Biology of Sex Differences最新文献

Background: The apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease; however, risk varies by sex and lifestyle. Regular physical activity is known to mitigate cognitive decline; whether the degree of benefit differs by APOE genotype, sex, and race remains unknown.

Methods: Analyses utilized data from 2,985 participants in the Health, Aging, and Body Composition (HABC) cohort, comprising community-dwelling black and white older adults followed for 10 years. Cognitive performance was assessed multiple times across the 10 years using the Digit Symbol Substitution Test (DSST) for executive functions and processing speed and the Modified Mini-Mental State Examination (3MS) for global cognition. APOE genotypes were categorized into ε2, ε3, and ε4 groups. Annual self-reported walking time was used to quantify physical activity. Linear mixed models and latent growth curve modeling examined the interactions between APOE genotype, sex, and walking on cognitive trajectories with adjustments for race, study location, health score, age, education attained, and body mass index.

Results: APOE ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared to ε3 carriers, irrespective of sex (all β<-0.13, all p < 0.004). APOE ε2 was protective longitudinally for 3MS in females only (β = 0.15, p < 0.002). Walking showed the strongest protective effect in APOE ε4 carriers for females and males in the rate of change of DSST and 3MS scores (all β > 0.27, all p < 0.044).

Discussion: These findings underscore the importance of public messaging about the benefits of regular physical activity for retaining cognitive function especially for persons genetically at heightened risk.

Background: Sexual differentiation of the brain is a complex ontogenetic process orchestrated by genetic and hormonal influences, leading to sex‑specific physiological and behavioral traits in adulthood. In mammals, the sex chromosome complement (SCC) contributes to this process by encoding unequal genetic information in XX and XY cells. Furthermore, SCC upregulates aromatase and estrogen receptor β (ERβ) expression in amygdala neurons of XY compared to XX embryos at embryonic day (E) 14. These molecules are critically implicated in the steroid-dependent programming of neural circuits during the subsequent critical window of sexual differentiation (E17-PN10). Since epigenetic mechanisms play a key role in specific target gene expression forming a layer of gene regulation, we aimed to contribute to a better understanding of their impact on the sexual differentiation of the brain.

Methods: Four Core Genotypes mouse model was employed to study the epigenetic machinery involved in DNA methylation and histone deacetylation in different brain regions (amygdala, hypothalamus, and cortex) to elucidate the underlying epigenetic landscape at E14 by RT-qPCR. Amygdala primary neuronal cultures were then established to evaluate the epigenetic regulation of Cyp19a1 (aromatase) and Esr2 (ERβ) expression. To assess this, pharmacological inhibition of DNA methylation, using zebularine, as well as Chromatin Immunoprecipitation (ChIP-qPCR) assays were performed.

Results: Sex-specific expression of DNA methyltransferases 3a and 3b, along with histone deacetylases 2 and 8, was higher in XX than XY embryos in a region- and developmental stage- dependent manner. Pharmacological inhibition of DNA methylation did not significantly alter aromatase expression in male or female amygdala neuronal cultures under the conditions tested. However, ChIP-qPCR assays revealed a selective enrichment of Acetyl-H4 at the Cyp19a1 promoter in male cultures that was not observed in females. No significant enrichment of the examined epigenetic marks was detected at the Esr2 promoter.

Conclusions: Acetylation of histone H4 contributes to promoting the higher Cyp19a1 expression previously observed in male neurons. Our findings support a model in which SCC plays a role in the epigenetic regulation of aromatase, a key enzyme involved in hormone-driven sexual differentiation of the male brain. Furthermore, the presence of two X chromosomes shapes a distinct epigenetic landscape in the brain during early development, highlighting the influence of chromosomal sex on the neurodevelopmental programming.

The immune system is central to maintaining homeostasis and orchestrating defense against infection and the regulation of inflammatory responses, yet its activity is far from uniform across individuals. Sex differences profoundly shape immune responses, with sex hormones driving distinct patterns of susceptibility to infectious diseases and inflammatory conditions. Nutrition further adds a powerful layer of modulation: vitamins, amino acids, and other bioactive compounds influence immune function and disease outcomes, often in a sex-dependent manner. The microbiome, whose composition is itself influenced by sex, is a critical regulator of both intestinal and systemic immune disorders, making it an attractive target for therapeutic intervention. In this review, we examine the dynamic interplay between sex, nutrition, and the immune system, emphasizing their combined impact on infection, inflammation, and immunomodulation. A deeper understanding of these interactions will be key to advancing personalized nutritional and therapeutic strategies designed to optimize immune health.

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which genetic predisposition plays a key role, yet the sex-specific mechanisms linking genetic risk to early cognitive changes remain unclear. This study examined the impact of polygenic risk scores (PRS) on early cognitive changes in 318 cognitively unimpaired participants from the ALFA+ cohort, a nested longitudinal cohort from the ALFA study (see details in Study Participants Section, Methods). Participants were followed for three years, with assessments across five cognitive domains and a preclinical composite (PACC). Global AD PRS, including and excluding the apolipoprotein E (APOE) gene, alongside five biologically informed pathway-specific PRS (amyloid, immune, external stimuli signaling, cholesterol efflux, lipoprotein metabolism) were computed. Generalized linear models including interaction by sex and stratified by sex and amyloid status (CSF Aβ42/40 < 0.071) assessed associations between PRS and cognitive change. In women, APOE-independent AD genetic risk predicted worse executive function, particularly via cholesterol efflux and external stimuli signaling pathways. Among Aβ + women, PRS also predicted lower memory performance, partially modulated by reproductive span. In Aβ - women, worse executive functioning performance was linked to amyloid, immune, and signaling pathways. In contrast, men showed associations between AD PRS and worse visual (Aβ-) and attentional (Aβ+) performance, independent of pathway-specific mechanisms. These findings reveal distinct, domain-specific cognitive vulnerabilities to AD genetic risk by sex and amyloid status, highlighting APOE-independent and mechanistic contributions to early and subtle cognitive changes. Results support the need for sex-aware, biologically informed genetic models in preclinical AD for risk stratification and early intervention.

AMPA receptors are a type of ionotropic glutamate receptor that is important for fast excitatory neurotransmission. healthy brain function. Glutamate signaling is regulated, in part, by the trafficking of glutamate receptors in and out of the synapse. Multiple different trafficking and auxiliary proteins govern this process. Disruptions in this trafficking are linked to various psychiatric diseases, including schizophrenia, major depressive disorder. Glutamate, the primary excitatory neurotransmitter, is crucial for synaptic plasticity and and substance use disorder. Moreover, the incidence and symptomology of these psychiatric diseases impact males and females differently. Despite these epidemiological sex differences, very little research has considered the influence of biological sex on glutamatergic trafficking. Here, we review the current literature on glutamate trafficking proteins for AMPA receptors, most of which have mainly utilized male rodents and cell cultures. The following proteins were explored for AMPA receptors: GRIP, PICK1, NSF, SAP97, AKAP79/150, Protein 4.1 N, and PSD-95. Overall, these studies revealed that our fundamental understanding of glutamate trafficking is based almost completely on studies performed in male animals, and the assumption that the same mechanisms govern AMPAR trafficking in females may not be correct. To fully grasp how these proteins are impacted in disease models, it's crucial to first understand the baseline sex differences. This is especially important if we want to investigate new research avenues for treating diseases that affect each sex differently.

Sex- and gender-related contributions to behavior "in the wild", as observed in humans in the natural context of their daily lives, can vary strikingly across individuals and be highly enmeshed - so much so that it is impossible to determine whether an average difference between women and men, for instance, reflects biological or sociocultural factors, respectively. Indeed, empirical insights may not just be limited, but may even be distorted, if study designs and data analyses continue to place unique people in ill-assumed homogenous groups for mean-based calculations. Findings may ultimately generalize to no one. An idiographic, or personalized, approach, however, reveals the intricate ways in which sex-related characteristics, such as gonadal hormones, and gender-related experiences combine to matter for behavior. This approach often requires novel data, that is, many repeated observations from the same people on the same variables, and time series analyses. The goal of this article is to briefly review perspectives on sex and gender in research, and then to illustrate how sex- and gender-related factors can be studied together in unique individuals using an idiographic approach. Specifically, person-specific analyses of data from select participants in three different intensive longitudinal studies with 75 or 100 assessment days will showcase unique relations between sex-related neuroendocrinology (i.e., menopause, oral contraceptive use, and puberty) and gender-related self-concepts (i.e., perceptions of masculinity and femininity), or demonstrate links with cognition or mental health. These illustrations will highlight the importance of leveraging methodological innovation to study the individualization of sex and gender, and the necessity of decreasing reliance on sex- and gender-linked assumptions of homogeneity in human neuroendocrine research.

Background: C-reactive protein (CRP) is a readily available test widely used to assess neonatal sepsis (NS). In children with sepsis or other infectious conditions, CRP is more likely to be higher in females than males, however, evidence is lacking on sex differences in CRP in the neonatal population. This study aims to describe sex differences of CRP evolution in the ascending and decreasing phase after its peak in neonates with likely NS.

Methods: This is a monocentric retrospective cohort study conducted at Etterbeek-Ixelles Hospital in Brussels. We included all neonates born in the facility between January 2017 and December 2022 who received antibiotics in the first 72 hours of life. Patients whose CRP concentrations remained under 10 mg/L were excluded. To describe the ascending kinetics of CRP and its logarithm for male and female neonates, we fitted a piecewise linear mixed-effects regression model with birth considered as time zero and one knot at 12 hours of life. We used a linear mixed-effects regression model with CRP peak considered as time zero to describe CRP's descending kinetics and its logarithm for male and female neonates.

Results: We included 506 neonates (60.1% male and 39.9% female). CRP concentration in the first 12 hours of life doubled every 3.2 and 2.8 hours, respectively, in males and females, with female neonates having a statistically significant faster rise of base 2 logarithm of CRP (+0.04 log2 mg/L/hour 95% CI= +0.01 +0.07). After 12 hours of life, CRP doubled every 6.5 and 8.6 hours, respectively, in males and females, with female neonates having a statistically significant slower rise of base 2 logarithm of CRP (-0.039 log2 mg/L/hour 95% CI= -0.02 -0.06). After its peak, CRP decreased by half every 31.1 and 30.9 hours, respectively, for males and females. No statistically significant sex differences were found in CRP peak or decline.

Conclusion: In neonates of both sexes with likely but unconfirmed NS, CRP seems to increase, reach a peak, and then decrease, following a logarithmic pattern. Before antibiotic treatment, female neonates in our population showed an earlier increase in CRP levels, with no difference in peak CRP levels.

Background: Several lines of evidence suggest that the sex-chromosome complement influences autosomal gene regulation and DNA methylation, however, the exact molecular mechanisms responsible for such effects remain elusive. X-linked epigenetic modifiers that escape X-chromosome inactivation, and hence have higher dosage in female cells, are the primary gene candidates for mediating the effects of X-dosage, whereas Y-linked paralogs may rescue such imbalance or have distinct effects on methylation.

Methods: Here, we tested the impacts of mutations in mouse histone lysine 4 demethylases Kdm5c (X-linked) and Kdm5d (Y-linked) on DNA methylation in mouse liver. KDM5C and KDM5D demethylate H3K4me2/3 thereby facilitating DNA methylation of their target DNA regions. Therefore, loss of either Kdm5c or Kdm5d is expected to reduce DNA methylation at such regions. We hypothesized that Kdm5c gene dosage was responsible for the X-dosage dependent DNA methylation in mouse liver and compared DNA methylation patterns in heterozygous mutant Kdm5c+/- and wild type females using whole genome bisulfite sequencing (WGBS) and DSS.

Results: We examined the impacts of mutations in Kdm5c or Kdm5d on genome-wide DNA methylation and found that they had different targets but tended to map close to H3K4me1-enriched regions. We also compared the Kdm5c and Kdm5d sensitive regions to regions with sex-chromosome complement dependent DNA methylation and found no overlaps.

Conclusions: In summary, while Kdm5c and Kdm5d have multi-locus effects on DNA methylation in mouse liver, they are unlikely to be solely responsible for sex-chromosome complement effects on DNA methylation in adult mouse liver.

Structural variants (SVs) may increase SOX3 expression in the gonads and have been observed in individuals with ovotesticular differences in sex development (OT-DSD) and XX testicular differences in sex development (T-DSD). Most of the SVs found in OT-DSD individuals are whole-gene duplications, and to date, only one SV affecting SOX3 expression by a positional effect has been described. We report an individual raised as a female with SRY-negative OT-DSD. Karyotype analysis showed a pericentric inversion in one of the X chromosomes - 46,X, inv(X)(p22;q27). The breakpoints and fusion were mapped using optical genome mapping (OGM) and short-read whole genome sequencing. One of the breakpoints was mapped on Xq27.1 (genomic position chrX:140,420,874 - GRCh38), 82 kb downstream of the SOX3 gene. This breakpoint was predicted to interrupt a topological associate domain (TAD) affecting 24 enhancer-promoter interactions of SOX3. RNA sequencing (RNA-seq) of a formalin-fixed paraffin-embedded (FFPE) sample of the gonads confirmed increased SOX3 expression. The present study is the first to analyze gene expression in gonadal tissues from an OT-DSD individual, and the first reporting an inversion-based mechanism leading to XX OT-DSD. Additionally, an X-inactivation assay on DNA extracted from the gonads revealed random inactivation. These findings support the hypothesis that inappropriate SOX3 expression may result from the positional effects of SVs, leading to OT-DSD in 46,XX individuals.

Background: Disorders of sex development (DSDs) exhibit high genetic and phenotypic heterogeneity, and genotype-phenotype correlations are not fully understood. 5α-Reductase type 2 (5α-RD2) deficiency, a common form of DSD, is caused by SRD5A2 inactivation. This study investigated the role of SRD5A2 haplotypes in DSD, focusing on their corresponding phenotypes, structural changes and impacts on enzyme activity.

Methods: This study enrolled 216 individuals with DSD who underwent genetic analysis and 2,794 controls. Linkage disequilibrium analysis was performed in individuals with 5α-RD2 deficiency to identify SRD5A2 haplotypes, and haplotype frequencies were analysed across cohorts. The clinical manifestations of individuals with different SRD5A2 haplotypes were characterized. Structural predictions were employed to investigate the impacts of haplotypes on the 5α-RD2 structure and interactions with ligands. Functionally, kinetic assays were conducted to validate the effects of different haplotypes on enzyme activity.

Results: A SRD5A2 haplotype composed of c.265C > G and c.680G > A (Hap3: G-A) was identified, and the haplotype frequency was 64.71% in individuals with 5α-RD2 deficiency, 2.59% and 1.22% in non-5α-RD2 deficiency DSD cases without or with known DSD-related gene variants, respectively, and 1.57% in in-house controls. Globally, Hap3: G-A was enriched in southern Chinese individuals and showed high population differentiation, indicating a potential founder effect of the haplotype. The majority of homozygotes of Hap3: G-A presented microphallus, and nearly half of them manifested isolated microphallus. Structurally, Hap3: G-A was predicted to result in an increase in the solvent-accessible surface area (10.72 Ų), a redistribution of hydrogen bonds within 5α-RD2, and a loss of key hydrogen bonds with NADPH. Functionally, kinetic assays showed that the catalytic efficiency of the enzyme encoded by Hap3: G-A was between that of Hap1: G-G and that of Hap2: C-A.

Conclusions: Hap3: G-A, which is prevalent in individuals with 5α-RD2 deficiency, suggests a potential founder effect. Structurally, compared with other haplotypes, Hap3: G-A seems to have a combined effect on the structure and interaction of 5α-RD2, rather than have merely additive effects of its constituent variants. Functionally, kinetic assays suggested a hypomorphic effect of Hap3: G-A. These findings provide valuable insights for understanding genotype-phenotype correlations, genetic counselling, early intervention and clinical management of individuals with 5α-RD2 deficiency or even other DSDs.