Biology of Sex Differences最新文献

Systemic lupus erythematosus (SLE or lupus) is an immune-mediated disease associated with substantial medical burden. Notably, lupus exhibits a striking female bias, with women having significantly higher susceptibility compared to men, up to 14-fold higher in some ethnicities. Supernumerary X chromosome syndromes, like Klinefelter (XXY) and Triple X syndrome (XXX), also present higher SLE prevalence, whereas Turner syndrome (XO) displays lower prevalence. Taken together, SLE prevalence in different X chromosome dosage sceneries denotes a relationship between the number of X chromosomes and the risk of developing lupus. The dosage of X-linked genes, many of which play roles in the immune system, is compensated between males and females through the inactivation of one of the two X chromosomes in female cells. X-chromosome inactivation (XCI) initiates early in development with a random selection of which X chromosome to inactivate, a choice that is then epigenetically maintained in the daughter cells. This process is regulated by the X-Inactive-Specific Transcript (XIST), encoding for a long non-coding RNA, exclusively expressed from the inactive X chromosome (Xi). XIST interacts with various RNA binding proteins and chromatin modifiers to form a ribonucleoprotein (RNP) complex responsible for the transcriptional silencing and heterochromatinization of the Xi. This ensures stable silencing of most genes on the X chromosome, with only a few genes able to escape this process. Recent findings suggest that the molecular components involved in XCI, or their dysregulation, contribute to the pathogenesis of lupus. Indeed, nonrandom XCI, elevated gene escape from XCI, and the autoimmune potential of the XIST RNP complex have been suggested to contribute to auto-immune diseases, such as lupus. This review examines these current hypotheses concerning how this dosage compensation mechanism might impact the development of lupus, shedding light on potential mechanisms underlying the pathogenesis of the disease.

Background: Sex differences exist not only in the efficacy but also in adverse event rates of many vaccines. Here we compared the safety of BNT162b2 vaccine administered off-label in female and male children younger than 5 years in Germany.

Methods: This is a retrospective cohort study, in which we performed a post-hoc analysis of a dataset collected through an authentication-based survey of individuals having registered children aged 0-<5 years for vaccination against SARS-CoV-2 in six private practices and/or two lay person-initiated vaccination campaigns. We analyzed the safety profiles of the first 3 doses of 3-10 µg BNT162b2. Primary outcome was comparison in frequencies of 4 common post-vaccination symptom categories such as local, general, musculoskeletal symptoms and fever. Data were analyzed according to sex in bivariate analyses and regression models adjusting for age, weight, and dosage. Interaction between sex and BNT162b2 dosage was assessed. An active-comparator analysis was applied to compare post-vaccination symptoms after BNT162b2 versus non-SARS-CoV-2 vaccines.

Results: The dataset for the present analysis consisted of 7801 participants including 3842 females (49%) and 3977 males (51%) with an age of 3 years (median, interquartile: 2 years). Among individuals receiving 3 µg BNT162b2, no sex differences were noted, but after a first dose of 5-10 µg BNT162b2, local injection-site symptoms were more prevalent in girls compared to boys. In logistic regression, female sex was associated with higher odds of local symptoms, odds ratio (OR) of 1.33 (95% confidence interval [CI]: 1.15-1.55, p < 0.05) and general symptoms with OR 1.21 (95% CI: 1.01-1.44, p < 0.05). Following non-BNT162b2 childhood vaccinations, female sex was associated with a lower odds of post-vaccination musculoskeletal symptoms (OR: 0.29, 95% CI: 0.11-0.82, p < 0.05). An active comparator analysis between BNT162b2 and non-SARS-CoV-2 vaccinations revealed that female sex positively influenced the association between BNT162b2 vaccine type and musculoskeletal symptoms.

Conclusions: Sex differences exist in post-vaccination symptoms after BNT162b2 administration even in young children. These are of importance for the conception of approval studies, for post-vaccination monitoring and for future vaccination strategies (German Clinical Trials Register ID: DRKS00028759).

Background: Adolescent stress and alcohol exposure increase the risk of maladaptive behaviors and mental disorders in adulthood, with distinct sex-specific differences. Understanding the mechanisms underlying these early events is crucial for developing targeted prevention and treatment strategies.

Methods: Male and female Wistar rats were exposed to acute restraint stress and intermittent alcohol during adolescence. We assessed lasting effects on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, and mRNA expression of genes related to corticotropin releasing hormone (CRH), neuropeptide Y (NPY), corticoid, opioid, and arginine vasopressin systems in the amygdala and hypothalamus.

Results: The main findings are as follows: (1) blood alcohol concentrations (BAC) increased after the final alcohol administration, but stressed males had lower BAC than non-stressed males; (2) Males gained significantly more weight than females; (3) Stressed females showed higher ACTH levels than non-stressed females, with no changes in males; (4) Stress increased CORT levels in males, while stressed, alcohol-treated females had lower CORT levels than non-stressed females; (5) CRH: Females had lower Crhr1 levels in the amygdala, while alcohol reduced Crhr2 levels in males but not females. Significant interactions among sex, stress, and alcohol were found in the hypothalamus, with distinct patterns between sexes; (6) NPY: In the amygdala, stress reduced Npy and Npy1r levels in males but increased them in females. Alcohol decreased Npy2r levels in males, with varied effects in females. Similar sex-specific patterns were observed in the hypothalamus; (7) Corticoid system: Stress and alcohol had complex, sex-dependent effects on Pomc, Nr3c1, and Nr3c2 in both brain regions; (8) Opioid receptors: Stress and alcohol blunted the elevated expression of Oprm1, Oprd1, and Oprk1 in the amygdala of males and the hypothalamus of females; (8) Vasopressin: Stress and alcohol interacted significantly to affect Avp and Avpr1a expression in the amygdala, with stronger effects in females. In the hypothalamus, alcohol increased Avp levels in females.

Conclusions: This study demonstrates that adolescent acute stress and alcohol exposure induce lasting, sex-specific alterations in systems involved in reward and stress responses. These findings emphasize the importance of considering sex differences in the prevention and management of HPA dysfunction and psychiatric disorders.

Background: Blotched snakehead (Channa maculata) displays significant sexual dimorphism, with males exhibiting faster growth rates and larger body sizes compared to females. The cultivation of the all-male population of snakeheads holds substantial economic and ecological value. Nonetheless, the intricate processes governing the development of bipotential gonads into either testis or ovary in C. maculata remain inadequately elucidated. Therefore, it is necessary to determine the critical time window of sex differentiation in C. maculata, providing a theoretical basis for sex control in production practices.

Methods: The body length and weight of male and female C. maculata were measured at different developmental stages to reveal when sexual dimorphism in growth initially appears. Histological observations and spatiotemporal comparative transcriptome analyses were performed on ovaries and testes across various developmental stages to determine the crucial time windows for sex differentiation in each sex and the sex-related genes. Additionally, qPCR and MG2C were utilized to validate and locate sex-related genes, and levels of E₂ and T were quantified to understand sex steroid synthesis.

Results: Sexual dimorphism in growth became evident starting from 90 dpf. Histological observations revealed that morphological sex differentiation in females and males occurred between 20 and 25 dpf or earlier and 30-35 dpf or earlier, respectively, corresponding to the appearance of the ovarian cavity or efferent duct anlage. Transcriptome analyses revealed divergent gene expression patterns in testes and ovaries after 30 dpf. The periods of 40-60 dpf and 60-90 dpf marked the initiation of molecular sex differentiation in females and males, respectively. Male-biased genes (Sox11a, Dmrt1, Amh, Amhr2, Gsdf, Ar, Cyp17a2) likely play crucial roles in male sex differentiation and spermatogenesis, while female-biased genes (Foxl2, Cyp19a1a, Bmp15, Figla, Er) could be pivotal in ovarian differentiation and development. Numerous biological pathways linked to sex differentiation and gametogenesis were also identified. Additionally, E₂ and T exhibited sexual dimorphism during sex differentiation and gonadal development. Based on these results, it is hypothesized that in C. maculata, the potential male sex differentiation pathway, Sox11a-Dmrt1-Sox9b, activates downstream sex-related genes (Amh, Amhr2, Gsdf, Ar, Cyp17a2) for testicular development, while the antagonistic pathway, Foxl2/Cyp19a1a, activates downstream sex-related genes (Bmp15, Figla, Er) for ovarian development.

Conclusions: This study provides a comprehensive overview of gonadal dynamic changes during sex differentiation and gametogenesis in C. maculata, establishing a scientific foundation for sex control in this species.

Background: Hepatitis B, a liver infection caused by the hepatitis B virus (HBV), can develop into a chronic infection that puts patients at high risk of death from cirrhosis and liver cancer. In this study, we aimed to investigate the difference of reactome pre-Notch expression and processing between males and females by using gene to function analysis in FUMA.

Methods: We analyzed Taiwan Biobank (TWB) data pertaining to 48,874 women and 23,178 men individuals which were collected from 2008 to 2019. According to hepatitis B surface antigen (HBsAg) status in hematology, positive and negative were classified into case and control in the genome-wide association study (GWAS) analysis.

Results: We found 4715 women and 2656 men HBV cases. The genomic risk loci were different between males and females. In male, three risk loci (rs3732421, rs1884575 and Affx-28516147) were detected while eight risk loci (Affx-4564106, rs932745, rs7574865, rs34050244, rs77041685, rs107822, rs2296651 and rs12599402) were found in female. In addition, sex also presented different results. In females, the most significant SNPs are gathered in chromosome 6. However, except for chromosome 6, significant HBV infection SNPs also could be found in chromosome 3 among males. We further investigated gene function in FUMA to identify the difference in reactome pre-Notch expression and processing between males and females. We found that POGLUT1 and HIST1H2BC only appeared in men but not in women.

Conclusion: According to our study, the reactome pre-Notch expression including POGLUT1 and HIST1H2BC was associated with a risk of Hepatitis B in Taiwanese men when compared to women.

Background: Lowering LDL-cholesterol is a fundamental goal for both primary and secondary prevention of atherosclerotic cardiovascular diseases. Our study aims to analyse potential sex disparities regarding the tolerability and effectiveness of lipid-lowering therapy in patients with and without reported statin intolerance who are being treated at a lipid-outpatient clinic.

Methods: From 2017 to 2022, n = 1062 patients (n = 612 men, n = 450 women) at high-risk were referred to our lipid-outpatient clinic because of difficulties in lipid control by primary healthcare providers. The main therapeutic objective was to optimize lipid-lowering therapy according to current treatment guidelines.

Results: Patients presented with high LDL-C baseline levels (4.97 ± 1.81 mmol/l (192 ± 70 mg/dL) in men and 5.46 ± 2.04 mmol/l (211 ± 79 mg/dL) in women). Intolerance towards statins was reported more frequently by women (48.2%) than by men (38.9%, p = 0.004). LDL-C continuously decreased with individual treatment adjustments across follow-up visits. In total, treatment goals (LDL < 1.4 mmol/l (< 55 mg/dl) or < 1.8 mmol/l (< 70 mg/dl)) were accomplished in 75.8% of men and 55.5% of women after the last follow-up visit (p < 0.0001). In men, these data are almost identical in subjects with statin intolerance. In contrast, treatment goals were reached less frequently in women with statin intolerance compared to women tolerant to statin therapy.

Conclusion: Even if treated in a specialized lipid clinic, women are less likely to reach their target LDL-C than men, particularly when statin intolerant. Nevertheless, many patients with statin intolerance can be successfully treated using oral combination and PCSK9 inhibitor therapy. However, ongoing follow-up care to monitor progress and to adjust treatment plans is necessary to reach this goal.