into sex-dimorphic developmental reprogramming of fetal brain by maternal estradiol excess. They establish a framework for developing targeted interventions against gestational endocrine disruption-induced neurodevelopmental disorders.

Background: Sex-dependent differences in prevalence and severity are characteristics of Alzheimer's disease (AD). Using the 3×Tg-AD mouse model, we previously reported that adult males show early behavioral dysfunction, altered epigenetic factors and lack of plaque/tangle pathology. Conversely, adult females retain more severe AD-like pathology and behavior. The present study examines whether gonadal hormones play a role in these differences in current cohorts of 3×Tg-AD mice.

Methods: 3×Tg-AD and wild-type mice were gonadectomized or sham-operated at 3 months of age. After behavioral phenotyping at 6 months of age, the animals were assessed for molecular markers of AD pathology and expression of genes and histone variants associated with neurodegeneration.

Results: In female transgenic (AD) mice, gonadectomy resulted in poorer spatial learning performance. In contrast, in transgenic male animals, gonadectomy improved spatial learning and memory. Compared to sham-operated AD females, gonadectomized AD females exhibited enhanced expression of mouse (m) Mapt and App genes, consistent with reduced binding activity of the repressive histone variant macroH2A1 at the mMapt gene, but there was no effect on Aβ₄₂ or pTau181 levels. In contrast, gonadectomized AD males showed significantly increased macroH2A1 binding at the mPsen1 promoter, reduced expression of the App and MacroH2A1 genes, and reduced cortical soluble Aβ₄₂ levels compared to sham-operated AD males.

Conclusions: In sum, the results suggest that reduction in serum levels of female gonadal hormones impairs spatial learning capacity, whereas loss of male gonadal hormones enhances spatial learning and memory. In females, gonadectomy reduces binding of the repressive histone variant MacroH2A1 to the mouse Mapt gene and increases expression of the mouse App and Mapt genes without affecting Aβ₄₂ or pTau181 levels. Conversely, loss of male gonadal hormones increases binding of MacroH2A1 to the mouse Psen1 gene and decreases App expression and Aβ₄₂ levels but has no effect on tau expression. Our work suggests that adult gonadal hormones contribute to sex differences in AD-like pathology and performance in learning and memory tasks. Moreover, sex-specific differences in AD-like pathology are partially due to the action of histone variants associated with neurodegeneration, such as macroH2A1.

Background: The brain-gut system, which involves bidirectional communication between the central nervous system and the gut, plays a central role in stress responses. Its dysregulation is implicated in irritable bowel syndrome (IBS), a stress-sensitive, female-predominant disorder characterized by abdominal pain and altered bowel habits. Adverse childhood experiences (ACE) increase the risk and severity of IBS, likely by amplifying stress responsiveness and gut-brain dysfunction in females. However, the mechanisms involved are unknown.

Aim: This study aimed to identify a multi-omic signature linking ACE exposure to IBS females via clinical, neuroimaging, and gut microbiome features as compared to healthy control (HC) females.

Methods: Data was analyzed from participants with Rome positive IBS and HCs. Four subgroups were created based on IBS diagnosis and ACE score with high ACE defined as ≥2 and low as ACE 0-1. Validated questionnaires assessed clinical variables. Biological markers included multimodal brain MRI, and gut microbial function using metagenomics. eXtreme gradient boosting (XGBoost) identified key differentiating features between the groups. Connectograms visualized relationships across mutli-omics data within each group.

Results: Among 188 female participants, the four groups included IBS with high ACE (n=37), IBS with low ACE (n=55), HCs with high ACE (n=19), and HCs with low ACE (n=77). Key findings include: 1. High ACE participants with IBS versus their HC counterparts showed increased depression and anxiety symptoms, GI-symptom related anxiety, perceived stress, somatic symptom severity, and poorer physical and mental health scores. 2. High ACE participants with IBS had negative associations between key bacteria such as Akkermansia (a beneficial bacteria) and somatic symptom severity, and between Bifidobacterium and ACE parental divorce/separation and alterations in the salience and central autonomic networks. 3. The ensemble model accurately distinguished IBS patients with high ACE (AUC of 0.87), demonstrating strong predictive performance with an overall model accuracy of 78%.

Conclusions: Our findings highlight the unique microbiota and brain networks contributing to a complex interplay of chronic stress as measured by early life adversity, the brain-gut-microbiome system, and IBS pathophysiology which can inform therapeutic targets aimed at mitigating the long-term impacts of early life stress in female IBS patients.

Many systematic reviews have summarized evidence on the association between behavioural factors and incident cancers. To date, there has been little synthesis of heterogeneity by sex/gender of this evidence.An umbrella review was conducted of systematic reviews with quantitative synthesis (meta-analysis, meta-regression) examining the exposures of body size; physical activity; wholegrains, vegetables, fruit and beans; "fast foods"; red and processed meat; sugar sweetened drinks; dietary supplements; alcohol; tobacco; and sun exposure with incident non-sex-specific cancers. A search of Ovid MEDLINE, Ovid Embase, and Cochrane library from database inception to May 2023 was conducted. We calculated the proportion of systematic reviews that provided quantitative sex/gender findings (e.g., subgroup analyses) and summarized findings narratively. Methodological quality was appraised with the AMSTAR-2 tool.From 13,227 records, 705 full-text systematic reviews were identified as meeting inclusion criteria. Of these, 361 (51.2%) reported quantitative sex/gender findings. The terms "sex" and "gender" were used interchangeably by 36.3% of the 361 systematic reviews and none reported findings for transgender, gender-diverse, or non-binary individuals. Overall, 98.6% (356/361) of systematic reviews were rated "critically low" with the AMSTAR-2 tool. Most of the 361 systematic reviews with quantitative sex/gender findings reported no statistically significant differences by sex/gender.This umbrella review found conflation of sex and gender in systematic reviews of behavioural factors and non-sex-specific cancers and a lack of research among non-cisgender individuals. The existing evidence base is of critically low quality and our findings of no sex/gender-specific trends must be interpreted with caution.

Background: Brain-derived neurotrophic factor (BDNF) is highly expressed in the hypothalamus where it exerts regulatory functions over neurogenesis, reproduction, energy balance, and metabolism. Analyzing a hypothalamic single-nucleus transcriptomic, we identified Fezf1 ventromedial hypothalamic (VMH) neurons as an important source of BDNF. During development, Fezf1 neurons are involved in the organization of the olfactory bulb, and mutations on this gene are responsible for Kallmann syndrome; however, in adult life, little is known about the functions of Fezf1 neurons.

Methods: In this study, we aimed at providing advance in the characterization of Fezf1 neurons and exploring the role of Fezf1-BDNF in the regulation of the metabolic phenotype of mice. Hypothalamic immunofluorescence was employed to determine the distribution and projections of Fezf1 neurons. Mice with a Fezf1-specific knockout of BDNF were constructed and used in the determination of the metabolic phenotype.

Results: Using a Cre-Lox system to express mCherry specifically in Fezf1 neurons of the VMH, we identified projections to the dorsomedial hypothalamus and the zona incerta, regions involved in metabolic control and motor activity, respectively. The Fezf1-specific knockout of BDNF resulted in increased cold tolerance in males, and protection against diet-induced obesity due to a reduction in food intake and increased spontaneous ambulatory activity in females. This was accompanied by protection against glucose intolerance, and increased insulin sensitivity, in females.

Conclusions: Thus, the present work provides advance in the understanding of the biology of VMH Fezf1 neurons, revealing the details of its distribution and projections, and demonstrating that the expression of BDNF in these neurons is involved, according to a sexual dimorphic pattern, in the regulation of metabolic function. In addition, this is the first evidence that, in a specific hypothalamic cell population, BDNF may have a detrimental rather than positive role in the regulation of systemic metabolism.