Search Results (206)

Sex-based immunological differences significantly influence the outcome of vaccination, yet the molecular mediators underpinning these differences remain largely elusive. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have emerged as critical modulators of innate and adaptive immune responses. In this study, we investigated the expression profile of selected circulating miRNAs as potential biomarkers of sex-specific humoral responses to the mRNA COVID-19 vaccine in a cohort of health care workers. Plasma samples were collected longitudinally at a defined time point (average 71 days) post-vaccination and analyzed using RT-qPCR to quantify a panel of immune-relevant miRNAs. Anti-spike (anti-S) IgG titers were measured by chemiluminescent immunoassays. Our results revealed sex-dependent differences in miRNA expression dynamics, with miR-221-3p and miR-148a-3p significantly overexpressed in vaccinated female HCWs and miR-155-5p overexpressed in vaccinated males. MiR-148a-3p showed a significant association with anti-S/RBD (RBD: receptor binding domain) IgG levels in a sex-specific manner. Bioinformatic analysis for miRNA targets indicated distinct regulatory networks and pathways involved in innate and adaptive immune responses, potentially underlying the differential immune activation observed between males and females. These findings support the utility of circulating miRNAs as minimally invasive biomarkers for monitoring and predicting sex-specific vaccine-induced immune responses and provide mechanistic insights that may inform tailored vaccination strategies. Full article

Background: We recently reported sex-dependent impairment in cognitive functions in male and female mice exposed for 24 h, 48 h or 15 days to 2G hypergravity (HG). Methods: In the present study, we investigated brain functional correlates by analyzing synaptic activity and plasticity in the CA1 area of the hippocampus in both genders of mice previously exposed to 2G for the same duration. This was assessed by electrophysiological extracellular recordings in ex vivo slice preparations. Results: Basal synaptic transmission and glutamate release were unchanged regardless of HG duration. However, plasticity was altered in a sex- and time-specific manner. In males, long-term potentiation (LTP) induced by strong high-frequency stimulation and NMDA receptor (NMDAr) activation was reduced by 26% after 24 h of exposure but recovered at later timepoints. This deficit was reversed by D-serine or glycine, suggesting decreased activation at the NMDAr co-agonist site. In females, LTP deficits (23%) were found only after 15 days following mild theta burst stimulation and were not reversed by D-serine. Long-term depression (LTD) was unaffected in both sexes. Conclusions: This study highlights, for the first time, sex-dependent divergence in the CA1 hippocampal plasticity timeline following 2G exposure. The synaptic changes depend on exposure duration and the stimulation protocol and could underlie the previously observed cognitive deficits. Full article

Autoimmune diseases such as systemic lupus erythematosus and Sjögren’s syndrome show pronounced sex disparities in prevalence, severity, and clinical outcomes, with females disproportionately affected. Emerging evidence highlights sex-based differences in immune and inflammatory responses as key contributors to this bias. Genetic factors—including sex chromosomes, skewed X chromosome inactivation, and sex-biased microRNAs—as well as sex hormones and pregnancy modulate gene expression and immune cell function in a sex-specific manner. Additionally, sex hormone-dependent epigenetic modifications influence the transcription of critical immune regulators. These genetic and hormonal factors collectively shape the activation, differentiation, and effector functions of diverse immune cell types. Environmental factors—including infections, gut microbiota, environmental chemicals and pollutants, and lifestyle behaviors such as diet, smoking, UV exposure, alcohol and caffeine intake, physical activity, and circadian rhythms—further modulate immune function and autoimmune disease pathogenesis in a sex-dependent manner. Together, these mechanisms contribute to the heightened risk and distinct clinical features of autoimmunity in females. A deeper understanding of sex-biased immune regulation will facilitate the identification of novel biomarkers, enable patient stratification, and inform the development of sex-specific diagnostic and therapeutic strategies for autoimmune diseases. Full article

Preterm birth (PTB) refers to a labor before 37 gestational weeks. This is a major global contributor to neonatal morbidity and mortality. Although fetal sex is frequently treated as a confounding variable in PTB research, relatively few studies have conducted sex-stratified analyses to investigate how male and female fetuses may respond differently to various intrauterine exposures. This represents an underexplored area with important implications for understanding fetal sexual dimorphism-specific vulnerability to adverse pregnancy outcomes. Understanding the role of fetal sex differences in the pathophysiology of preterm birth (PTB) regarding processes such as inflammation, placental dysfunction, and oxidative stress is crucial. These delicate processes are tightly interrelated, but also independently contribute to pregnancy complications. Recognizing fetal sex as a biological variable for such processes is essential for improving mechanistic insight, providing refined predictive models. Full article

Previous research has demonstrated sex-specific differences in muscle cells regarding sex hormone release and steroidogenic enzyme expression after testosterone exposure. The present study aims to elucidate sex-related differences in intracellular processes involved in myogenesis and regeneration. Neonatal 46XX and 46XY human primary skeletal muscle cells were treated with increasing doses of testosterone (0.5, 2, 5, 10, 32, and 100 nM) for 24 h. The molecular pathways involved in muscle metabolism and growth, as well as the release of myokines involved in satellite cell activation, were analyzed using western blot, real-time PCR, and a Luminex assay. The unpaired Student’s t-test and one-way ANOVA for repeated measures were used to determine significant variations within and between groups. An increase in the expression and release of MYF6, IGF-I, IGF-II, and CXCL1, as well as a decrease in GM-CSF, IL-9, and IL-12, was observed in 46XX cells. Conversely, testosterone up-regulated GM-CSF and CXCL1 in 46XY cells but did not affect the release of the other myokines. Preferential activation of the MAPK pathway was observed in 46XX cells, while the PI3K/AKT pathway was preferentially activated in 46XY cells. In conclusion, our findings demonstrate differential responses to androgen exposure in 46XX and 46XY cells, resulting in the activation of muscle cell growth and energy metabolic pathways in a sex-specific manner. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, with increasing evidence suggesting that their origins may lie in prenatal life. Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in the alteration of fetal programming mechanisms that cause a predisposition to long-term cardiovascular vulnerability. However, the impact of prenatal endocrine disruption on fetal heart development and its sex-specific nature remains incompletely understood. This study investigates the molecular and structural effects of low-dose prenatal BPA exposure on fetal rat hearts. Our results reveal that BPA disrupts estrogen receptor (ER) signaling in a sex-dependent manner, with distinct alterations in ERα, ERβ, and GPER expression. BPA exposure also triggers significant inflammation, oxidative stress, and ferroptosis; this is evidenced by elevated NF-κB, IL-1β, TNF-α, and NLRP3 inflammasome activation, as well as impaired antioxidant defenses (SOD1, SOD2, CAT, and SELENOT), increased lipid peroxidation (MDA) and protein oxidation, decreased GPX4, and increased ACSL4 levels. These alterations are accompanied by increased markers of cardiac distension (ANP, BNP), extracellular matrix remodeling mediators, and pro-fibrotic regulators (Col1A1, Col3A1, TGF-β, and CTGF), with a more pronounced response in males. Histological analyses corroborated these molecular findings, revealing structural alterations as well as glycogen depletion in male fetal hearts, consistent with altered cardiac morphogenesis and metabolic stress. These effects were milder in females, reinforcing the notion of sex-specific vulnerability. Moreover, prenatal BPA exposure affected myocardial fiber architecture and vascular remodeling in a sex-dependent manner, as evidenced by reduced expression of desmin alongside increased levels of CD34 and Ki67. Overall, our findings provide novel insights into the crucial role of prenatal endocrine disruption during fetal heart development and its contribution to the early origins of CVD, underscoring the urgent need for targeted preventive strategies and further research into the functional impact of BPA-induced alterations on postnatal cardiac function and long-term disease susceptibility. Full article

The anti-Müllerian hormone (amh) and its receptor, amhr2, along with the downstream bone morphogenetic protein receptors (bmprs), have been recognized as the central regulators in teleost sex determination (SD) and differentiation. However, their evolution and function in reproduction among diverse teleost lineages may represent species-specific patterns and still need more explanation. In this study, systematic investigations of amh signaling genes, including amh, amhy (Y-linked paralog of amh), amhr2, bmpr1, and bmpr2, were conducted among teleost species. The results revealed generally conserved gene copy number, phylogeny, structure, and synteny, among teleost amh signaling genes. Notably, significantly accelerated evolutionary rates (dN/dS) were found in teleost amhy compared to amh, and amh exhibited faster molecular evolution in amhy-SD teleosts than in non-amhy-SD teleosts, suggesting their enhanced evolutionary plasticity in teleosts. Expression profiling identified testis-biased expression of the most amh signaling genes in fish species with different SD genes and mechanisms, including Lateolabrax maculatus and Dicentrarchus labrax from Order Perciformes, Cynoglossus semilaevis and Paralichthys olivaceus from Order Pleuronectiformes, and Salmo salar and Oncorhynchus mykiss from Order Salmoniformes, with ovary-biased expression also found in Salmoniformes. A weighted gene co-expression network analysis further uncovered strong species-specific functional interactions between amh signaling components and genes of germ-cell development, the meiotic process, etc. Collectively, the integrated evidence from this study supports the hypothesis that amh signaling provides the key molecules governing sex differentiation in a species-specific manner in diverse teleost lineages, independent of its SD role, and interacts with functions of both testis and ovary development. Full article

Hormone-dependent phosphorylation of steroid receptors is a mechanism for modulating glucocorticoid receptor (GR) transcriptional responses. Evidence indicates that GR phosphorylation can influence receptor transcriptional activation in a gene-specific manner, which could have positive or negative impacts, where the relative level of phosphorylation is an important determinant of overall GR function. This review provides insights into the regulatory mechanism of GR phosphorylation in the brain, cellular and molecular specificity affecting neurovascular function, and the impact of GR phosphorylation in neurological disorders. Furthermore, the role of various endogenous and exogenous factors and sex-dependent associations with GR functional changes due to phosphorylation and other interlinking mechanisms are considered. Finally, we highlight the potential therapeutic approaches which have been evaluated, while challenging GR phosphorylation and the overall influence on the activity of GR in brain disorders. Full article

Background: The long-term effects of a perinatal high-fat diet on the cardiovascular function of offspring are not well elucidated. We hypothesize that perinatal exposure to a high-fat diet alters adult cardiovascular and immune responses in a sex-specific manner. Methods: Male and female offspring were born to perinatal high-fat (pHFD) or control diet (pCD)-fed C57BL/6 mothers and weaned to a control diet. Cardiovascular function (baseline and response to an acute isoproterenol stress test) was quantified at 8 weeks of age, and acute blood inflammatory response to a single low dose of lipopolysaccharide at 9 weeks of age. Results: Male pHFD offspring had identical baseline cardiovascular function compared to pCD mice but a blunted response to isoproterenol (20–45% reductions in cardiac output, stroke volume, and left ventricular fractional shortening). In contrast, baseline cardiovascular parameters were reduced in female pHFD compared to pCD offspring, but there was no effect of perinatal diet on response to isoproterenol. Concentrations of TNF-α and IL-6 in plasma two hours after a low-dose LPS administration were highest in female pCD mice. Conclusions: Perinatal high-fat diet exposure resulted in sex-specific adaptations in cardiovascular function and immune response. Female offspring displayed baseline impairments, whereas male offspring showed latent vulnerability under stress. These differences may reflect underlying hormonal or epigenetic mechanisms that diverge by sex. Future studies should examine the roles of sex hormones and gene regulation pathways to better understand these dimorphic outcomes. These findings emphasize the importance of maternal diet in shaping offspring cardiometabolic risks and highlight potential avenues for nutritional interventions during pregnancy. Full article

Malaria, the deadliest parasitic disease in the world, is sexually dimorphic, inflammatory, and oxidative. Males experience more severe symptoms and mortality than females do; therefore, the roles of 17β-estradiol and testosterone in this phenomenon have been studied. Both hormones affect oxidative stress, the primary mechanism of Plasmodium elimination. Estradiol has antioxidant activity, but the role of testosterone is controversial. Testosterone increases oxidative stress by reducing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities, which increase lipoperoxidation in the testis. However, the antioxidant properties of testosterone in prostate and nervous tissue have also been reported. The discrepancies are probably because when testosterone levels increase, the aromatase enzyme transforms testosterone into estrogens that possess antioxidant activity, which masks the results. Therefore, it is unknown whether testosterone is involved in the sexual dimorphism that occurs in oxidative stress in malaria. In this work, we administered testosterone and simultaneously inhibited aromatase with letrozole to evaluate the role of testosterone in the sexually dimorphic pattern of oxidative stress that occurs in the blood, spleen, and brain of male and female CBA/Ca mice infected with Plasmodium berghei ANKA (P. berghei ANKA). Testosterone triggers parasitemia in males, who also display more oxidative stress than females in the absence of infection, leading to sexually dimorphic patterns. Interestingly, increasing testosterone levels in infected mice reduced oxidative stress in males and increased oxidative stress in females, reversing or eliminating the dimorphic patterns observed. Oxidative stress varies in each tissue; the brain was the most protected, while the blood was the greatest damaged. Our findings highlight the role of testosterone as a regulator of oxidative stress in a tissue and sex-specific manner; therefore, understanding the role of testosterone in malaria may contribute to the development of sex-specific personalized antimalarial therapies. Full article

Anseriformes represent a basal order in the phylogeny of neognath birds and are of particular interest in cytogenetic research due to their distinctive chromosomal features. However, aspects of their chromosomal evolution, such as the distribution and organization of microsatellite sequences, remain poorly understood. Given the role of these dynamic repetitive sequences in chromosome organization, differentiation, and evolution, we analyzed microsatellite distribution in three Anatidae species, each representing a different subfamily: Amazonetta brasiliensis-Brazilian Teal (Anatinae), Coscoroba coscoroba-Coscoroba Swan (Anserinae), and Dendrocygna viduata-White-faced Whistling Duck (Dendrocygninae). This is the first karyotypic description for White-faced Whistling Duck (2n = 78) and Brazilian Teal (2n = 80), whereas Coscoroba Swan, previously analyzed, exhibits a notably high diploid number (2n = 98). Despite sharing a similar macrochromosome morphology, the three showed differences in diploid numbers and microsatellite distribution. Extensive microsatellite accumulation was found in both autosomal and sex chromosomes (Z and W) of Brazilian Teal and Coscoroba Swan, while White-faced Whistling Duck displays minimal hybridization signals and an absence of microsatellites on the sex chromosomes. The accumulation of specific microsatellites, such as (CAC)₁₀ and (GAG)₁₀, in centromeric and pericentromeric regions suggests an association with transposable elements, potentially driving chromosomal evolution. Notably, the substantial accumulation of these sequences on the Z and W chromosomes of Brazilian Teal and Coscoroba Swan, but not White-faced Whistling Duck, supports the hypothesis that repetitive sequence expansion occurs in a species-specific manner, contributing to sex chromosome differentiation. These findings highlight microsatellite mapping as a valuable tool for understanding chromosomal evolution and genomic differentiation in Anseriformes. Full article

Background: Left ventricular hypertrophy (LVH) is a key predictor of cardiovascular disease. This study aimed to investigate the correlation between LVH and regional adipose tissue deposits, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT), and sex-related differences in these correlations. Methods: A total of 416 individuals (median age 66 years, range 20–95), without structural heart disease or a history of hypertension and coronary artery disease, underwent echocardiography and abdominal computed tomography. Statistical analyses included logistic and linear regression to assess the associations between adipose tissue measures and LVH. Results: LVH was associated with older age, higher systolic blood pressure, and increased EAT thickness. EAT thickness was independently associated with LVH in women (OR 1.21, 95% CI 1.03–1.44, p = 0.024) but not in men. Scatter plot analysis revealed a positive correlation between EAT and left ventricular mass index (LVMI) in women (r = 0.366, p < 0.001) and a negative correlation in men (r = −0.153, p = 0.038). Conclusions: VAT and SAT showed no significant associations with LVMI or LVH in either sex. These findings suggest that EAT, but not VAT or SAT, is linked to cardiac remodeling in a sex-specific manner. Full article

Asthma, a chronic inflammatory airway disease, leads to airflow obstruction and exhibits sex differences in prevalence and severity. Immunomodulatory diets, such as the ketogenic diet (high fat, low carbohydrate, moderate protein), may offer complementary benefits in managing airway inflammation. While anti-inflammatory effects of ketogenic diets are documented in cardiovascular diseases, their impact on asthma, especially regarding sex-specific differences, remains unexplored. Few studies on diet and asthma have considered sex as a biological factor. To test the hypothesis that a ketogenic diet affects airway inflammation in a sex-specific manner, we used a mouse allergic airway inflammation model. Male and female C57BL/6J mice (3–4 weeks old, n = 5–6/group) were fed a ketogenic diet or normal chow for 12 weeks. From weeks 7 to 12, mice were challenged intranasally with house dust mite allergens (HDM) 5 days/week to induce airway inflammation. Lung tissue was analyzed 72 h post-exposure using flow cytometry to assess immune cell populations, and data were analyzed with two-way ANOVA. The ketogenic diet increased body weight in allergen-exposed mice, with a greater effect in males than females (p = 0.0512). Significant sex–diet interactions were noted for alveolar macrophages, CD103⁺, CD11B⁺, and plasmacytoid dendritic cells (p < 0.05). Eosinophil reductions were observed in males but not females on the ketogenic diet. The diet also increased NKT cells and decreased NK cells in males but not females (p < 0.001). These findings highlight sex-specific effects of ketogenic diets on lung immune responses, with stronger impacts in males. Full article

Why might women who experience intimate partner violence (IPV) become more likely to engage in risky sexual behavior? Women’s interest in casual sex may satisfy relational expectations and connection needs, while avoiding the types of close attachments that previously were violent. Specifically, attachment avoidance was tested as a mechanism linking IPV victimization and risky sexual behavior. Women who experienced (vs. did not experience) partner violence reported higher rates of risky sexual behavior, and this association was mediated by attachment avoidance (Study 1, N = 312; age range 18–58 years, M = 28). Making IPV salient via an experimental manipulation caused more avoidant perceptions (Study 2, N = 140; age range 19–57 years, M = 31), and inducing an avoidant mindset via an experimental manipulation caused greater sexual interest (Study 3, N = 128; age range 19–66 years, M = 33). These findings suggest that IPV disrupts expectations of security and reinforces a manner of connecting with partners that leads to risky sexual encounters. Full article

The dietary habits of fruit flies profoundly influence their fitness, morphology, and physiology yet the mechanisms underlying these effects remain incompletely understood. To address this gap, the relationship between dietary regimens and the composition and function of adult Drosophila melanogaster microbiota was investigated in the present study. The adult fly microbiota communities that were reared for long time on five different diets were characterized by means of 16S rRNA sequencing. Obtained results revealed distinct community structures associated with each dietary regimen, which was additionally corroborated through machine learning-based analysis. In general, sugar-rich diets correlate with microbial ecosystems of higher richness/diversity. Dominance of the phyla Proteobacteria and Firmicutes in the microbiota was confirmed irrespective of diet, with the varying proportions of the most abundant families: Acetobacteraceae, Lactobacillaceae, Moraxellaceae, Bradyrhizobiaceae, and Leucostonocaceae. Bacterial families of lower abundance also emerged as differentially present among the studied fly groups. Additionally, functional prediction provided initial clues into how nutrient availability might modulate the metabolic traits of adult fly microbiota in a sex-specific manner to meet host metabolic needs. Overall, the presented findings highlight the intricate interplay between diet, microbiota composition, and host phenotype in fruit flies, underscoring the importance of diet as a determinant of host-microbiota interactions. Full article