Mediate Sex Differences Research Articles

Leading mediators of sex differences in the incidence of dementia in community-dwelling adults in the UK Biobank: a retrospective cohort study

BackgroundLittle is known regarding whether sex assigned at birth modifies the association between several predictive factors for dementia and the risk of dementia itself.MethodsOur retrospective cohort study included 214,670 men and 214,670 women matched by age at baseline from the UK Biobank. Baseline data were collected between 2006 and 2010, and incident dementia was ascertained using hospital inpatient or death records until January 2021. Mediation analysis was tested for 133 individual factors.ResultsOver 5,117,381 person-years of follow-up, 5928 cases of incident all-cause dementia (452 cases of young-onset dementia, 5476 cases of late-onset dementia) were documented. Hazard ratios (95% CI) for all-cause, young-onset, and late-onset dementias associated with the male sex (female as reference) were 1.23 (1.17–1.29), 1.42 (1.18–1.71), and 1.21 (1.15–1.28), respectively. Out of 133 individual factors, the strongest mediators for the association between sex and incident dementia were multimorbidity risk score (percentage explained (95% CI): 62.1% (45.2–76.6%)), apolipoprotein A in the blood (25.5% (15.2–39.4%)), creatinine in urine (24.9% (16.1–36.5%)), low-density lipoprotein cholesterol in the blood (23.2% (16.2–32.1%)), and blood lymphocyte percentage (21.1% (14.5–29.5%)). Health-related conditions (percentage (95% CI) explained: 74.4% (51.3–88.9%)) and biomarkers (83.0% (37.5–97.5%)), but not lifestyle factors combined (30.1% (20.7–41.6%)), fully mediated sex differences in incident dementia. Health-related conditions combined were a stronger mediator for late-onset (75.4% (48.6–90.8%)) than for young-onset dementia (52.3% (25.8–77.6%)), whilst lifestyle factors combined were a stronger mediator for young-onset (42.3% (19.4–69.0%)) than for late-onset dementia (26.7% (17.1–39.2%)).ConclusionsOur analysis matched by age has demonstrated that men had a higher risk of all-cause, young-onset, and late-onset dementias than women. This association was fully mediated by health-related conditions or blood/urinary biomarkers and largely mediated by lifestyle factors. Our findings are important for understanding potential mechanisms of sex in dementia risk.

Lean Mass is Associated with, but Does Not Mediate Sex Differences in Pressure Pain Sensitivity in Healthy Adults.

Sex differences exist in pain sensitivity, however, the underlying mechanism(s) that explain these differences are not fully understood. Pain sensitivity has been shown to be influenced by body mass index, but limited data exist on the role of body composition on pain sensitivity. The purpose was to examine the influence of body composition on pain sensitivity in males and females. This cross-sectional study design used pressure pain thresholds (PPT) of 87 participants (45 female) who were assessed in the vastus lateralis (leg PPT) and brachioradialis (arm PPT) using a pressure algometer. Fat and lean tissue were assessed via dual-energy X-ray absorptiometry (DXA). A two group by two limb, repeated measured ANOVA was used to assess differences between limbs and sex. Spearman correlations and hierarchical regression analyses were employed to determine the association between body composition and PPT. Males had higher PPTs then females (P<0.05) and had higher DXA assessed lean and lower levels fat mass (P<0.05). Total body and limb specific lean mass was associated with PPTs (r≥0.34; P<0.05). Hierarchical regression analysis revealed lean mass was a significant predictor of 8% of the variance in arm PPT (P<0.006) and 18% of the variance in leg PPT (P<0.001). However, lean mass was not found to statistically mediate the observed sex differences in PPT. This finding suggests lean mass may play a previously unknown role in sex differences in pressure pain sensitivity. Future studies are needed to confirm this finding and a larger sample size is likely required to have sufficient power to perform the mediation analysis.

BDNF expression partially mediates greater verbal learning and memory ability in a cohort enriched with risk for Alzheimer’s disease

AbstractBackgroundIn cognitively normal adults, women score higher than men in verbal learning ability (VLM)—a cognitive domain sensitive to decline in Alzheimer’s disease (AD). Sex‐specific mechanisms of action in brain‐derived neurotrophic factor (BDNF), a growth factor important for modulating memory and long‐term brain health, may explain this observed sex difference. Therefore, this study examines whether circulating BDNF expression mediates sex differences in VLM scores in a cohort enriched with risk for AD.MethodCognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=201, age 63.81±6.04y, 66.2% women, 65.7% family history of AD, 38% APOE‐ε4 carriers) underwent the Rey Auditory Verbal Learning Test (RAVLT). Scores from the delayed recall test and trials 3‐5 and were aggregated as a VLM performance index. Serum BDNF levels were measured using a Human BDNF Quatikine Immunoassay (R&amp;D Systems). Mediation analysis and bootstrapping were performed using the Hayes and Preacher macro for SPSS, first using the full participant sample. Stratified models were then assembled to test the conditional dependence of BDNF mediation on APOE‐ε4 allele carriage.ResultFrom the full sample, women had significantly higher VLM scores [β=‐0.68; p&lt;0.01] and serum BDNF levels [β=‐0.61; p&lt;0.01] than men; BDNF expression was likewise positively correlated with VLM [β=0.17; p=0.014]. Bootstrapping indicated that BDNF was indeed a significant partial mediator of the association between sex and VLM [β=‐0.07; 95% CI: ‐0.164, ‐0.005]. Models stratified by APOE‐ε4 carriage showed no significant association between sex and BDNF in APOE‐ε4+ individuals [β=‐0.13; p=0.63], but women in this group again had significantly higher VLM scores than men [β=‐0.57; p=0.02]. By comparison, in the APOE‐ε4‐ group, women had significantly higher BDNF levels [β=‐0.65; p&lt;0.01] and VLM scores [β=‐1.01; p&lt;0.01], and bootstrapping again showed BDNF to be a significant mediator [β=‐0.16; 95% CI: ‐0.324, ‐0.037].ConclusionOur findings indicate that higher circulating BDNF levels in women might be an important factor in building resilience against verbal memory decline, but this relationship may be attenuated by the deleterious effects of APOE‐ε4 allele carriage.

Sex and N-terminal pro B-type natriuretic peptide: The potential mediating role of iron biomarkers.

Levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a marker of heart failure and cardiovascular risk, are generally higher in women than men. We explored whether iron biomarkers mediate sex differences in NT-proBNP levels. We included 5,343 community-dwelling individuals from the Prevention of Renal and Vascular Endstage Disease study. With linear regression analyses, we investigated the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. The assessed iron biomarkers included ferritin, transferrin saturation (TSAT), hepcidin, and soluble transferrin receptor (sTfR). Next, we performed mediation analyses to investigate to which extent iron biomarkers influence the association between sex and NT-proBNP. Of the included 5,343 participants, the mean standard deviation age was 52.2 ± 11.6 years and 52% were females. After adjustment for potential confounders, women compared to men, had higher NT-proBNP (β = 0.31; 95%CI = 0.29, 0.34), but lower ferritin (β = -0.37; 95%CI = -0.39, -0.35), hepcidin (β = -0.22, 95%CI = -0.24, -0.20), and TSAT (β = -0.07, 95% CI = -0.08, -0.06). Lower ferritin (β = -0.05, 95%CI = -0.08, -0.02), lower hepcidin (β = -0.04, 95%CI = -0.07, -0.006), and higher TSAT (β = 0.07; 95%CI = 0.01, 0.13) were associated with higher NT-proBNP. In mediation analyses, ferritin and hepcidin explained 6.5 and 3.1% of the association between sex and NT-proBNP, respectively, while TSAT minimally suppressed (1.9%) this association. Our findings suggest that iron biomarkers marginally explain sex differences in levels of NT-proBNP. Future studies are needed to explore causality and potential mechanisms underlying these pathways.

Neural Mechanisms Mediating Sex Differences in Motivation for Reward: Cognitive Bias, Food, Gambling, and Drugs of Abuse.

Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research.

Sex Differences in Racing History of Recreational 10 km to Ultra Runners (Part B)-Results from the NURMI Study (Step 2).

Sex differences in anatomy and physiology are the primary underlying factor for distinctions in running performance. Overall participation in recreational running events has been dominated by males, although increasing female participation has been reported in recent years. The NURMI study participants filled in a survey following the cross-sectional study design with questions on sociodemographic data, running and racing motivations, training behaviors, and racing history and experience. Data analysis included 141 female and 104 male participants aged 39 (IQR 17) with a healthy median BMI (21.7 kg/m²; IQR 3.5). Statistical analyses revealed sex differences with the males performing faster at half-marathon (p < 0.001) and marathon (p < 0.001) events but no difference at ultra-marathons (p = 0.760). Mediation analyses revealed no significant sex differences in the performance of half-marathon and marathon when considering training behaviors (p > 0.05), racing history (p > 0.05), or racing experience (p > 0.05). Differences in recreational performance may be more closely related to social constraints and expectations of females rather than the physiological advantages of the male athlete. Health professionals who guide and support recreational runners as well as the runners themselves and their coaches may benefit from this study’s results in order to improve the best time performance through a deeper understanding of the areas that mediate sex differences.

Sex Differences in Traditional School Bullying Perpetration and Victimization among Adolescents: A Chain-Mediating Effect.

The study explored sex differences in traditional school bullying perpetration and victimization among Chinese adolescents and the effects of Machiavellianism and school climate. Data were collected from 727 adolescents (M = 16.8 years, SD = 0.9) who completed the Olweus Bully/Victim Questionnaire, Kiddie Machiavellian Scale, and School Climate Perception Questionnaire. Results showed: (1) boys were more likely to bully others and be bullied; (2) both Machiavellianism and school climate partially mediated sex differences in school bullying perpetration and victimization; (3) the chain-mediating effect of Machiavellianism and school climate on sex differences in bullying perpetration and victimization was significant. These results provide insight into the sex differences in Chinese traditional school bullying perpetration and victimization. The implications are interpreted and discussed.

Ovarian Steroids Mediate Sex Differences in Alcohol Reward After Brain Injury in Mice.

Intoxication is a leading risk factor for injury, and TBI increases the risk for later alcohol misuse, especially when the injury is sustained in childhood. Previously, we modeled this pattern in mice, wherein females injured at postnatal day 21 drank significantly more than uninjured females, while we did not see this effect in males. However, the biological underpinnings of this sex difference have remained elusive. In this study, we utilize this preclinical model and traditional endocrine manipulations to assess the effect of perinatal sex steroids on post-injury ethanol response. We found that perinatal androgen administration and adult ovariectomy prevented the development of conditioned place preference to ethanol in females, while there was not an effect of gonadectomy either developmental time point on the severity of axonal degeneration. Finally, although TBI increased the number of microglia in males, there was no corresponding effect of gonadectomy, which suggests that males exhibit prolonged neuroinflammation after brain injury irrespective of circulating sex steroids. Taken together, our results indicate a potential role for ovarian sex steroids in the development of greater alcohol preference after a juvenile TBI in female mice.

Sex Hormones Mediate Sex Differences in Hemodynamics and Inflammation During Arteriovenous Fistula Maturation

Arteriovenous fistulae (AVF) fail to mature, that is dilate and thicken, in women more than in men, leading to inferior outcomes and decreased utilization in women. As our mouse AVF model recapitulates human AVF maturation, including decreased maturation and patency in female mice, we hypothesize that sex hormones mediate sex differences during AVF maturation.

The role of serum testosterone and dehydroepiandrosterone sulfate in kidney function and clinical outcomes in chronic kidney disease: a systematic review and meta-analysis.

Objective/designTestosterone might mediate sex differences in kidney function and chronic kidney disease (CKD). However, few studies analyzing the association between testosterone and kidney function showed conflicting results. Therefore, we performed a systematic review and meta-analysis.MethodsSix electronic databases were searched from inception to March 4, 2020, for studies that investigated the association of (i) testosterone status with kidney function in the general population or (ii) testosterone status with clinical outcomes (kidney function decline, kidney failure, cardiovascular (CV) events, and cardiovascular and all-cause mortality) in CKD patients. We used random and fixed-effect models to obtain pooled effect estimates with 95% confidence intervals (CIs).ResultsNo randomized–controlled trials that met the inclusion criteria were identified. One study was conducted in the general population and reported an increased risk of incident CKD with low vs normal testosterone (hazard ratio (HR): 1.38, 95% CI: 1.05;1.80). Seven studies were conducted in men with CKD and included testosterone as determinant, of which six could be meta-analyzed. Low testosterone was associated with an increased risk of all-cause mortality and CV events (pooled HR: 1.98, 95% CI: 1.36;2.89; pooled HR of 2.40, 95% CI: 1.22;4.71, respectively). Two studies showed an increased risk of all-cause mortality with decreased dehydroepiandrosterone sulfate (DHEAS) in men with CKD; results regarding CV events were conflicting.ConclusionsAlthough literature is scarce, evidence suggests that lower testosterone may increase CKD risk in the general population and risk of all-cause mortality and CV events in men with CKD. Whether testosterone supplementation could prevent these potential detrimental outcomes should be determined in future intervention studies.

Abstract 327: Sex Hormones Mediate Sex Differences In Hemodynamics And Inflammation During Arteriovenous Fistula Maturation

Background: Arteriovenous fistulae (AVF) fail to mature, that is dilate and thicken, in women more than in men, leading to inferior outcomes and decreased utilization in women. As our mouse AVF model recapitulates human AVF maturation, including decreased maturation and patency in female mice, we hypothesize that sex hormones mediate sex differences during AVF maturation. Methods: C57Bl/6 mice (9-11 months) were treated with sham or aortocaval AVF surgery; some were pretreated with gonadectomy 1 week prior to surgery. AVF diameter was measured via ultrasound (days 0-21). Blood was collected for FACS, and tissue examined using immunofluorescence or ELISA (days 3,7); wall thickness was assessed using histology (day 21). Results: At baseline, female and male mice had similar inferior vena cava (IVC) diameter (p=0.611) and wall thickness (p=0.491). After AVF creation, female mice had increased normalized IVC diameter (p=0.0012), flow velocity (p=0.0013), and shear stress (p=0.002; days 3-21; n=10); however, there was no difference in wall thickness (female, 15.8±0.2 um; male, 12.4±2.3 um; p=0.638; n=10). There were also increased circulating CD11b+ macrophages in female compared with male mice (31.8 ± 4.0% vs 18.7 ± 1.9%; p=0.001; day 3; n=22) and CD4+ T cells (57.9 ± 2.9% vs 34.5 ± 6.1%, p=0.0001). In the AVF wall there were increased CD45+ cells on immunofluorescence in females (22.5 ± 1.5 cells/hpf vs 13 ± 2 cells/hpf, p=0.063; day 3; n=4) as well as increased IL-10 immunoreactivity (3.98 ± 0.44 ng/ug vs 2.49 ± 0.47 ng/ug; p=0.076). In mice with gonadectomy, baseline IVC diameter, velocity, and shear stress were similar between female and male mice. After gonadectomy, male mice had increased AVF wall thickness than intact males (24.2 ± 1.6 um vs 12.4 ± 2.3; p=0.014); conversely, female mice had decreased thickness than intact females (6.1 ± 0.6 um vs 15.8 ± 0.2; p=0.005). There was loss of differences among circulating immune cells after gonadectomy (CD11b, p=0.0882; CD4, p=0.7095). Conclusions: Sex differences in hemodynamics and inflammation are present during venous remodeling, whereas these differences disappear after gonadectomy. Sex hormones mediate AVF maturation and suggest that hormone receptor signaling may be a target to improve AVF maturation.

Androgen Receptor Deficiency Eliminates Sex Differences in Mast Cells

Abstract A sex bias exists in mast cell (MC)-associated inflammatory diseases with females at increased risk. Our previous studies demonstrated that MCs exhibit a sexually dimorphic phenotype with male MCs exhibiting significantly reduced concentration and release of MC granule mediators (histamine, serotonin, and proteases) which was associated with reduced severity of anaphylaxis in males. Further, we showed that perinatal androgens are important in organizing male MC sex differences. The mechanisms by which androgens organize MC sex differences remain poorly understood. Utilizing male mice with reduced androgen receptor (AR) expression induced by Cre-LoxP technology (induced TFM; iTfm), we tested the hypothesis that ARs mediate sex differences in MC histamine storage and release, and severity of anaphylaxis. Isolated peritoneal MCs (pMCs) from iTFm male mice exhibited a feminized MC phenotype characterized by a greater level of histamine compared with control male pMCs, but similar to female controls. Following induction of IgE-mediate anaphylaxis in vivo, iTFM male and female pMCs contained lower (n=5–6; P&amp;lt;0.01) histamine contents compared with control males, suggesting enhanced release of histamine. Preliminary results also indicate that iTFm male mice exhibit greater IgE-mediated histamine releases and hypothermia. Experiments with bone marrow derived MCs (BMMCs) showed that IgE-mediated histamine release from iTFm male and female BMMCs was greater (n=5–6; P&amp;lt;0.01) relative to control male BMMCs. Together, these studies demonstrate that sex differences in MC phenotype and function are mediated via Ars and that iTFm mice are a valid model to explore AR-mediated sex differences in MC function and disease pathogenesis. Supported by NIH R01 HD072968, NIH R21 AI140413

Sex-biased autophagy as a potential mechanism mediating sex differences in ischemic stroke outcome

Stroke is the second leading cause of death and a major cause of disability worldwide, and biological sex is an important determining factor in stroke incidence and pathology. From childhood through adulthood, men have a higher incidence of stroke compared with women. Abundant research has confirmed the beneficial effects of estrogen in experimental ischemic stroke but genetic factors such as the X-chromosome complement can also play an important role in determining sex differences in stroke. Autophagy is a self-degrading cellular process orchestrated by multiple core proteins, which leads to the engulfment of cytoplasmic material and degradation of cargo after autophagy vesicles fuse with lysosomes or endosomes. The levels and the activity of components of these signaling pathways and of autophagy-related proteins can be altered during ischemic insults. Ischemic stroke activates autophagy, however, whether inhibiting autophagy after stroke is beneficial in the brain is still under a debate. Autophagy is a potential mechanism that may contribute to differences in stroke progression between the sexes. Furthermore, the effects of manipulating autophagy may also differ between the sexes. Mechanisms that regulate autophagy in a sex-dependent manner in ischemic stroke remain unexplored. In this review, we summarize clinical and pre-clinical evidence for sex differences in stroke. We briefly introduce the autophagy process and summarize the effects of gonadal hormones in autophagy in the brain and discuss X-linked genes that could potentially regulate brain autophagy. Finally, we review pre-clinical studies that address the mechanisms that could mediate sex differences in brain autophagy after stroke.

Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer.

Sex bias exists in the development and progression of nonreproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8+ T cell-dependent antitumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7/TCF1+ progenitor exhausted CD8+ T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8+ T cells and a pertinent contribution from AR as a direct transcriptional transactivator of Tcf7/TCF1. The T cell-intrinsic function of AR in promoting CD8+ T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8+ T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

Differential expression of placental 11β-HSD2 induced by high maternal glucocorticoid exposure mediates sex differences in placental and fetal development

A variety of adverse environmental factors during pregnancy cause maternal chronic stress. Caffeine is a common stressor, and its consumption during pregnancy is widespread. Our previous study showed that prenatal caffeine exposure (PCE) increased maternal blood glucocorticoid levels and caused abnormal development of offspring. However, the placental mechanism for fetal development inhibition caused by PCE-induced high maternal glucocorticoid has not been reported. This study investigated the effects of PCE-induced high maternal glucocorticoid level on placental and fetal development by regulating placental 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) expression and its underlying mechanism. First, human placenta and umbilical cord blood samples were collected from women without prenatal use of synthetic glucocorticoids. We found that placental 11β-HSD2 expression was significantly correlated with umbilical cord blood cortisol level and birth weight in male newborns but not in females. Furthermore, we established a rat model of high maternal glucocorticoids induced by PCE (caffeine, 60 mg/kg·d, ig), and found that the expression of 11β-HSD2 in male PCE placenta was decreased and negatively correlated with the maternal/fetal/placental corticosterone levels. Meanwhile, we found abnormal placental structure and nutrient transporter expression. In vitro, BeWo cells were used and confirm that 11β-HSD2 mediated inhibition of placental nutrient transporter expression induced by high levels of glucocorticoid. Finally, combined with the animal and cell experiments, we further confirmed that high maternal glucocorticoid could activate the GR-C/EBPα-Egr1 signaling pathway, leading to decreased expression of 11β-HSD2 in males. However, there was no significant inhibition of placental 11β-HSD2 expression, placental and fetal development in females. In summary, we confirmed that high maternal glucocorticoids could regulate placental 11β-HSD2 expression in a sex-specific manner, leading to differences in placental and fetal development. This study provides the theoretical and experimental basis for analyzing the inhibition of fetoplacental development and its sex difference caused by maternal stress.

Sex Hormones Mediate Sex Differences in Hemodynamics and Inflammation during Arteriovenous Fistula Maturation

Sex Hormones Mediate Sex Differences in Hemodynamics and Inflammation during Arteriovenous Fistula Maturation

DNA methylation "GrimAge" acceleration mediates sex differences in verbal learning and memory: Findings from the health and retirement study

AbstractBackgroundEvidence from cognitive science support sex differences in verbal memory, that tend to favor women. Epigenetic research has also shown slower rates of biological aging in women compared to men. The aim of the current study examined whether sex differences in biological aging mediate sex differences in verbal learning/memory in older adults.MethodData was obtained from the Harmonized Cognitive Assessment Protocol and the 2016 Venous Blood Study, sub‐studies of the 2016 wave of the Health and Retirement Study (HRS). Thirteen epigenetic “clocks” were constructed from these data and made publicly available by HRS staff. DNA methylation “GrimAge” clock was used as the indicator of biological aging, given evidence relating it to cognition in prior studies. A sample of 1,505 participants (mean age =75, SD= 6.8, male= 42%, White= 81%, Black=13%, Hispanic= 6%), with full data were included in the analyses. The residual from age adjusted GrimAge (AgeAccelGrim) was used as the measure of age acceleration. Cognitive composites were constructed from the learning and delayed recall trials of the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Task and the Wechsler Memory Scale‐IV, Logical Memory subtest and used as the outcome measures. Mediation analysis tested whether AgeAccelGrim mediated (5,000 resamples) the association between sex and learning/recall composites. Chronological age, years of education, smoking status, white blood cell count, and race/ethnicity were included as covariates.ResultMediation analyses revealed a total direct effect of sex on learning (β=.32, 95% CI [.26, .37]), with a significant indirect effect of AgeAccelGrim, that explained 12.5% of the total effect of sex (CI [.02, .06]). A similar pattern was revealed for delayed recall (total effect of sex β= .26, 95% CI [.20, .32]), with AgeAccelGrim accounting for 11.5% of the total effect (95% CI [.01, .04]).ConclusionWomen performed better on verbal learning/recall measures compared to men, and this association was partially explained by slower biological aging in women. These findings demonstrate the potential for epigenetic markers of aging to increase understanding of sex differences in verbal learning and memory in older adults.

Peer support mediates sex differences in self-esteem and problem behaviors among children: Does parental migration make a difference?

Peer support mediates sex differences in self-esteem and problem behaviors among children: Does parental migration make a difference?

Sex difference in adrenal developmental toxicity induced by dexamethasone and its intrauterine programming mechanism

Dexamethasone is widely used to treat preterm labor and related diseases. However, prenatal dexamethasone treatment (PDT) can cause multiorgan developmental toxicities in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with adrenal developmental programming alterations in offspring. Here, we investigated the effects of PDT on adrenal function in offspring and its intrauterine programming mechanism. A rat model of PDT was established to observe the alterations of adrenal steroidogenesis in offspring. Furthermore, we confirmed the sex differences of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiments. PDT caused a decrease in adrenal steroidogenic function in fetal rats, but it was decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDT offspring were decreased in males and increased in females, suggesting that 11β-HSD2 might mediate sex differences in adrenal function. We further confirmed that dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through the GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy of adult PDT offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression of AR and ERβ was proven to be involved in regulating the sex difference in 11β-HSD2 expression. This study demonstrated the sex difference in adrenal steroidogenic function of PDT offspring after birth and elucidated a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.

Estrogen mediates sex differences in preoptic neuropeptide and pituitary hormone production in medaka

The preoptic area (POA) is one of the most evolutionarily conserved regions of the vertebrate brain and contains subsets of neuropeptide-expressing neurons. Here we found in the teleost medaka that two neuropeptides belonging to the secretin family, pituitary adenylate cyclase-activating polypeptide (Pacap) and vasoactive intestinal peptide (Vip), exhibit opposite patterns of sexually dimorphic expression in the same population of POA neurons that project to the anterior pituitary: Pacap is male-biased, whereas Vip is female-biased. Estrogen secreted by the ovary in adulthood was found to attenuate Pacap expression and, conversely, stimulate Vip expression in the female POA, thereby establishing and maintaining their opposite sexual dimorphism. Pituitary organ culture experiments demonstrated that both Pacap and Vip can markedly alter the expression of various anterior pituitary hormones. Collectively, these findings show that males and females use alternative preoptic neuropeptides to regulate anterior pituitary hormones as a result of their different estrogen milieu.