Biology of Sex Differences最新文献

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.

Background: Women tend to progress from initial alcohol use to dependence more rapidly than men, a phenomenon known as the "telescoping effect". This suggests different consequences of early alcohol use, which can impact the development of an Alcohol Use Disorder (AUD). Previous evidence demonstrated that nucleus accumbens core (NAcC) chemogenetic manipulations resulted in opposite effects on binge-like drinking [stimulation decreased ethanol intake in C57BL/6J (B6) females, while inhibition decreased intake in males]. In humans, ethanol cue conditioning is linked to the positive subjective effects of alcohol intake and intoxication. We tested the hypothesis that chemogenetic manipulation of NAcC activity alters ethanol reward (measured by conditioned place preference, CPP) in a sex-specific manner.

Methods: In Experiment 1, surgery naïve B6 mice (n = 11-12/sex/treatment) underwent an ethanol CPP protocol and were administered the Designer Receptors Exclusively Activated by Designer Drugs (DREADD) actuator clozapine-N-oxide (CNO, 1 mg/kg) or vehicle prior to ethanol (2 g/kg) conditioning. In Experiment 2, B6 mice underwent surgery to deliver control (mCherry), excitatory (hM3Dq), or inhibitory (hM4Di) DREADDs to the NAcC (n = 8-13/sex/treatment). After recovery, mice underwent ethanol CPP as in Experiment 1. CPP was conducted in a 3-chamber apparatus. Time spent in each chamber was recorded during the pre-test (before conditioning), and the test (after 4 ethanol and 4 saline conditioning sessions). Data were analyzed separately by sex, viral condition, and treatment with a 2-way RM ANOVA [factors: Time (repeated measure), Chamber].

Results: Both surgery naïve (Experiment 1) and mCherry-expressing female and male B6 mice condition similarly to an intoxicating dose of ethanol and CNO did not interfere with ethanol CPP in the absence of DREADDs. Experiment 2 revealed that NAcC chemogenetic stimulation prevented ethanol CPP in males, while NAcC chemogenetic inhibition prevented ethanol CPP in females.

Conclusions: NAcC chemogenetic manipulations alter ethanol reward differently in male and female B6 mice. Together with prior work, we demonstrate that NAcC activity has a sex-specific role during ethanol reward and consumption. Evidence of sex differences in ethanol reward may help future research to uncover the mechanisms underlying the "telescoping effect" and why women have an increased risk for developing an AUD.

Background: Obesity is a global health challenge that can lead to various complications, such as metabolic syndrome, diabetes mellitus, and cardiovascular diseases. Heat shock proteins are evolutionarily conserved chaperones that help maintain cellular protein homeostasis. Their expression is dysregulated in various chronic diseases, including diabetes mellitus and hyperlipidemia, and they also regulate inflammatory processes. Therefore, the present study aimed to investigate the effects of a small heat shock protein, HSPB1, on the comorbidities and complications of obesity in a transgenic mouse model.

Methods: Male and female human apolipoprotein B-100 (APOB) transgenic mice fed with a high-fat diet (HFD) from months 3-10 of age were used as a model of metabolic syndrome (MetS). To study whether HSPB1 influences the development of MetS, APOB animals were crossed with HSPB1-overexpressing mice. Age and sex-matched wild-type and human HSPB1-overexpressing mice were used as controls. Changes in cardiac morphology and function were assessed by transthoracic echocardiography at month 9. At month 10, serum triglyceride and cholesterol concentrations were determined by enzymatic colorimetric assays. Pathological changes in the liver were studied on hematoxylin-eosin-stained sections. Expression levels of genes involved in inflammation and metabolism were measured by quantitative real-time polymerase chain reaction in the liver, left ventricle, and visceral white adipose tissue (vWAT).

Results: The body weight and serum LDL-cholesterol levels were significantly higher in the APOB animals than in the wild-type mice in both sexes. Notably, HSPB1 overexpression further increased weight gain in female APOB animals. Conversely, in APOB males, HSPB1 overexpression decreased LDL-cholesterol levels without significantly affecting body weight. Furthermore, in APOB females, HSPB1 overexpression elevated Fgf-21 expression in the vWAT, restored Lpl levels, and reduced the expression of several cytokines in the liver. APOB males developed left ventricular hypertrophy (LVH) with diastolic dysfunction. HSPB1 overexpression induced LVH without cardiac dysfunction in the wild-type animals.

Conclusions: Both sexes of APOB animals developed MetS. APOB males presented LVH with preserved ejection fraction (EF); however, APOB females showed enlarged left ventricular end-systolic volume (LVESV). In APOB animals, HSPB1 overexpression exerted a sex-dependent influence on obesity-related alterations, including weight gain, hypercholesterolemia, and hepatic and vWAT gene expression.