Sex-specific Responses Research Articles

Sex-Specific B Cell and Anti-Myelin Autoantibody Response After Peripheral Nerve Injury.

Immunotherapy holds promise as a non-addictive treatment of refractory chronic pain states. Increasingly, sex is recognized to impact immune regulation of pain states, including mechanical allodynia (pain from non-painful stimulation) that follows peripheral nerve trauma. This study aims to assess the role of B cells in sex-specific responses to peripheral nerve trauma. Using a rat model of sciatic nerve chronic constriction injury (CCI), we analyzed sex differences in (i) the release of the immunodominant neural epitopes of myelin basic protein (MBP); (ii) the levels of serum immunoglobulin M (IgM)/immunoglobulin G (IgG) autoantibodies against the MBP epitopes; (iii) endoneurial B cell/CD20 levels; and (iv) mechanical sensitivity behavior after B cell/CD20 targeting with intravenous (IV) Rituximab (RTX) and control, IV immunoglobulin (IVIG), therapy. The persistent MBP epitope release in CCI nerves of both sexes was accompanied by the serum anti-MBP IgM autoantibody in female CCI rats alone. IV RTX therapy during CD20-reactive cell infiltration of nerves of both sexes reduced mechanical allodynia in females but not in males. IVIG and vehicle treatments had no effect in either sex. These findings provide strong evidence for sexual dimorphism in B-cell function after peripheral nervous system (PNS) trauma and autoimmune pathogenesis of neuropathic pain, potentially amenable to immunotherapeutic intervention, particularly in females. A myelin-targeted serum autoantibody may serve as a biomarker of such painful states. This insight into the biological basis of sex-specific response to neuraxial injury will help personalize regenerative and analgesic therapies.

410 Mild Maternal Undernutrition Results in a Premature Neonatal Leptin Surge and Resistance in Male Offspring to a High Fat Diet

OBJECTIVES/GOALS: Maternal undernutrition, a form of malnutrition, can alter neonatal leptin signaling and result in metabolic dysfunction in adulthood. We developed a mild undernutrition model to relate more to societys nutritional challenges and to test the hypothesis that a shift in the neonatal leptin surge would result in sex-specific metabolic changes. METHODS/STUDY POPULATION: We studied pups from undernourished dams which were calorically restricted by 20% (CR20) from embryonic day 15 until postnatal day (PND) 21. We tested 216 offspring from 11 Fed dams and 13 undernourished dams (CR20), detecting a leptin surge in control fed progeny at PND11. At 3 months of age, offspring from 3 dams per maternal nutrient status were either exposed to a 45% high fat diet (HFD) or control diet (10% fat) for 16 weeks. Anterior pituitary hormones were analyzed in the pituitary and serum of neonates and adults. To determine the mechanism of the phenotype observed in male adult offspring on the HFD, single cell RNA sequencing was used to analyze the pituitary, fat and liver. RESULTS/ANTICIPATED RESULTS: Offspring of CR20 dams had an early leptin surge peaking at PND8 and GH levels at PND1 were higher in CR20 progeny. Weights of both male and female CR20 offspring were lower and body lengths were shorter than controls. As adults, Fed mice from both sexes had increased weight gain with HFD. However, although CR20 females gained weight on the HFD, male progeny from CR20 dams did not gain weight on the HFD and appeared protected from impact. We found sex-specific changes in pituitary Gh, Ghrhr, and Ghsr mRNA levels. Single cell RNA sequencing of pituitary, fat and liver of male offspring showed significant regulation of transcripts in fat of male offspring from Fed dams that was not found in CR20 males when compared to control fed mice. DISCUSSION/SIGNIFICANCE: Mild undernutrition causes a prematurely high leptin surge and sex-specific growth responses to a HFD, including resistance to a HFD in underfed males. Transcript analysis in fat of males resistant to HFD induced obesity may reveal mechanisms that provide protection against HFD induced weight gain.

Responses of sea urchins (Strongylocentrotus intermedius) with different sexes to CO2-induced seawater acidification: Histology, physiology, and metabolomics

Responses of different sexes of farmed Strongylocentrotus intermedius to chronic CO2-induced seawater acidification were investigated in 120-day lab-based experiments. Four experimental groups were set up as one control group and three seawater acidification groups. The results showed that 1) Specific growth rate and the numbers of mature gamete cells declined in a pH-dependent way in both sexes of adult S. intermedius. 2) There were differences in SDMs identified in females and males reared in acidified seawater reflecting sex-specific response variation in adult S. intermedius. 3) The number of altered metabolic pathways exhibited a linear increasing trend as seawater pH declined in both sexes of adult S. intermedius. Meanwhile seawater acidification might affect metabolic processes via changing the relative expression and activity of key enzymes controlling the corresponding metabolic pathways of adult S. intermedius.

Transcriptome analysis reveals sex-specific alterations in gonads of green mussel exposed to organophosphorus insecticide triazophos

Triazophos (TP) is a widespread pollutant in aquatic environments. A sex-specific metabolic response in green-lipped mussel Perna viridis to TP exposure was observed in our previous study, and this led us to investigate the mechanisms associated with its toxicity. P. viridis were subjected to chronic exposure (15 days) to TP at 35 μg/L to compare the sex-biased transcriptomic profiles in the gonads of male and female mussels. We identified 632 differentially expressed genes (DEGs) (348 up-regulated and 284 down-regulated) in TP-exposed males, and only 61 DEGs (9 up-regulated and 52 down-regulated) in TP-exposed females. Many DEGs were found to be involved in the nervous, reproductive endocrine, oxidative stress, and immune systems of P. viridis. Additionally, enzymatic activity analysis indicated TP induced neurotoxic effects and oxidative damage to the mussels. Our results demonstrate that the stress response and molecular mechanisms of TP toxicology are different between female and male mussels.

Molecular signature of cardiac remodeling associated with Polymerase Gamma mutation

AimsMetabolic function/dysfunction is central to aging biology. This is well illustrated by the Polymerase Gamma (POLG) mutant mouse where a key residue of the mitochondrial DNA polymerase is mutated (D257A), causing loss of mitochondrial DNA stability and dramatically accelerated aging processes. Given known cardiac phenotypes in the POLG mutant, we sought to characterize the course of cardiac dysfunction in the POLG mutant to guide future intervention studies. Materials and methodsCardiac echocardiography and terminal hemodynamic analyses were used to define the course of dysfunction in the right and left cardiac ventricles in the POLG mutant. We also conducted RNA-seq analysis on cardiac right ventricles to identify mechanisms engaged by severe metabolic dysfunction and compared this analysis to several publically available datasets. Key findingsInteresting sex differences were noted as female POLG mutants died earlier than male POLG mutants and LV chamber diameters were impacted earlier in females than males. Moreover, male mutants showed LV wall thinning while female mutant LV walls were thicker. Both males and females displayed significant RV hypertrophy. POLG mutants displayed a gene expression pattern associated with inflammation, fibrosis, and heart failure. Finally, comparative omics analyses of publically available data provide additional mechanistic and therapeutic insights. SignificanceAging-associated cardiac dysfunction is a growing clinical problem. This work uncovers sex-specific cardiac responses to severe metabolic dysfunction that are reminiscent of patterns seen in human heart failure and provides insights to the molecular mechanisms engaged downstream of severe metabolic dysfunction that warrant further investigation.

Hormones and Sex-Specific Medicine in Human Physiopathology.

A prodigious increment of scientific evidence in both preclinical and clinical studies is narrowing a major gap in knowledge regarding sex-specific biological responses observed in numerous branches of clinical practices. Some paradigmatic examples include neurodegenerative and mental disorders, immune-related disorders such as pathogenic infections and autoimmune diseases, oncologic conditions, and cardiovascular morbidities. The male-to-female proportion in a population is expressed as sex ratio and varies eminently with respect to the pathophysiology, natural history, incidence, prevalence, and mortality rates. The factors that determine this scenario incorporate both sex-associated biological differences and gender-dependent sociocultural issues. A broad narrative review focused on the current knowledge about the role of hormone regulation in gender medicine and gender peculiarities across key clinical areas is provided. Sex differences in immune response, cardiovascular diseases, neurological disorders, cancer, and COVID-19 are some of the hints reported. Moreover, gender implications in occupational health and health policy are offered to support the need for more personalized clinical medicine and public health approaches to achieve an ameliorated quality of life of patients and better outcomes in population health.

Sex-dependent multimodal response profiles to psychosocial stress.

Sex differences in stress reactions are often reported in the literature. However, the sex-dependent interplay of different facets of stress is still not fully understood. Particularly in neuroimaging research, studies on large samples combining different indicators of stress remain scarce. In a functional magnetic resonance imaging study, a sample of 140 healthy participants (67 females using oral contraceptives) underwent a standardized stress induction protocol, the ScanSTRESS. During the experiment, salivary cortisol and subjective ratings were obtained at multiple time points and heart rate was recorded. Sex differences emerged in different facets of the stress response:Women reacted with enhanced subjective feelings of stress and increases in heart rate, while men showed more pronounced neural activation in stress-related brain regions such as the inferior frontal gyrus and insula. Subjective feelings of stress and (para) hippocampal activity were negatively related in women,whereas a slightly positive association was observed in men. These results provide further insight in the sex-specific stress response patterns. Moreover, they emphasize the role of the hippocampus in the regulation of the stress response. This paves the way for the identification of sex-dependent vulnerability factors that can, in the future, be implemented in the prevention and treatment of stress-related disorders.

Biological Response of Irisin Induced by Different Types of Exercise in Obese Subjects: A Non-Inferiority Controlled Randomized Study.

Simple SummaryAmong healthy male and female obese individuals undergoing a 12-week aerobic exercise program with either moderate intensity endurance or high-intensity interval training for losing weight, a reduction of circulating irisin was observed. Irisin is an important adipo-myokine implicated in the regulation of energy metabolism and cardiovascular health. Sex differences in the circulating levels of this biomarker have been previously reported and are likely related to the different anthropometric features between the sexes. A sex-specific modulation of circulating irisin levels should be further explored to tailor sex-specific training approaches for improving the cardiovascular health of obese subjects.Background: Weight loss through physical exercise is warranted among obese individuals. Recently, a greater benefit in cardiorespiratory fitness was achievable with high-intensity interval training (HIIT) as compared with moderate intensity continuous training. The beneficial effect of training on CV health might be related to a specific modulation of circulating irisin, an adypo-myokine implicated in the regulation of energy expenditure. Methods: The present study investigates the circulating plasma levels of irisin at baseline and in response to 12-week of training program either with HIIT or moderate-intensity continuous training (MICT) among young female and male obese subjects. Clinical, anthropometric, and training characteristics for each participant were available. A sex-disaggregated data for circulating plasma levels of irisin pre- and post-training are provided as well as an adjusted multivariate linear regression model to identify the determinants of post-training irisin levels. Results: Data from a total of 32 obese healthy individuals (47% female, mean age 38.7 years, mean BMI 35.6 kg/m2), randomized in a 1:1 manner to HIIT or MICT were analyzed. Circulating plasma levels of irisin similarly and significantly decreased in both MICT and HIIT interventional groups. Females had higher post-exercise irisin levels than males (6.32 [5.51–6.75] vs. 4.97 [4.57–5.72] μg/mL, p = 0.001). When stratified by an interventional group, a statistically significant difference was observed only for the MICT group (male, 4.76 [4.20–5.45] μg/mL vs. female 6.48 [4.88–6.84] μg/mL p = 0.03). The circulating post-training level of irisin was independently associated with post-training fat-free mass (β −0.34, 95% confidence interval, CI −0.062, −0.006, p = 0.019) in a model adjusted confounders. When female sex was added into the adjusted model, it was retained as the only factor independently associated with irisin levels (β 1.22, 95% CI, 0.50, 1.93, p = 0.002). Conclusions: In obese healthy subjects, circulating irisin levels were reduced in response to 12-weeks of exercise involving either HIIT or MICT. A sex-specific differences in circulating irisin levels at baseline and as biological response to chronic exercise was described. Sex-specific biological response of irisin to exercise should be further explored to tailor sex-specific training approaches for improving the cardiovascular health of obese healthy subjects.

Sex-specific responses to anthropogenic risk shape wild chimpanzee social networks in a human-impacted landscape

Large animal species are most likely to survive human-induced rapid environmental change if they display high levels of behavioural flexibility. Examining social responses in species that form closely bonded social groups and display high fission–fusion dynamics, such as chimpanzees, Pan troglodytes , will help determine their resilience to dynamic human activities and the potential for sustainable human–wildlife interactions. Coinciding with the seasonal availability of cultivated jackfruit, Artocarpus heterophyllus , a dominant food available in croplands and village gardens, we examined the social adjustments of wild chimpanzees to risks presented by a human-modified landscape at Bulindi, Uganda. Absolute party size decreased when chimpanzees moved from low-risk ‘natural’ habitat (forest fragments) to high-risk ‘anthropogenic’ habitat (croplands and other village areas), driven mainly by parties containing fewer females. Using social network analysis, we found that chimpanzee social structure showed partial flexibility in response to anthropogenic risk. The strength of social ties in a 5 m proximity network stayed similar and individual centrality measures were correlated between low- and high-risk habitats. Nevertheless, in high-risk habitat males were more central than females and exclusively dominated the core of the network's core–periphery structure. However, sex differences were not apparent when we corrected for party membership, indicating that differences were driven by changes to party membership between habitat types rather than changes in social proximity within parties. We suggest that perception of anthropogenic risk can drive continual adjustments to grouping dynamics in response to changing conditions that modify social lives of male and female chimpanzees in different ways. Consequently, changes in grouping patterns induced by continuing anthropogenic change could impact ecological and evolutionary processes influenced by social structure, including cultural evolution and the spread of infectious disease. • Party size decreased from low-risk ‘natural’ to high-risk ‘anthropogenic’ habitat. • Males had higher social centrality than females in high-risk habitat only. • Sex differences in centrality were caused by females avoiding high-risk habitat. • No sex difference in centrality was apparent when controlling for party membership. • Chimpanzee social structure showed partial flexibility to anthropogenic risk.

Sex-Specific Catabolic Metabolism Alterations in the Critically Ill following High Dose Vitamin D.

Pharmacological interventions are essential for the treatment and management of critical illness. Although women comprise a large proportion of the critically ill, sex-specific pharmacological properties are poorly described in critical care. The sex-specific effects of vitamin D3 treatment in the critically ill are not known. Therefore, we performed a metabolomics cohort study with 1215 plasma samples from 428 patients from the VITdAL-ICU trial to study sex-specific differences in the metabolic response to critical illness following high-dose oral vitamin D3 intervention. In women, despite the dose of vitamin D3 being higher, pharmacokinetics demonstrated a lower extent of vitamin D3 absorption compared to men. Metabolic response to high-dose oral vitamin D3 is sex-specific. Sex-stratified individual metabolite associations with elevations in 25(OH)D following intervention showed female-specific positive associations in long-chain acylcarnitines and male-specific positive associations in free fatty acids. In subjects who responded to vitamin D3 intervention, significant negative associations were observed in short-chain acylcarnitines and branched chain amino acid metabolites in women as compared to men. Acylcarnitines and branched chain amino acids are reflective of fatty acid B oxidation, and bioenergesis may represent notable metabolic signatures of the sex-specific response to vitamin D. Demonstrating sex-specific pharmacometabolomics differences following intervention is an important movement towards the understanding of personalized medicine.

Intergenerational effects of early-life health shocks during the Chinese 1959–1961 famine

AbstractA large literature has examined early-life insult and later-life health outcomes. However, whether early-life exposure might persist into the outcomes of future generations remains unclear. Using data from the China Family Panel Studies, this study examines the intergenerational effects of early-life health shocks during the great famine in China, distinguishes the intergenerational effects of in utero and early-life famine exposure, and estimates whether there is a sex-specific transgenerational response. Difference-in-difference results show that first-generation male in utero famine exposure (1959–1961) is associated with a series of health and economic disadvantages in the second generation, compared with the unexposed post-famine-born cohort (1964–1965) in China. The effect persists in the third generation but attenuates, and there is no same-sex transgenerational response. These findings may suggest a novel source of multigenerational persistence in health and economic poverty and may point to a need to consider evidence of transgenerational mechanisms.

Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.

Nitrogen addition alleviated sexual differences in responses to cadmium toxicity by regulating the antioxidant system and root characteristics, and inhibiting Cd translocation in mulberry seedlings

Cadmium (Cd) toxicity and nitrogen (N) deposition are two major environmental stresses which can affect plant growth. It’s less clear that how the combined Cd accumulation and N deposition affect the male and female plants of dioecious species. The aim of the present study was to detect sex-specific responses to Cd stress and simulated N deposition in one-year-old male, female and hermaphrodite seedlings of Morus alba. Changes in morphology, physiology, root architecture and biomass of the three sex types of mulberry seedlings were determined. The results showed that Cd toxicity caused limited growth, impaired photosynthetic apparatus and decreased gas exchange rates with significant sex-specific differences. Mulberry was found to deploy detoxification mechanisms to avoid or tolerate toxic Cd effects through the activation of the antioxidant system, increasing proline and non-protein thiol contents, translocating Cd into different plant parts and decreasing biomass. Females displayed a low tolerance to high Cd and were more sensitive to Cd stress. Simulated N deposition alleviated the negative effects of Cd on leaves and decreased sex-specific differences in the three kinds of mulberry seedlings, but N fertilizer did not affect the total biomass. The N-stimulated increasing in proline and non-protein thiol contents might play a crucial role in resisting the damage caused by Cd stress, and the three kinds of mulberry seedlings had slightly different ways of improving Cd tolerance by N deposition. Sexual differences in Cd accumulation are correlated with root architecture. This study provides evidence for the utilization of mulberry to treat Cd-contaminated soils under N deposition.

The genetic basis and adult reproductive consequences of developmental thermal plasticity.

Increasing temperature and thermal variability generate profound selection on populations. Given the fast rate of environmental change, understanding the role of plasticity and genetic adaptation in response to increasing temperatures is critical. This may be especially true for thermal effects on reproductive traits in which thermal fertility limits at high temperatures may be lower than for survival traits. Consequences of changing environments during development on adult phenotypes may be particularly problematic for core traits such as reproduction that begin early in development. Here we examine the consequences of developmental thermal plasticity on subsequent adult reproductive traits and its genetic basis.We used a panel of Drosophila melanogaster (the Drosophila Genetic Reference Panel; DGRP) in which male fertility performance was previously defined as either showing relatively little (status = ‘high’‐performing lines) or substantial (‘low’‐performing lines) decline when exposed to increasing developmental temperatures. We used a thermal reaction norm approach to quantify variation in the consequences of developmental thermal plasticity on multiple adult reproductive traits, including sex‐specific responses, and to identify candidate genes underlying such variation.Developmental thermal stress impacted the means and thermal reaction norms of all reproductive traits except offspring sex ratio. Mating success declined as temperature increased with no difference between high and low lines, whereas increasing temperature resulted in declines for both male and female fertility and productivity but depended on line status. Fertility and offspring number were positively correlated within and between the sexes across lines, but males were more affected than females.We identified 933 SNPs with significant evolved genetic differentiation between high and low lines. In all, 54 of these lie within genomic windows of overall high differentiation, have significant effects of genotype on the male thermal reaction norm for productivity and are associated with 16 genes enriched for phenotypes affecting reproduction, stress responses and autophagy in Drosophila and other organisms.Our results illustrate considerable plasticity in male thermal limits on several reproductive traits following development at high temperature, and we identify differentiated loci with relevant phenotypic effects that may contribute to this population variation. While our work is on a single population, phenotypic results align with an increasing number of studies demonstrating the potential for stronger selection of thermal stress on reproductive traits, particularly in males. Such large fitness costs may have both short‐ and long‐term consequences for the evolution of populations in response to a warming world.

Stem xylem traits and wood formation affect sex-specific responses to drought and rewatering in Populus cathayana.

The increased frequency and intensity of drought pose great threats to the survival of trees, especially in dioecious tree species with sexual differences in mortality and biased sex ratios. The sex-specific mechanisms underlying stem xylem anatomy and function and carbon metabolism in drought resistance and recovery were investigated in dioecious Populus cathayana Rehder. The sex-specific drought resistance and subsequent recovery were linked to the xylem anatomy and carbon metabolism. Females had a greater xylem vessel area per vessel, biomass and theoretically hydraulic efficiency under well-watered conditions. Conversely, males had a lower xylem lumen area, but greater vessel numbers, and a higher cell wall thickness, suggesting a theoretically conservative water-use strategy and drought resistance. The recovery of photosynthetic ability after drought in males was largely dependent on the recovery of xylem function and the regulation of the xylem carbohydrate metabolism. Additionally, the number of upregulated genes related to xylem cell wall biogenesis was greater in males relative to females under drought stress and subsequent rewatering, which facilitated drought resistance and xylem function restoration in males. These results suggested that sex-specific drought resistance and restoration were related to xylem anatomy and function, carbohydrate metabolism and cell turgor maintenance.

Sex-specific responses of the reproductive system of zebrafish (Danio rerio) to electrolysis

Adult zebrafish (Danio rerio) were electrolyzed at different current densities to explore the effects of electrolysis on their reproductive system, especially on embryo production, and to uncover the molecular mechanism of changes in sex hormone and vitellogenin (VTG) levels. The results showed that embryo reproduction of zebrafish was reduced at a current density of 0.64 A/m2 after 28 days of exposure. In addition, the 17β-estradiol concentration significantly decreased and the testosterone concentration increased in female zebrafish above 0.53 A/m2. However, opposite trends were observed in male zebrafish. The VTG concentration was reduced considerably in the livers of female zebrafish in the 0.64 A/m2 electrolysis group (p < 0.05). In addition, the mRNA expression of hormone-regulating genes was significantly altered in female and male zebrafish when the current density was greater than 0.53 A/m2, and their change trends were sex-dependent. The genes expression levels of vtg1 and esr1 were downregulated in female zebrafish. However, the gene expression of esr1 and cyp19a was upregulated in male zebrafish. These changes were related to disruption in the hormone balance and VTG levels of adult zebrafish. Thus, electrolysis could cause masculinization of female zebrafish and feminization of male zebrafish. Nonetheless, there were few influences on the hormone levels and reproduction rate of adult zebrafish at the threshold of 0.26 A/m2. Thus, the current density of electrolysis needs to be controlled within a specific range to reduce its harmful effects on the reproductive system of aquatic animals.

Exercise training worsens cardiac performance in males but does not change ejection fraction and improves hypertrophy in females in a mouse model of metabolic syndrome

BackgroundMetabolic syndrome (MetS) refers to a cluster of co-existing cardio-metabolic risk factors, including visceral obesity, dyslipidemia, hyperglycemia with insulin resistance, and hypertension. As there is a close link between MetS and cardiovascular diseases, we aimed to investigate the sex-based differences in MetS-associated heart failure (HF) and cardiovascular response to regular exercise training (ET).MethodsHigh-fat diet-fed male and female APOB-100 transgenic (HFD/APOB-100, 3 months) mice were used as MetS models, and age- and sex-matched C57BL/6 wild-type mice on standard diet served as healthy controls (SD/WT). Both the SD/WT and HFD/APOB-100 mice were divided into sedentary and ET groups, the latter running on a treadmill (0.9 km/h) for 45 min 5 times per week for 7 months. At month 9, transthoracic echocardiography was performed to monitor cardiac function and morphology. At the termination of the experiment at month 10, blood was collected for serum low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol measurements and homeostatic assessment model for insulin resistance (HOMA-IR) calculation. Cardiomyocyte hypertrophy and fibrosis were assessed by histology. Left ventricular expressions of selected genes associated with metabolism, inflammation, and stress response were investigated by qPCR.ResultsBoth HFD/APOB-100 males and females developed obesity and hypercholesterolemia; however, only males showed insulin resistance. ET did not change these metabolic parameters. HFD/APOB-100 males showed echocardiographic signs of mild HF with dilated ventricles and thinner walls, whereas females presented the beginning of left ventricular hypertrophy. In response to ET, SD/WT males developed increased left ventricular volumes, whereas females responded with physiologic hypertrophy. Exercise-trained HFD/APOB-100 males presented worsening HF with reduced ejection fraction; however, ET did not change the ejection fraction and reversed the echocardiographic signs of left ventricular hypertrophy in HFD/APOB-100 females. The left ventricular expression of the leptin receptor was higher in females than males in the SD/WT groups. Left ventricular expression levels of stress response-related genes were higher in the exercise-trained HFD/APOB-100 males and exercise-trained SD/WT females than exercise-trained SD/WT males.ConclusionsHFD/APOB-100 mice showed sex-specific cardiovascular responses to MetS and ET; however, left ventricular gene expressions were similar between the groups except for leptin receptor and several stress response-related genes.

Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is an important health concern worldwide and progresses into nonalcoholic steatohepatitis (NASH). Although prevalence and severity of NAFLD/NASH are higher in men than premenopausal women, it remains unclear how sex affects NAFLD/NASH pathophysiology. Formyl peptide receptor 2 (FPR2) modulates inflammatory responses in several organs; however, its role in the liver is unknown. Here we show that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH. NASH-like liver injury was induced in both sexes during choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) feeding, but compared with females, male mice had more severe hepatic damage. Fpr2 was more highly expressed in hepatocytes and healthy livers from females than males, and FPR2 deletion exacerbated liver damage in CDAHFD-fed female mice. Estradiol induced Fpr2 expression, which protected hepatocytes and the liver from damage. In conclusion, our results demonstrate that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH, suggesting a novel therapeutic target for NAFLD/NASH.

Sex-specific neural responses to acute psychosocial stress in depression

Major Depressive Disorder (MDD) is characterized by increased stress sensitivity. Emerging findings in healthy adults suggest that stress responses within limbic/striatal-prefrontal regions are moderated by sex and unfold over time. Thus, we hypothesized that stress response abnormalities in MDD might be affected by sex and stress exposure time. The Montreal Imaging Stress Task was administered to 124 unmedicated patients with first-episode MDD (76 females) and 243 healthy controls (HC; 137 females) during functional magnetic resonance imaging (fMRI). Based on prior studies, amygdala, hippocampus, medial orbitofrontal cortex (mOFC), nucleus accumbens (NAc) and dorsolateral prefrontal cortex (dlPFC) were selected as a priori regions of interest. In a complementary approach, we probed the effects of stress on the frontoparietal network (FPN) and a network including the amygdala, NAc and anterior cingulate cortex (ACC). Across groups, males exhibited higher dlPFC activity and right FPN amplitude than females. Relative to female HCs, the female MDD group had less deactivation in limbic/striatal regions (amygdala, NAc, hippocampus, Amygdala-NAc-ACC network). Furthermore, unlike female HCs, the female MDD group failed to show a significant increase of deactivation over stress exposure time in the amygdala, mOFC and NAc. Our findings confirm the importance of considering sex differences when investigating neural stress responses. Case-control differences in neural stress responses observed in females (but not males) provide insights into sex differences in the etiology and pathophysiology of depression. The failure to deactivate limbic/NAc regions in depressed females point to dysfunction of adaptive stress responses over stress exposure time.

Genes That Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts.

Aortic valve stenosis is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain underexplored. Hydrogel biomaterials were designed to recapitulate key aspects of the valve tissue microenvironment and to serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to profibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA sequencing was used to define pathways involved in driving sex-dependent activation. Interventions with small molecule inhibitors and siRNA transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker α-smooth muscle actin compared with male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-smooth muscle actin stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than in male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase signaling as a potential driver of this sex-dependent myofibroblast activation. Furthermore, we found that genes that escape X-chromosome inactivation such as BMX and STS (encoding for Bmx nonreceptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation through Rho-associated protein kinase signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation through Rho-associated protein kinase signaling. Together, in vivo and in vitro results confirm sex dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent aortic valve stenosis progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of aortic valve stenosis and to help guide sex-based precision therapies.