Biology of Sex Differences最新文献

Background: Men have consistently experienced higher COVID-19 mortality than women across most countries and time periods, prompting widespread investigation into potential biological causes. Early research focused on sex-related genetic, hormonal, and immunological mechanisms to explain these disparities.

Main body: This narrative review traces the evolution of scientific explanations for women/men mortality differences in COVID-19, from early biological hypotheses to more nuanced gendered and intersectional models. While some studies suggest sex-linked genetic variants, chromosomal mechanisms, or hormone-regulated expression of viral entry receptors might partially explain men's higher mortality, the overall evidence remains inconsistent and inconclusive. Increasingly, attention has shifted to social and structural factors, including occupational exposure, pre-existing health conditions, healthcare access, and behaviors, that can differently shape vulnerability to COVID-19 in women and men. Data disaggregated by gender and race further revealed significant heterogeneity in outcomes, underscoring the influence of intersecting axes of inequality. International comparisons suggested that gender inequality at the societal level was associated with wider women/men COVID-19 mortality gaps. Analyses that overlook the interaction between sex- and gender-related factors and their intersection with racial disparities and socioeconomic status risk obscuring the underlying drivers of COVID-19 disparities.

Conclusion: Sex-related biological factors may have influenced COVID-19 outcomes, but they do not adequately account for the observed differences in mortality between women and men. Approaching the study of health inequities through a gendered, intersectional framework is essential for accurately identifying and addressing underlying risk factors, and for better understanding how sex- and gender-related factors may interact, not only in COVID-19, but across a broad range of health conditions.

Background: The circadian system influences many different biological processes across the lifespan, including memory performance and daily activity patterns. The biological process of aging causes decreased control of the circadian system that is accompanied by a decline in memory performance, suggesting that these two processes may be linked. Indeed, our previous work has shown that in male mice, the clock gene Per1 functions within the dorsal hippocampus to exert diurnal control over memory and repression of Per1 in the old hippocampus contributes to age-related impairments in spatial memory. Although it is clear that Per1 may be a key molecular link between memory and the circadian rhythm, next to nothing is known about how sex impacts this role in the young or old brain. Here, we are interested in understanding how the factors of sex and age impact memory performance, circadian activity patterns, sleep behavior, and hippocampal Per1 expression.

Methods: We used a combination of spatial memory (Object Location Memory (OLM)) and circadian activity monitoring to determine how male and female mice change across the lifespan. In addition, we used RT-qPCR to quantify the change in Per1 levels in response to learning in young and old, male and female mice.

Results: Young female mice resist diurnal oscillations in memory, showing robust spatial memory across the diurnal cycle. In contrast, old female mice show an emergence of diurnal memory oscillations, with better memory during the day than at night (similar to what we observed previously in young male mice). In contrast, old male mice showed better memory performance during the night than the day, suggesting that their peak memory performance is drastically shifted compared to young males. We also measured activity patterns and sleep behavior across the diurnal cycle and found that sex was more of an influence than age in multiple analyses, but age did have an impact, with old male mice showing stronger circadian rhythm disruptions than any other cohort. Finally, we investigated whether the circadian clock gene Per1 plays a role in these sex- and age-dependent effects in diurnal memory performance. We found that, in general, learning-induced Per1 and memory performance peaked at similar times of day in each group, consistent with our hypothesis that Per1 exerts diurnal control over memory performance.

Conclusions: This work supports a role for Per1 in exerting diurnal control over memory and suggests that Per1 may be an appealing therapeutic target to improve memory and circadian dysfunction in old age.

Highlights: Diurnal oscillations in spatial memory are sex- and age-dependent in mice. Per1 learning-induced expression matches diurnal memory patterns. Circadian rhythm patterns are sex- and age-dependent in mice. Young females show good memory across the diurnal cycle. Diurnal memory o

Background: RAW 264.7 (male-derived) and J774A.1 (female-derived) cell lines are widely used in immunology research and are considered preferred models for studying signaling pathways, yet their responses to gonadal hormones remain poorly understood. Gonadal hormones, particularly estrogen, shape immune cell function and contribute to sex differences in disease outcomes, with macrophages playing a central role through their expression of intracellular estrogen receptors (ERs). Herein, we investigated ER expression and functional responses to 17β-estradiol (E2) in male-derived RAW 264.7 and female-derived J774A.1 macrophages, in 2D culture. Additionally, we looked at sex-matched and mismatched media conditions in a 3D hydrogel system. Our results reveal distinct phenotypic and functional differences between the cell lines, emphasizing the need for sex-aware approaches in immunological research and model design.

Methods: RAW 264.7 and J774A.1 macrophages were cultured in basal media for 24 hours, then treated with varying concentrations of 17β-estradiol (5, 25, 100 nM), as well as hormone-free and control media. Post-treatment analyses included viability, estrogen receptor expression, phenotype skewing, matrix metalloprotease 9 (MMP9) activity, and phagocytosis. These macrophages were also used to condition sex-specific media environments and were encapsulated in a hydrogel network containing adhesive and cleavable sites. Encapsulated cells were then exposed to sex-matched or sex-mismatched conditioned media, and proliferation and MMP9 activity were assessed.

Results: Our results revealed distinct differences in estrogen receptor gene and protein expression, as well as in core macrophage functions such as proliferation, inflammation, matrix remodeling, and phenotype skewing. Additionally, the sex-derivation of the surrounding molecular environment affected macrophage behavior in a 3D hydrogel system. Female-derived macrophages were more sensitive in terms of proliferation to sex-mismatched environments, while male-derived macrophages exhibited altered enzyme activity when exposed to female-conditioned media.

Conclusions: These findings underscore the importance of accounting for both the origin of immune cells as well as the hormonal and environmental context in which they are studied. Without these considerations, experimental models risk missing critical biological differences that shape immune responses and disease outcomes.

Background: Sex is an important factor in the development and symptom expression of Parkinson's disease (PD). Risk of developing PD, motor and non-motor symptoms and response to treatment differ between men and women, with women showing lower disease incidence, later onset of motor deficits and generally milder symptoms than men. We previously reported that male mice lacking the NF-κB/c-Rel protein (c-rel^-/- mice) undergo age-related accumulation of α-synuclein, and loss of dopaminergic neurons, in the substantia nigra (SN). In addition, c-rel^-/- male mice present a progressive PD-like phenotype characterized by both motor deficits and non-motor symptoms (such as constipation, hyposmia, anxiety, depressive-like behavior and apathy). In this study, we give evidence that female mice reproduce only part of the parkinsonian pathology and do not show behavioral manifestations.

Methods: Nigro-striatal alterations as well as motor and non-motor symptoms were assessed in aged c-rel^-/- and wild-type (wt) male and female mice through histological techniques and behavioral tests.

Results: Likewise c-rel^-/- males, c-rel^-/- females displayed significant reduction of dopaminergic neurons in the SN at 18 months of age, but only minor reduction of striatal TH-positive (TH+) and DAT-positive (DAT+) dopaminergic fibers compared to wt littermates. Besides, c-rel^-/- females did not develop significant motor deficits and non-motor symptoms, as constipation, hyposmia, depressive-like and apathetic behaviors.

Conclusions: Our results show that, differently from aged males, c-rel^-/- females do not develop a parkinsonian behavior, in line with evidence from the human PD. The phenotype mice display a nigral dopaminergic neuron degeneration but conserved nigrostriatal fiber density. The degeneration and PD-like symptoms are compatible with the sex-related differences on incidence and symptoms progression observed in PD patients.

Males are more susceptible to neurodevelopmental cognitive deficits in their perception of visual information. Subliminally-presented visual stimuli might be subconsciously perceived and consequently influence upcoming decisions, however it is still unclear whether subconscious perception differs between males and females. In this study, young adults performed a two-choice target detection task. In the Baseline condition (trials), participants relied only on their ability to detect the target. In the Cued-conscious condition, a visual cue (information) was presented (250 ms) on the same side of an upcoming target and indicated its location (left/right). In the Subliminal-same condition, a briefly presented (~16 ms) cue correctly indicated the target location, however in the Subliminal-opposite condition the cue was shown on the opposite side of the upcoming target and provided incorrect information. Participants' performance in the Cued-conscious condition was significantly higher than the Baseline and subliminal conditions. In both females and males, performance in the Subliminal-same and Subliminal-opposite conditions was higher and lower than the Baseline condition respectively; indicating that the subliminal cues (information) affected upcoming decisions. However, the effects were significantly larger in males, suggesting males express heightened sensitivity to subliminal visual information, compared to age- and education-matched females. In both males and females, background acoustic stimuli (Music, White noise or Silence) influenced conscious and subconscious visual information processing. Autonomic nervous system activity, assessed through event-related electrodermal activity, was also differentially modulated by supraliminal and subliminal visual information. Our findings indicate remarkable sex dependency in the effects of subliminal visual information on cognitive functions.

Background: Lung adenocarcinoma shows distinct differences between males and females in incidence, prognosis, and treatment response, suggesting unique molecular mechanisms that remain underexplored. This study aims to identify sex-specific molecular signatures and therapeutic targets in lung adenocarcinoma using multi-omics approaches to inform personalized treatment strategies.

Methods: We conducted an integrative analysis of transcriptomic and proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) datasets, comparing male and female lung adenocarcinoma profiles. Transcription factor activity was assessed using TIGER on gene expression data, while kinase activity was evaluated with PTM-SEA on proteomic data. These results were combined to build a kinase-transcription factor signaling network. Potential sex-specific drugs were identified using the PRISM drug screening database.

Results: The analysis revealed significant sex-based differences in transcription factor and kinase activity. Notably, NR3C1, AR, and AURKA exhibited sex-biased expression and activity. The constructed signaling network highlighted druggable pathways linked to cancer-related processes, with distinct profiles in males and females. PRISM screening identified glucocorticoid receptor agonists and aurora kinase inhibitors as promising sex-specific therapeutic candidates.

Conclusions: Our findings underscore the importance of considering sex differences in lung adenocarcinoma molecular profiles. The integration of transcriptomic and proteomic data reveals sex-specific pathways and potential therapies, paving the way for personalized treatment approaches tailored to male and female patients.

Background: Emerging evidence suggests that genetic variants and environmental toxicants may synergistically contribute to DSD. To test this hypothesis, we employed Lhcgr^W495X/+ (luteinizing hormone/chorionic gonadotropin receptor) male mice subjected to prenatal Di-(2-ethylhexyl) phthalate (DEHP) exposure, a model designed to investigate steroidogenic gene expression in gene-environment interactions.

Methods: Pregnant wild-type (WT) dams (mated with Lhcgr^W495X/+ heterozygote (HET) received varying levels of DEHP: no exposure, low-dose (100 mg/kg/d) DEHP, and high-dose (1000 mg/kg/d) DEHP during gestation, which led to prenatal exposure in male offspring. Male offspring were divided into HET (Lhcgr^W495X/+) and WT groups based on genotype in three levels of DEHP exposure. The study assessed phenotypic characteristics (DSD, testosterone levels, and semen quality) and examined the expression of steroidogenic genes (Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd17b3, and Hsd3b2).

Results: Lhcgr^W495X/+ male offspring without DEHP exposure exhibited normal phenotypes and steroidogenic gene profiles. Low-dose DEHP had no detectable effects on WT offspring, but synergistically induced DSD in Lhcgr^W495X/+ male offspring by interfering with steroidogenic gene expression (Lhcgr, Hsd17b3, Hsd3b2). High-dose DEHP caused DSD in both genotypes, but the severity of DSD and interference with steroidogenic gene expression were more pronounced in Lhcgr^W495X/+ male offspring.

Conclusions: This study verifies that Genetic variants (Lhcgr^W495X/+) and environmental toxicants (DEHP) synergistically induce DSD, thereby elucidating the pathogenesis of DSD. Interfering with steroidogenic gene expression may be an important synergistical mechanism. This finding highlights the clinical imperative to minimize prenatal exposure to endocrine disruptors, particularly in pregnancies with variants of DSD.

Background: Systemic lupus erythematosus (SLE) is a complex immune-mediated disease with a strong female predominance. This sex bias may be linked to the presence of two X chromosomes, which are not always adequately dosage compensated by X chromosome inactivation (XCI). Disruption in X-linked transcriptome expression may contribute to altered immune function and increased susceptibility to autoimmunity.

Methods: To investigate the role of X-linked gene expression in SLE, we performed a comprehensive transcriptome analysis of 27 immune cell types from 125 female SLE patients and 66 healthy controls. We further applied a multivariate approach to integrate X-linked gene expression across all immune cell types and classify SLE patients. Additionally, we extended these models to other chromosomes and explored the correlation between autosome disease markers, including members of the XIST-interactome, and X-linked expression.

Results: We observed a significant increase in X-linked gene expression in T cells, B cells and plasmablasts, while monocytes and plasmacytoid dendritic cells exhibited the opposite trend. Multivariate models based solely on X-linked expression were highly accurate and highlighted key disease-associated markers. Interestingly, autosome-based models relied on markers highly correlated with X-linked gene expression and components of the XIST-interactome, which regulates XCI. Notably, we found that XIST lncRNA was consistently downregulated across multiple cell types, particularly in monocytes and Th1 cells. Such downregulation correlated with increased expression of SLE-associated genes, interferon signalling, and epigenetic regulators like KMT2D. Further analysis revealed extensive dysregulation of the XIST-interactome in SLE, predicting X-linked transcriptome alterations in a cell-type-specific manner.

Conclusions: Here, we present a comprehensive analysis of X-linked gene expression across immune cells in SLE. Our study highlights the complexity of X-linked transcriptional changes, with distinct patterns observed across both innate and adaptive immune cell types. These findings offer novel insights into the role of the X-transcriptome in sex-biased autoimmune susceptibility and may support future efforts to identify molecular targets relevant to SLE pathogenesis.

Background: Available evidence indicates that blood-brain-barrier (BBB) dysfunction exacerbates with the advancing age and is implicated in a variety of neurological diseases and that there are significant sex differences in these diseases. However, the sex differences and age-related changes in BBB structure and function are still unclear under physiological conditions.

Methods: In this study, the mRNA was extracted from the cortical tissues and brain microvessels of male and female mice aged 3 months and 10 months to detect the expression of important BBB-related genes by qPCR.

Results: Under physiological conditions, compared with age-matched male counterparts, female mice reported a significantly lower mRNA expression of tight junction-related genes (cldn5 and occludin), transporters (Glut1 and D-gp), pericyte marker (Pdgfrb), microvessel marker (Cd31), basement membrane component (Col4a2), glycocalyx-related genes (Hs3st1, Extl2, and Clgalt), vascular homeostasis-related genes (Hif1a, Ddit4, and Pik3ca), and some regulatory genes (Adm, Zfpm2 and Nr3c1). A similar outcome was found in the 10-month mice when compared with the 3-month counterparts.

Conclusion: This study systematically analyzes the expression characteristics of key BBB regulatory genes in different sexes and ages under physiological conditions and reveals a marked sex difference in the expression of BBB structure/function-related genes, which may persist with the advancing age. The findings may provide important theoretical insights into the pathogenesis of sex-and age-related neurological diseases.