Biology of Sex Differences最新文献

Sex differences play a crucial role in determining tumor incidence, treatment sensitivity, and prognosis among men and women. However, current clinical cancer treatment strategies fail to account for these differences. Furthermore, the underlying mechanisms of tumor disparities between sexes remain elusive. Sex differences in sex chromosomes, hormone levels, metabolism, and immunity synergistically contribute to tumor-related disparities. As the demand for precision medicine escalates, there is an urgent need to conduct further exploration and research to address the tumor differences between sexes. In this review, we discuss the impact of biological sex differences on tumor cells and the tumor microenvironment, aiming to identify more effective strategies for tumor prevention and treatment.

Background: Sex determination and differentiation are complex processes shaped by a wide variety of molecular factors. In contrast to teleost species, many aspects of these processes remain poorly understood in basal non-teleost fishes such as the Siberian sturgeon (Acipenser baerii). Genetic sexing of this important aquaculture species now enables studies of undifferentiated males and females to identify factors involved in early sexual differentiation.

Methods: Twelve undifferentiated Siberian sturgeon (six males, six females) were genetically sexed at 2.5 months of age. High-quality RNA was extracted from gonad samples, and transcriptomes were assembled using a reference dataset. Bioinformatic analyses were performed to identify sex-biased genes through differential expression analysis, Gene Ontology (GO) enriched terms, and classification of coding and non-coding sequences.

Results: Genes potentially associated with sex differentiation were identified in gonadal tissue. Female-biased genes included classical estrogens production genes (hsd17b1, cyp19a1, foxl2) and immediate early response genes known to react rapidly to estrogens (jun-b, c-fos, egr1), as well as genes not previously linked to estradiol (di-ras2, ier2, aanat). The enriched Gene Ontology results suggested that melatonin signaling and hypothalamic pathways may also contribute to female differentiation. In males, the well-known factor tbx1 was upregulated along with novel candidates (plin1, nrxn3, chs2, mmp9). No sex-biased genes related to androgen production were identified.

Conclusion: By 2.5 months of age, sex-specific gonadal differences are already apparent in Siberian sturgeon. This study highlights the estrogen response pathway, including immediate early response genes described here for the first time in the context of fish gonadal differentiation. At the same time, an estrogen-independent ovarian pathway cannot be ruled out. Male differentiation appears to involve tbx1 together with new candidates for testis regulation in the absence of sex-biased androgen-producing enzymes. These novel genes expressed near the onset of sex differentiation merit further investigation.

The ancient DMRT family of transcription factors has been proposed as evolutionarily conserved effectors of sexual differentiation. While brain sexual differentiation has traditionally been attributed to a paracrine role of steroid hormones and intrinsic cues directly controlled by sex chromosomes, the downstream effector mechanisms remain elusive. To elucidate the role of Dmrts in mammalian brain sexual differentiation, we generated a comprehensive expression atlas for all family members in the mouse brain using in situ hybridization across sexes and development (E12.5, E14.5, E18.5, adulthood and, sometimes, P7). We found that all Dmrts, except Dmrt7, were expressed in the brain. This study expands understanding of the DMA-Dmrt subfamily beyond pallial structures and identifies their expression maintenance in adult neurogenic sites. For the first time, we described the neuronal expression of Dmrt2 and Dmrt6. Mouse Dmrts did not show clear sexually dimorphic patterns, but did show quantitative expression differences between sexes. Most Dmrts were maintained in postmitotic neurons during embryonic and postnatal stages, suggesting potential interactions with gonadal sex hormones during organizational (perinatally, with testosterone peaking at E18.5 in males) and activational phases (after puberty, with androgens in males and estrogens in females). Our analysis of Dmrt5 expression revealed its prominent presence in the mouse olfactory system. The olfactory system shows sex differences and is fundamental for controlling sex-specific innate behaviors in rodents. Thus, it represents an ideal scenario to test, as a proof of concept, the role of Dmrts in the sexual differentiation of the mammalian brain. The absence of Dmrt5 similarly affected the main olfactory epithelium, where sensory neurons reside, in both sexes; however, cell number-related defects in the olfactory bulb and piriform cortex differed between male and female embryos, revealing Dmrt5 interaction with sex in deeper layers of innate neural circuits. Our results provide a valuable resource for uncovering novel sites and mechanisms of sexual differentiation in the mammalian nervous system, potentially contributing to sex biases observed in psychiatric and neurological disorders.

Problematic smartphone use has been associated with altered reward and executive control network activity, yet potential sex differences in the underlying neural mechanisms remain insufficiently understood. We investigated sex-specific neural correlates of smartphone cue reactivity (CR) in 69 healthy young adult smartphone users (age range 18-30 years, female/male n = 45/24). Participants completed the Smartphone Addiction Inventory (SPAI) and underwent functional MRI during a smartphone CR paradigm. In addition, resting-state data were acquired to ensure that neural differences between female and male participants could be attributed to the CR paradigm rather than to sex differences in intrinsic neural activity. Whole-brain analyses revealed stronger activation in males compared to females in response to the presentation of smartphone cues within the right middle frontal gyrus (MFG), thalamus, cortical sensorimotor, parietal and occipital regions, whereas females showed no suprathreshold clusters compared to males. No overlap with resting-state amplitude of low-frequency fluctuation maps was observed with CR results, confirming task specificity. In males, right MFG correlated positively with SPAI-I total score, craving, and sleep interference scores, while in females, right parietal cortex activity correlated negatively with SPAI-I total score, daily life interference, and craving. Complementary cross-modal analyses showed that CR-related activation patterns were associated with several cortical excitatory and inhibitory neuronal and cellular markers, revealing subtle sex differences. These findings suggest sex-specific frontoparietal mechanisms underlying smartphone CR and highlight neurochemical pathways potentially linking excessive smartphone use to differential motivational and cognitive control processes in males compared to females.

Background: Poverty, a low resource state, is a common adverse childhood experience (ACE) and early life stress (ELS). People who experienced childhood poverty are at greater risk for developing hypertension during adulthood, with sex differences. To determine the possible mechanisms of these sex differences, we investigated the alterations in blood pressure (BP), autonomic activity, and inflammation in the brain and kidneys of rats exposed to an impoverished environment during the early life, by using the limited bedding and nesting (LBN) rodent model.

Methods: The LBN model mimics childhood poverty by creating a low resource environment on postnatal days 2-9. After weaning, offspring were separated by sex and LBN exposure and were evaluated at 16-18 weeks of age (Adulthood).

Results: LBN males displayed an increase in BP compared to the control (CON), whereas LBN females showed no changes. Sympathetic nerve activity (SNA) was increased in LBN males and females compared to the CON, while only parasympathetic nerve activity (PNA) was increased in LBN vs. CON females. Pro-inflammatory cytokines, IL-17 and TNF-α, were decreased in the brains of LBN vs. CON males, with no alterations in females.

Conclusion: Adult LBN males have elevated BP, due to increased SNA, while LBN females may be protected from increased BP due to a simultaneous increase in SNA and PNA. The reduction in IL-17 and TNF-α in LBN males may serve as a compensatory mechanism to lower BP. This study provides insights into sex differences in BP for adults who experienced childhood poverty.

Background: The gut microbiota significantly influences cardiovascular health by regulating host metabolism and generating bioactive compounds like trimethylamine-N-oxide (TMAO) and indoxyl sulfate (IS), both linked to coronary artery disease (CAD). Emerging research indicates sex-based differences in microbial composition and metabolite production, yet their impact on CAD pathophysiology remains unclear. This scoping review summarizes current findings on sex-specific microbial and metabolic differences in individuals with CAD.

Methods: A systematic search of PubMed and EMBASE was conducted through March 2025 for peer-reviewed studies comparing gut microbiota or metabolite profiles between male and female patients with CAD. Eligible studies used 16S rRNA sequencing, shotgun metagenomics, or metabolite profiling to analyze microbial communities and atherosclerosis-associated metabolites. Mechanistic links from genetics, epigenetics, and hormone-microbiota interactions were integrated to provide a more comprehensive understanding of how gut microbiota may contribute to sex differences in CAD.

Results: Eleven studies met the inclusion criteria for this review. Men with CAD exhibited increased relative abundances of taxa such as Prevotella, Clostridia_UCG_014, UCG_010, and other pro-inflammatory genera, whereas women microbiota was comparatively enriched in Barnesiella, Bifidobacteriales, and other potentially beneficial taxa. Parallel differences emerged in microbial metabolite profiles: men demonstrated elevated plasma levels of TMAO and IS, both associated with heightened cardiovascular risk and disease burden. Conversely, women with CAD had higher circulating levels of secondary bile acids and lower TMAO concentrations.

Conclusion: Preliminary studies suggest sex-related differences in gut microbiota composition and metabolite profiles in CAD patients. Integrating mechanistic links from microbial metabolism, genetics, epigenetics, and hormones supports a potential role of the microbiota in sex-dependent disease pathways. Current evidence is limited and mostly observational; well-designed studies are needed to clarify mechanisms, clinical relevance of sex-specific microbiome signatures and specifically assess whether these sex-specific microbial and metabolic differences influence CAD progression and outcomes.

The global incidence of nephrolithiasis has increased significantly in recent decades. The prevalence remains higher in males than females, the exact mechanisms responsible for this gender-based disparity in nephrolithiasis risk remain incompletely understood. Although dietary and lifestyle factors contribute to this difference, they do not entirely account for the observed variation. Emerging evidence suggests that steroid hormones may play a pivotal role in modulating renal stone formation through their influence on calcium, oxalate, and phosphate metabolism, as well as regulating the renal inflammatory microenvironment. This review synthesizes current knowledge on the interplay between steroid hormones and nephrolithiasis pathogenesis, providing a theoretical framework for understanding gender-specific susceptibility and highlighting potential avenues for tailored preventive and therapeutic approaches.

Background: Exogenous sex hormones have been extensively studied for their influence on stroke risk and outcome. This meta-analysis served to update the pre-clinical acute ischemic stroke (AIS) literature and provide the first synthesis of the intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) literature on how estrogen, progesterone, and testosterone affect post-stroke outcomes.

Methods: This study was pre-registered with PROSPERO (CRD42024544794). Medline, EMBASE, Scopus, and Web of Science were searched; studies using animal models of stroke investigating exogenous estrogen, progesterone, or testosterone, alone or in combination, compared to non-treated controls were included. Assessments of injury volume, edema, and behaviour (neurological deficits, sensorimotor and cognitive outcomes) were analyzed via hierarchical meta-analyses. Risk of bias was assessed via SYRCLE and CAMARADES, and evidence certainty via an adaptation of the GRADE tool.

Results: In total, 211 studies were included. Estrogen and progesterone improved all post-AIS outcomes (SMDs = 0.32-1.30, 95% CIs [0.02, 2.07], very low to moderate certainty of evidence), whereas testosterone had mostly null effects (very low to moderate certainty). Fewer studies investigated hemorrhagic stroke, with null effects of estrogen (very low to low certainty) and conflicting results of progesterone (SMDs = 0.15-1.16 [-2.20, 2.58], very low to moderate certainty) in ICH, as well as benefit of progesterone in SAH (SMD = 2.63 [0.98, 4.30], very low certainty). Uncertainty in our evidence arose from low scientific and translational rigor. Sex and gonadal status were consistent moderators of these effects, and gonadal depletion length (i.e., the 'timing hypothesis') was a significant moderator of estrogen's effect on post-AIS injury volume.

Conclusions: Estrogen and progesterone are promising cerebroprotectants for AIS. Further focussed and rigorous pre-clinical research on remaining research gaps (e.g., dosage parameters) are needed to guide clinical investigations and maximize the likelihood of translational success. The impact of testosterone and sex hormones in hemorrhagic stroke remain inconclusive due to lack of research.

Background: Long COVID (LC) is a post-infectious condition affecting millions worldwide, characterized by persistent multisystem symptoms. Females are disproportionately affected, reporting higher symptom burden, particularly neurocognitive and neurosensory complaints. While short-term immunopathology has been described, the long-term clinical course, immune dysregulation, and sex-specific underpinnings remain poorly understood.

Methods: We analyzed 34 participants experiencing persisting symptoms from 9 months to 5 years post-SARS-CoV-2 infection, alongside 26 SARS-CoV-2-infected controls without symptoms. Clinical assessments, symptom inventories, comorbidity analysis, and work capacity evaluation were performed. Immune profiling included flow cytometry of CD4⁺ and CD8⁺ T cells, NK cells, and B cells, as well as quantification of plasma cytokines, soluble factors, and cytotoxic molecules, analyzed in a sex-disaggregated manner.

Results: Females with LC exhibited higher symptom burden, particularly persistent fatigue, neurocognitive and neurosensory complaints, which increased with age and tended to increase with disease duration, whereas males showed no clear age- or duration-related patterns. Comorbidities, especially affecting endocrine, metabolic, and circulatory systems, were more frequent in females and aligned with symptom severity. Immune profiling revealed subtle but sex-specific differences: females had reduced CD8⁺ T cell cytotoxic profile, lower NKG2D and granzyme K expression, increased sCD40L and sFAS, and decreased perforin, whereas males displayed elevated TNF-α. NK cell function, B cells, and humoral immunity remained largely intact. Over half of participants reported functional impairments affecting work capacity.

Conclusions: Even though our cohort is small it suggests that prolonged LC is characterized by sex-specific differences in symptom burden and immune profiles. Reduced cytotoxic CD8⁺ T cell profile in females may contribute to viral persistence and neurological symptoms, whereas elevated inflammatory markers in males suggest distinct immune pathways. These findings highlight the need for sex- and duration-specific management strategies, the identification of biomarkers, and the development of personalized therapies targeting specific LC endotypes.

Alzheimer's disease (AD) displays striking sex differences in incidence, progression, and resilience, yet the mechanisms that drive female-biased vulnerability remain incompletely understood. Emerging evidence indicates that gut dysbiosis, increasingly prevalent with ageing, acts as a systemic amplifier of neuroinflammation, vascular instability, and metabolic dysfunction. Here, we synthesize converging findings linking gut microbial alterations to noradrenergic pathology in the locus coeruleus (LC), one of the earliest brain regions affected in AD. We outline how dysbiosis-associated inflammatory signaling, including endotoxin exposure and impaired vagal-neuroimmune regulation, targets LC circuits. In parallel, disruptions in microbial metabolite pathways involving short-chain fatty acids, bile acids, and tryptophan metabolism further promote oxidative stress, tau phosphorylation, and neurodegeneration. We further argue that sex-dependent differences in immune reactivity, autonomic regulation, and hormonal transitions, particularly peri- and post-menopausal estrogen decline, render female LC neurons uniquely vulnerable to microbial and inflammatory perturbation. We propose a mechanistic framework in which gut dysbiosis destabilizes LC integrity through parallel immune-vascular, metabolite, endocrine, and vagal neural pathways, thereby accelerating cognitive decline and AD progression. Understanding how microbial signaling intersects with sex biology and neuromodulatory circuitry may reveal therapeutic windows for early intervention, including microbiome restoration, neuromodulatory tuning, and sex-specific metabolic targeting.