Biology of Sex Differences最新文献

Objective: Volumes of the hippocampus and amygdala, both major hubs for neural stress regulation amongst others, are associated with social stressors, cortisol awakening response (CAR) and sex. Importantly, the interplay of these different factors in affecting the morphology of both brain regions remains unclear. This study aimed to elucidate the intricate influence of these factors on grey matter volumes (GMV) of the hippocampus and amygdala.

Methods: We analyzed associations between structural brain data, self-reported chronic social stress (including subscales on social tension, social overload, lack of social recognition and social isolation) and CAR of 83 healthy participants (40 females) with multiple regression analyses.

Results: In males, but not females, higher levels of social tension were associated with lower bilateral hippocampal GMV. Amygdala GMV was related to CAR and social stress, with social overload being associated with reduced amygdala GMV in individuals not showing the typical CAR (reflecting a blunted physiological response to awakening), while the opposite pattern emerged in those with a typical CAR.

Conclusions: The association between chronic social stress and HC and AMY volume is interacting with CAR-pattern and sex. The brain morphology in males and in individuals with an atypical CAR showed reductions in association with chronic social stress. Our findings point to a complex interaction between social stress, cortisol patterns, sex and brain architecture, which needs to be assessed in more detail in future research.

Background: Cardiovascular risk factors are determinants of coronary artery calcium (CAC) progression. However, whether the effect of cardiovascular risk factors on CAC progression among participants with CAC = 0 differs by sex remains unclear.

Method: This study included 1815 participants 33-45 years of age from the Coronary Artery Risk Development in Young Adults study at baseline who had CAC measured both at baseline and five years later. CAC was measured using computed tomography. Risk factor measurements included body mass index (BMI), waist circumference, total cholesterol, triglycerides, glucose, systolic blood pressure (BP), low-density lipoprotein cholesterol, and smoking status.

Results: CAC progression was significantly higher among men than women (2.25 (8.68) vs. 0.89 (6.7), P < 0.0001). In the restricted cubic spline models, the associations between systolic BP and CAC progression in women followed a nonlinear relationship. The slope for the regression of systolic BP on CAC progression in women was relatively flat until around 125 mmHg of systolic BP and then started to increase rapidly afterwards, with a β of 0.16. BMI was associated with CAC progression only in men. Similar associations were observed when replacing BMI with waist circumference. There were no sex differences in the associations between CAC progression and smoking.

Conclusion: Systolic BP in women and BMI (and/or waist circumference) in men may have different contributions to CAC progression between the sexes among participants with CAC = 0. Our study provides evidence that understanding sex differences in cardiovascular risk factors is essential for implementing targeted interventions to prevent CAC progression.

Background: Despite growing recognition of sex differences in medicine, little is known about their role in neonatology, particularly among extremely premature infants (EPI, < 28 weeks gestation), who face high morbidity and mortality driven by infections. Antibiotics therapy is widely used but may alter cellular metabolism, leading to adverse drug reactions. However, pharmacological studies in EPI remain limited, and sex-dependent effects of antibiotic treatments are largely unexplored. This study investigated sex-related metabolomic differences in EPI in relation to antibiotic exposure.

Methods: Targeted mass spectrometry (MS) was applied to dried blood spots (DBS) collected within the neonatal screening program of the Campania region (Italy) between 2018 and 2023. Amino acids (AA) and acylcarnitines (AC) were quantified in 116 EPI stratified by sex and antibiotics treatment.

Results: Untreated EPI of both sexes showed largely comparable metabolic profiles, with the exception of higher C16OH levels in males. Antibiotic treatment, however, markedly amplified sex-dependent divergence, with male EPI displaying significantly elevated AC concentrations (C0, C2, C3, C4, C5, C6, C5OH, C10:1, C16:1, C18, C18:1) compared to females. Stratification by penicillins + aminoglycosides treatment revealed distinct patterns: in EPI treated with a penicillins + aminoglycosides combination, males exhibited higher levels of C0, C2, C4, C6, C16:1, C18, and C18:1, while C3, C5, C5OH, and C10:1 no longer differed by sex. Furthermore, eight additional AC (C3DC, C14:1, C14, C16, C10DC, C16OH, C4OH, C16:1OH) were significantly elevated in treated males, differences that were not detected when all antibiotic classes were pooled.

Conclusions: These findings demonstrate that standard empirical antibiotic therapies for prematurity exert sex-dependent effects on neonatal metabolism, with antibiotics amplifying AC alterations in males. Our results underscore the need to consider sex as a key biological variable in neonatal pharmaco-metabolomics and highlight the potential of metabolic profiling to optimize individualized treatments in EPI.

Background: Up to 80% of Alzheimer's disease (AD) patients suffer from brain vascular damage resulting in multi-etiology dementia (MED). Sex is a well-known risk factor for dementia; out of three AD patients two are women. 17β-estradiol, a predominant ovarian hormone in woman before menopause, is known to have beneficial effects on the cerebrovasculature, neuroinflammation and neuroprotection. Here, we investigated the consequences of the loss of ovarian hormones caused by surgical menopause (ovariectomy) on AD and MED.

Methods: The App^NL-F knock-in mice were used to model AD. At about 5.5 months of age, a stage corresponding to early disease pathology, female App^NL-F mice were subjected to ovariectomy (OVX) or sham surgery (Intact) and left to recover for 3 weeks to clear any endogenous gonadal hormones. In half of the mice from each group, MED was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion), a model of vascular contributions to cognitive impairment and dementia (VCID). Control animals (AD only model) received sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and brains were collected to assess pathology.

Results: We found that loss of ovarian hormones impairs spatial learning and memory, impairs activities of daily living, and affects underlying pathology including compromising microglial response. Some of these effects were exacerbated by cerebral hypoperfusion (VCID).

Conclusions: These results shed light on the effects of ovarian hormone loss after surgical menopause in female mouse model of AD and MED in order to better understand sex-specific risk factors.

Sexual dimorphism has been implied to certain human physiology and diseases. This topic has recently garnered more attention, highlighting individual variances in precision medicine and individualized clinical trials. It is recognized that individual gene expression variations in males and females could have profound physiological impacts. Tissue specific expression profiles determine protein-coding gene activities and contribute additional physiological variations. Therefore, tissue specific gene expression profiles should be comprehensively analyzed among individual human subjects. In this report, we developed a user-friendly bioinformatic tool to visualize gene expression levels and variances across tissue samples, aiming to facilitate research into potential sexual dimorphism genes. The Gini coefficient metric was used with the most recent GTEx V10 datasets to examine variations in the expression profiles of human protein-coding genes across 43 tissue subtypes. Next, these variations were specifically evaluated using the Gini coefficient index for male and female individuals across all tissue subtypes. Our web-based visualization tool generated tissue specific expression profiles for individual male and female samples. It concurrently illustrates expression levels and variation comparisons between male and female groups across all tissue subtypes. Although most protein-coding genes had similar expression variation patterns between the two sexes, several genes exhibited distinct variations for some tissue subtypes, as indicated by their significant Z-scores in Gini index disparities. Users can explore differentially expressed protein-coding genes across tissue subtypes or search for genes of interest in the Tissue Prominent Sexual Dimorphism Gene database ( https://tpsdg.ibms.sinica.edu.tw ). This database can be employed to visualize expression levels and variations among individual samples within specific tissues, thereby facilitating future research into divergently expressed protein-coding genes in the human population.

Background: Selective serotonin reuptake inhibitors are widely prescribed during pregnancy. Their main route of administration is through the gut. However, their impact on the maternal and offspring gut microbiome and microbial metabolic pathways remains poorly understood. This study used metagenomic shotgun sequencing to examine the effects of perinatal citalopram exposure in rat dams and their offspring on gut composition and downstream metabolic pathways.

Methods: We treated pregnant and nursing rat dams with either citalopram or vehicle (water). Their feces were collected, DNA from these samples was extracted and then sequenced using shotgun metagenomic sequencing. The BioBakery suite of microbiome analysis tools was utilized in tandem with RStudio to analyze the gut composition and microbial metabolic pathways of the rat dams and their offspring.

Results: Pregnant and nursing dams treated with citalopram exhibited marked shifts in microbial community structure, including phylum-level alterations in Proteobacteria and Defferibacteria. Citalopram treated dams displayed significantly altered beta diversity. Species level alterations due to treatment were composed of five significantly altered microbes, two of which belong to the Proteobacteria phylum. These changes were highly diverse and were not congruent with microbe-level alterations observed in offspring. Alpha diversity of microbial metabolic pathways was compared using the Gini-Simpson index, which was significantly increased in dams suggesting greater metabolic functional diversity with age. Female offspring perinatally exposed to citalopram showed significant changes in gut beta diversity, with seven significant alterations at the microbe level. These microbial shifts were accompanied by twenty-one significantly altered microbial metabolic pathways. In contrast, male offspring showed no significant differences in microbial composition or beta diversity and only minor metabolic changes.

Conclusions: These findings demonstrate that maternal citalopram exposure during pregnancy and lactation has lasting, sex-specific impacts on the offspring's gut microbiome and microbial metabolic pathways. The pronounced alterations in female, but not male offspring, suggest that host sex may be a critical determinant in the developmental response to citalopram exposure. This work underscores the value of metagenomic approaches in uncovering complex host-microbiome interactions and highlights the need to consider offspring sex in evaluating the safety and long-term effects of antidepressant use during pregnancy.

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.