Sex differences in epigenetic mechanisms may underlie risk and resilience for mental health disorders

Alterations in the epigenetic programming of sex differences in the brain may underlie sexually dimorphic neurodevelopmental disorders. Sex differences have been found in DNA methyltransferases 3a, DNA methylation patterns, MeCP2, and nuclear corepressor within the developing brain. Natural variations in these epigenetic mechanisms have profound consequences on gene expression and brain function. Exogenous or endogenous perturbations during development may impact these epigenetic processes and alter the trajectory of the developing brain and confer sexually dimorphic risk and resilience for developing a neurological or mental health disorder.     

Sex differences in lipid metabolism and metabolic disease risk

The ability of nutrients to regulate specific metabolic pathways is often overshadowed by their role in basic sustenance. Consequently, the mechanisms whereby these nutrients protect against or promote a variety of acquired metabolic syndromes remains poorly understood. Premenopausal women are generally protected from the adverse effects of obesity despite having a greater proportion of body fat than men. Menopause is often associated with a transformation in body fat morphology and a gradual increase in the susceptibility to metabolic complications, eventually reaching the point where women and men are at equal risk. These phenomena are not explained solely by changes in food preference or nutrient intake suggesting an important role for the sex hormones in regulating the metabolic fate of nutrients and protecting against metabolic disease pathophysiology. Here, we discuss how differences in the acquisition, trafficking, and subceullular metabolism of fats and other lipid soluble nutrients in major organ systems can create overt sex-specific phenotypes, modulate metabolic disease risk, and contribute to the rise in obesity in the modern sedentary climate. Identifying the molecular mechanisms underpinning sex differences in fat metabolism requires the unravelling of the interactions among sex chromosome effects, the hormonal milieu, and diet composition. Understanding the mechanisms that give rise to sex differences in metabolism will help to rationalize treatment strategies for the management of sex-specific metabolic disease risk factors.     

工作记忆的负荷影响心理旋转任务中的性别差异

目的:探讨心理旋转任务中的性别差异是否受工作记忆的负荷的影响。方法:采用先后呈现提示刺激和目标刺激的范式,任务分为三种:1.无效提示的数字旋转;2.有效提示的数字旋转;3.有效提示的PMA图形旋转。结果:重复测量的方差分析表明:对无效提示的数字旋转任务,男性和女性之间的反应时和正确率都无差异;对有效提示的数字旋转任务,男性和女性之间的正确率无差异,而反应时的差异边缘显著;对有效提示的PMA图形旋转任务,男性和女性之间的正确率无差异,而反应时有显著差异。结论:工作记忆的负荷可能会影响心理旋转任务中的性别差异。     

Sex differences in depression and anxiety disorders: potential biological determinants

The phenomenon of higher rates of affective disorders in women illustrates many of the difficulties as well as promises of translating preclinical models to human disorders. Abnormalities in the regulation of the hypothalamic-pituitary adrenal axis and the sympathoadrenomedullary system have been identified in depression and anxiety disorders, and these disorders are clearly precipitated and exacerbated by stress. Despite the striking sex difference in the prevalence of depression and anxiety disorders, attempts to identify corresponding sex differences in stress response reactivity in animal models have met with limited success. Processes which may contribute to increased rates of affective disorders in women are greater fluxes in reproductive hormones across the life span, and increased sensitivity to catecholamine augmentation of emotional memory consolidation.     

Sex ratios and mental health: Evidence from China

While sex ratios (i.e., relative numbers of men and women) have been linked to various economic and social outcomes, how sex ratios affect mental health is underexplored. Using nationally representative data from the China Family Panel studies (CFPS) and Population Census, we evaluate the impact of sex ratios on mental health among Chinese men and explore potential mechanisms. Employing the instrumental variables (IV) approach where the One-Child Policy’s mandated fertility limits and implementation are used as exogenous variations in local sex ratios, we find that higher local sex ratios increase depressive symptoms and probability of depression among Chinese men. The impact is stronger for men with lower levels of education and living in rural areas. Analyses of potential mechanisms show that higher sex ratios increase the likelihood of marriage delay and unemployment for men, and prolong working hours for the employed men. The findings are of direct relevance to the health and population policy in China.     

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

We reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in osteoarthritis. We aimed to confirm those results by analyzing β-catenin levels and explored potential genetic and epigenetic mechanisms involved.     

Sex differences in mood disorders: perspectives from humans and rodent models

Mood disorders are devastating, often chronic illnesses characterized by low mood, poor affect, and anhedonia. Notably, mood disorders are approximately twice as prevalent in women compared to men. If sex differences in mood are due to underlying biological sex differences, a better understanding of the biology is warranted to develop better treatment or even prevention of these debilitating disorders. In this review, our goals are to: 1) summarize the literature related to mood disorders with respect to sex differences in prevalence, 2) introduce the corticolimbic brain network of mood regulation, 3) discuss strategies and challenges of modeling mood disorders in mice, 4) discuss mechanisms underlying sex differences and how these can be tested in mice, and 5) discuss how our group and others have used a translational approach to investigate mechanisms underlying sex differences in mood disorders in humans and mice.     

Sex differences in risk factors for cardiovascular disease: the PERU MIGRANT study

Introduction

Although men and women have similar risk factors for cardiovascular disease, many social behaviors in developing countries differ by sex. Rural-to-urban migrants have different cardiovascular risk profiles than rural or urban dwellers. The objective of this study was to evaluate the sex differences with specific cardiovascular risk factors in rural-to-urban migrants.

Methods and Results

We used the rural-to-urban migrant group of the PERU MIGRANT cross-sectional study to investigate the sex differences in specific cardiovascular risk factors: obesity, hypertension, metabolic syndrome, as well as exposures of socioeconomic status, acculturation surrogates and behavioral characteristics. Logistic regression analysis was used to characterize strength of association between sex and our outcomes adjusting for potential confounders. The sample of migrants was 589 (mean age 46.5 years) and 52.4% were female. In the adjusted models, women were more likely to be obese (OR=5.97; 95%CI: 3.21–11) and have metabolic syndrome (OR=2.22; 95%CI: 1.39–3.55) than men, explaining the greatest variability for obesity and metabolic syndrome but not for hypertension.

Conclusions

Our results suggest that interventions for CVD in Peru should be sex-specific and address the unique health needs of migrant populations living in urban shantytowns since the risk factors for obesity and metabolic syndrome differ between males and females.     

Prospects for incorporation of epigenetic biomarkers in human health and environmental risk assessment of chemicals

Epigenetic mechanisms have gained relevance in human health and environmental studies, due to their pivotal role in disease, gene × environment interactions and adaptation to environmental change and/or contamination. Epigenetic mechanisms are highly responsive to external stimuli and a wide range of chemicals has been shown to determine specific epigenetic patterns in several organisms. Furthermore, the mitotic/meiotic inheritance of such epigenetic marks as well as the resulting changes in gene expression and cell/organismal phenotypes has now been demonstrated. Therefore, epigenetic signatures are interesting candidates for linking environmental exposures to disease as well as informing on past exposures to stressors. Accordingly, epigenetic biomarkers could be useful tools in both prospective and retrospective risk assessment but epigenetic endpoints are currently not yet incorporated into risk assessments. Achieving a better understanding on this apparent impasse, as well as identifying routes to promote the application of epigenetic biomarkers within environmental risk assessment frameworks are the objectives of this review. We first compile evidence from human health studies supporting the use of epigenetic exposure‐associated changes as reliable biomarkers of exposure. Then, specifically focusing on environmental science, we examine the potential and challenges of developing epigenetic biomarkers for environmental fields, and discuss useful organisms and appropriate sequencing techniques to foster their development in this context. Finally, we discuss the practical incorporation of epigenetic biomarkers in the environmental risk assessment of chemicals, highlighting critical data gaps and making key recommendations for future research within a regulatory context.     

Sex differences and autism: brain function during verbal fluency and mental rotation

Autism spectrum conditions (ASC) affect more males than females. This suggests that the neurobiology of autism: 1) may overlap with mechanisms underlying typical sex-differentiation or 2) alternately reflect sex-specificity in how autism is expressed in males and females. Here we used functional magnetic resonance imaging (fMRI) to test these alternate hypotheses. Fifteen men and fourteen women with Asperger syndrome (AS), and sixteen typically developing men and sixteen typically developing women underwent fMRI during performance of mental rotation and verbal fluency tasks. All groups performed the tasks equally well. On the verbal fluency task, despite equivalent task-performance, both males and females with AS showed enhanced activation of left occipitoparietal and inferior prefrontal activity compared to controls. During mental rotation, there was a significant diagnosis-by-sex interaction across occipital, temporal, parietal, middle frontal regions, with greater activation in AS males and typical females compared to AS females and typical males. These findings suggest a complex relationship between autism and sex that is differentially expressed in verbal and visuospatial domains.     

Sex differences in sand lizard telomere inheritance: paternal epigenetic effects increases telomere heritability and offspring survival

Background

To date, the only estimate of the heritability of telomere length in wild populations comes from humans. Thus, there is a need for analysis of natural populations with respect to how telomeres evolve.

Methodology/Principal Findings

Here, we show that telomere length is heritable in free-ranging sand lizards, Lacerta agilis. More importantly, heritability estimates analysed within, and contrasted between, the sexes are markedly different; son-sire heritability is much higher relative to daughter-dam heritability. We assess the effect of paternal age on Telomere Length (TL) and show that in this species, paternal age at conception is the best predictor of TL in sons. Neither paternal age per se at blood sampling for telomere screening, nor corresponding age in sons impact TL in sons. Processes maintaining telomere length are also associated with negative fitness effects, most notably by increasing the risk of cancer and show variation across different categories of individuals (e.g. males vs. females). We therefore tested whether TL influences offspring survival in their first year of life. Indeed such effects were present and independent of sex-biased offspring mortality and offspring malformations.

Conclusions/Significance

TL show differences in sex-specific heritability with implications for differences between the sexes with respect to ongoing telomere selection. Paternal age influences the length of telomeres in sons and longer telomeres enhance offspring survival.     

Sex differences in health indicators among children in African DHS surveys

The study analyses various sex differences observed among children in WFS and DHS surveys conducted in sub-Saharan Africa. Four outcome indicators are presented: neonatal mortality, postneonatal mortality, child mortality and prevalence of malnutrition. Three indicators of health seeking behaviour are presented: vaccination, oral rehydration therapy and duration of breast-feeding. The statistical analysis focuses on comparison of the observed distributions of the sex ratios to theoretical distributions expected from the sample sizes of the various surveys. The results show the absence of any difference in health seeking behaviour between boys and girls, whether for preventive medicine (vaccination), curative medicine (oral rehydration therapy) or feeding practices (breast-feeding). On the other hand, mortality appears to be consistently higher for boys, more so among neonates (+28%) than among 1-12-month-olds (+8%) and 1-4-year-olds (+4%), and similarly malnutrition appears to be more prevalent among boys (+5%%). The contrast between the lack of differences in behavioural indicators and the significant differences in outcome indicators suggests a biological causality. Results are discussed in the light of biological factors.     

Sex/gender and socioeconomic differences in the predictive ability of self-rated health for mortality

Background

Studies have reported that the predictive ability of self-rated health (SRH) for mortality varies by sex/gender and socioeconomic group. The purpose of this study is to evaluate this relationship in Japan and explore the potential reasons for differences between the groups.

Methodology/Principal Findings

The analyses in the study were based on the Aichi Gerontological Evaluation Study''s (AGES) 2003 Cohort Study in Chita Peninsula, Japan, which followed the four-year survival status of 14,668 community-dwelling people who were at least 65 years old at the start of the study. We first examined sex/gender and education-level differences in association with fair/poor SRH. We then estimated the sex/gender- and education-specific hazard ratios (HRs) of mortality associated with lower SRH using Cox models. Control variables, including health behaviors (smoking and drinking), symptoms of depression, and chronic co-morbid conditions, were added to sequential regression models. The results showed men and women reported a similar prevalence of lower SRH. However, lower SRH was a stronger predictor of mortality in men (HR = 2.44 [95% confidence interval (CI): 2.14–2.80]) than in women (HR = 1.88 [95% CI: 1.44–2.47]; p for sex/gender interaction = 0.018). The sex/gender difference in the predictive ability of SRH was progressively attenuated with the additional introduction of other co-morbid conditions. The predictive ability among individuals with high school education (HR = 2.39 [95% CI: 1.74–3.30]) was similar to that among individuals with less than a high school education (HR = 2.14 [95% CI: 1.83–2.50]; p for education interaction = 0.549).

Conclusions

The sex/gender difference in the predictive ability of SRH for mortality among this elderly Japanese population may be explained by male/female differences in what goes into an individual''s assessment of their SRH, with males apparently weighting depressive symptoms more than females.