Sex Differences In Susceptibility Research Articles

Central amygdala CRF+ neurons promote heightened threat reactivity following early life adversity in mice

Failure to appropriately predict and titrate reactivity to threat is a core feature of fear and anxiety-related disorders and is common following early life adversity (ELA). A population of neurons in the lateral central amygdala (CeAL) expressing corticotropin releasing factor (CRF) have been proposed to be key in processing threat of different intensities to mediate active fear expression. Here, we use in vivo fiber photometry to show that ELA results in sex-specific changes in the activity of CeAL CRF+ neurons, yielding divergent mechanisms underlying the augmented startle in ELA mice, a translationally relevant behavior indicative of heightened threat reactivity and hypervigilance. Further, chemogenic inhibition of CeAL CRF+ neurons selectively diminishes startle and produces a long-lasting suppression of threat reactivity. These findings identify a mechanism for sex-differences in susceptibility for anxiety following ELA and have broad implications for understanding the neural circuitry that encodes and gates the behavioral expression of fear.

Reduced cardiac antioxidant defenses mediate increased susceptibility to workload-induced myocardial injury in males with genetic cardiomyopathy

Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG−/− model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG−/− mice. Male β-SG−/− hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG−/− hearts. This protection of females was independent of ovarian hormones. Male β-SG−/− hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of β-SG−/− male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male β-SG−/− mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male β-SG−/− heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury.

Ongoing effects of preterm birth on the dopaminergic and noradrenergic pathways in the frontal cortex and hippocampus of guinea pigs.

Children born preterm have an increased likelihood of developing neurobehavioral disorders such as attention-deficit hyperactivity disorder (ADHD) and anxiety. These disorders have a sex bias, with males having a higher incidence of ADHD, whereas anxiety disorder tends to be more prevalent in females. Both disorders are underpinned by imbalances to key neurotransmitter systems, with dopamine and noradrenaline in particular having major roles in attention regulation and stress modulation. Preterm birth disturbances to neurodevelopment may affect this neurotransmission in a sexually dimorphic manner. Time-mated guinea pig dams were allocated to deliver by preterm induction of labor (gestational age 62 [GA62]) or spontaneously at term (GA69). The resultant offspring were randomized to endpoints as neonates (24h after term-equivalence age) or juveniles (corrected postnatal day 40, childhood equivalence). Relative mRNA expressions of key dopamine and noradrenaline pathway genes were examined in the frontal cortex and hippocampus and quantified with real-time PCR. Myelin basic protein and neuronal nuclei immunostaining were performed to characterize the impact of preterm birth. Within the frontal cortex, there were persisting reductions in the expression of dopaminergic pathway components that occurred in preterm males only. Conversely, preterm-born females had increased expression of key noradrenergic receptors and a reduction of the noradrenergic transporter within the hippocampus. This study demonstrated that preterm birth results in major changes in dopaminergic and noradrenergic receptor, transporter, and synthesis enzyme gene expression in a sex- and region-based manner that may contribute to the sex differences in susceptibility to neurobehavioral disorders. These findings highlight the need for the development of sex-based treatments for improving these conditions.

Sexual Dimorphism in the Physiopathology and Immune Response during Acute Toxocara canis Infection.

Toxocara canis (T. canis) is a helminth parasite of zoonotic and veterinary health significance that causes the disease known as Toxocariasis. This disease has been associated with conditions of poverty, especially in tropical climate zones throughout the world. Although it rarely causes important clinical manifestations, T. canis can lead to blindness, meningoencephalitis, or other nervous manifestations in humans. Moreover, some studies show its importance in the development of tumor growth, which have been associated with the parasite's ability to modulate the host's immune response. While different studies have evaluated the immune response during this disease, currently, there are no studies where the infection is analyzed from the perspective of sexual dimorphism. To evaluate sex differences in susceptibility, we analyzed lesions and parasite loads in lung and liver at 7 days post-infection. In addition, immune cell subpopulations were analyzed in spleen, mesenteric and peripheral lymph nodes. Finally, the production of cytokines and specific antibodies were determined in the serum. Statical analyses were performed using a Two-way ANOVA and a post-hoc Bonferroni multiple comparison test. Female rats had a higher number of larvae in the liver, while male rats had them in the lungs. The percentages of immune cells were evaluated, and in most cases, no significant differences were observed. Regarding the cytokines production, infection can generate a decrease in Th1 such as IL-1β in both sexes and IL-6 only in females. In the case of Th2, IL-4 increases only in infected males and IL-5 increases in males while decreasing in females due to the effect of infection. IL-10 also decreases in both sexes as a consequence of the infection, and TGF-β only in females. Finally, the infection generates the production of antibodies against the parasite, however, their quantity is lower in females. This study demonstrates that T. canis infection is dimorphic and affects females more than males. This is due to a polarization of the inadequate immune response, which is reflected as a higher parasite load in this sex.

Pancreas agenesis and fetal growth: a semi-quantitative analysis.

Pancreas agenesis is a rare condition underlying a variant of permanent neonatal diabetes mellitus. Neonates with this condition are born small for gestational age, but less is known about which components of growth are impacted, the timing of the growth restriction and potential sex differences. Our objective was to assess in which periods in gestation complete pancreas agenesis restricts fetal growth and possible sex differences in susceptibility. Published cases (n=49) with pancreas agenesis providing relevant data (gestational age, fetal sex, birth weight, birth length, head circumference, placental weight) were identified by MEDLINE and secondary literature search covering the years 1950-January 2023. Semi-quantitative analysis of these case reports used centiles based on Intergrowth-21 reference charts. Neonates with pancreas agenesis were severely growth restricted, however, median centiles for birth weight, length and head circumference of those born before week 36 were significantly higher compared to those born from 36 weeks. Similar results were found when data were separated by before and from 38 weeks. Head circumference was less affected than birth weight or length. No sex differences were found. In conclusion, pancreas agenesis severely restricts fetal length and head circumference in addition to weight growth, with stronger effects evident from 36 weeks of gestation. In addition to the well-known effects of insulin on growth of fetal fat mass, the pronounced effect on birth length and head circumference indicates effects of insulin on fetal lean body growth as well. Lack of power may account for failure to find sex differences.

Proximal Tubule-Specific Transcriptomic Changes Mediate Sex Differences in Susceptibility to Aristolochic Acid I-Induced AKI in Mice

Proximal Tubule-Specific Transcriptomic Changes Mediate Sex Differences in Susceptibility to Aristolochic Acid I-Induced AKI in Mice

Sex differences in avoidance behavior and cued threat memory dynamics in mice: Interactions between estrous cycle and genetic background

Anxiety disorders are the most prevalent mental illnesses worldwide, exhibit high heritability, and affect twice as many women as men. To evaluate potential interactions between genetic background and cycling ovarian hormones on sex differences in susceptibility to negative valence behaviors relevant to anxiety disorders, we assayed avoidance behavior and cued threat memory dynamics in gonadally-intact adult male and female mice across four common inbred mouse strains: C57Bl/6J, 129S1/SVlmJ, DBA/2J, and BALB/cJ. Independent of sex, C57Bl/6J mice exhibited low avoidance but high threat memory, 129S1/SvlmJ mice high avoidance and high threat memory, DBA/2J mice low avoidance and low threat memory, and BALB/cJ mice high avoidance but low threat memory. Within-strain comparisons revealed reduced avoidance behavior in the high hormone phase of the estrous cycle (proestrus) compared to all other estrous phases in all strains except DBA/2J, which did not exhibit cycle-dependent behavioral fluctuations. Robust and opposing sex differences in threat conditioning and extinction training were found in the C57Bl/6J and 129S1/SvlmJ lines, whereas no sex differences were observed in the DBA/2J or BALB/cJ lines. C57Bl/6J males exhibited enhanced acute threat memory, whereas 129S1/SvlmJ females exhibited enhanced sustained threat memory, compared to their sex-matched littermates. These effects were not mediated by estrous cycle stage or sex differences in active versus passive defensive behavioral responses. Our data demonstrate that core features of behavioral endophenotypes relevant to anxiety disorders, such as avoidance and threat memory, are genetically driven yet dissociable and can be influenced further by cycling ovarian hormones.

Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low-dose kainic acid systemic injection paradigm in mice.

Sex differences in epilepsy appear driven in part due to effects of gonadal steroids, with varying results in experimental models based on species, strain, and method of seizure induction. Furthermore, removing the main source of these steroids via gonadectomy may impact seizure characteristics differently in males and females. Repeated low-dose kainic acid (RLDKA) systemic injection paradigms were recently shown to reliably induce status epilepticus (SE) and hippocampal histopathology in C57BL/6J mice. Here, we investigated whether seizure susceptibility in a RLDKA injection protocol exhibits a sex difference and whether gonadectomy differentially influences response to this seizure induction paradigm in males and females. Adult C57BL/6J mice were left gonad-intact as controls or gonadectomized (females: ovariectomized, OVX; males: orchidectomized, ORX). At least 2 weeks later, KA was injected ip, every 30 minutes at 7.5 mg/kg or less until the animal reached SE, defined by at least 5 generalized seizures (GS, Racine stage 3 or higher). Parameters of susceptibility to GS induction, SE development, and mortality rates were quantified. No differences in seizure susceptibility or mortality were observed between control males and control females. Gonadectomized mice exhibited increased susceptibility and reduced latency to both GS and SE in comparison to corresponding controls of the same sex, but the effects were stronger in males. In addition, ORX males, but not OVX females, exhibited strongly increased seizure-induced mortality. The RLDKA protocol is notable for its efficacy in inducing SE and seizure-induced histopathology in C57BL/6J mice, the background for many transgenic strains in current use in epilepsy research. The present results indicate that this protocol may be beneficial for investigating the effects of gonadal hormone replacement on seizure susceptibility, mortality, and seizure-induced histopathology, and that gonadectomy unmasks sex differences in susceptibility to seizures and mortality not observed in gonad-intact controls.

The association of circulating endocannabinoids with neuroimaging and blood biomarkers of neuro-injury

BackgroundPreclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex.MethodsThis exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011–2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer’s disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined.ResultsParticipants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (β ± SE = − 0.12 ± 0.06, p = 0.034 and β ± SE = 0.08 ± 0.04, p = 0.026, respectively).ConclusionsCirculating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer’s disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women.

Sex differences in susceptibility to substance use disorder: Role for X chromosome inactivation and escape?

There is a sex-based disparity associated with substance use disorders (SUDs) as demonstrated by clinical and preclinical studies. Females are known to escalate from initial drug use to compulsive drug-taking behavior (telescoping) more rapidly, and experience greater negative withdrawal effects than males. Although these biological differences have largely been attributed to sex hormones, there is evidence for non-hormonal factors, such as the influence of the sex chromosome, which underlie sex disparities in addiction behavior. However, genetic and epigenetic mechanisms underlying sex chromosome influences on substance abuse behavior are not completely understood. In this review, we discuss the role that escape from X-chromosome inactivation (XCI) in females plays in sex-associated differences in addiction behavior. Females have two X chromosomes (XX), and during XCI, one X chromosome is randomly chosen to be transcriptionally silenced. However, some X-linked genes escape XCI and display biallelic gene expression. We generated a mouse model using an X-linked gene specific bicistronic dual reporter mouse as a tool to visualize allelic usage and measure XCI escape in a cell specific manner. Our results revealed a previously undiscovered X-linked gene XCI escaper (CXCR3), which is variable and cell type dependent. This illustrates the highly complex and context dependent nature of XCI escape which is largely understudied in the context of SUD. Novel approaches such as single cell RNA sequencing will provide a global molecular landscape and impact of XCI escape in addiction and facilitate our understanding of the contribution of XCI escape to sex disparities in SUD.

Maternal stress increases risk of allergic lung inflammation in adult mice

BackgroundAllergies are increasing worldwide. The presence of atopic diseases in the mother propagates the onset of allergic diseases in the offspring with a considerably stronger penetrance than atopic diseases of the father. Such observation challenges genetic predispositions as the sole cause of allergic diseases. Epidemiological studies suggest that caregiver stress in the perinatal period may predispose offspring to asthma. Only one group has studied the link between prenatal stress and neonatal asthma susceptibility in a murine model. ObjectivesWe aimed to study if the neonatal increased risk of developing allergic lung inflammation persists after puberty and if there are sex differences in susceptibility. MethodsPregnant BALB/c mice were subjected to a single restraint stress exposure at day 15 of gestation. Pups were separated by gender and subjected to a well-known sub-optimal asthma model after puberty. ResultsAdult mice born to stressed dams were more susceptible to developing allergic pulmonary inflammation since an increase in the number of eosinophils in bronchoalveolar lavage (BAL), a greater peribronchial and perivascular infiltrate, a higher proportion of mucus-producing cells, and increased IL-4 and IL-5 levels in BAL were detected compared to control mice. These effects were more profound in females than males. Moreover, only females from stressed dams showed an increase in IgE levels. ConclusionsIncreased litter susceptibility to develop allergic lung inflammation induced by maternal stress persists after puberty and is more potent in females than in male mice.

Heterogeneities in infection outcomes across species: sex and tissue differences in virus susceptibility.

Species vary in their susceptibility to pathogens, and this can alter the ability of a pathogen to infect a novel host. However, many factors can generate heterogeneity in infection outcomes, obscuring our ability to understand pathogen emergence. Such heterogeneities can alter the consistency of responses across individuals and host species. For example, sexual dimorphism in susceptibility means males are often intrinsically more susceptible than females (although this can vary by host and pathogen). Further, we know little about whether the tissues infected by a pathogen in one host are the same in another species, and how this relates to the harm a pathogen does to its host. Here, we first take a comparative approach to examine sex differences in susceptibility across 31 species of Drosophilidae infected with Drosophila C Virus (DCV). We found a strong positive inter-specific correlation in viral load between males and females, with a close to 1:1 relationship, suggesting that susceptibility to DCV across species is not sex specific. Next, we made comparisons of the tissue tropism of DCV across seven species of fly. We found differences in viral load between the tissues of the seven host species, but no evidence of tissues showing different patterns of susceptibility in different host species. We conclude that, in this system, patterns of viral infectivity across host species are robust between males and females, and susceptibility in a given host is general across tissue types.

Reticulated evolution marks the rapid diversification of the Delphinoidae

Species vary in their susceptibility to pathogens, and this can alter the ability of a pathogen to infect a novel host. However, many factors can generate heterogeneity in infection outcomes, obscuring our ability to understand pathogen emergence. Such heterogeneities can alter the consistency of responses across individuals and host species. For example, sexual dimorphism in susceptibility means males are often intrinsically more susceptible than females (although this can vary by host and pathogen). Further, we know little about whether the tissues infected by a pathogen in one host are the same in another species, and how this relates to the harm a pathogen does to its host. Here, we first take a comparative approach to examine sex differences in susceptibility across 31 species of Drosophilidae infected with Drosophila C Virus (DCV). We found a strong positive inter-specific correlation in viral load between males and females, with a close to 1:1 relationship, suggesting that susceptibility to DCV across species is not sex specific. Next, we made comparisons of the tissue tropism of DCV across seven species of fly. We found differences in viral load between the tissues of the seven host species, but no evidence of tissues showing different patterns of susceptibility in different host species. We conclude that, in this system, patterns of viral infectivity across host species are robust between males and females, and susceptibility in a given host is general across tissue types.

Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma

Puberty is an important developmental period marked by hormonal, metabolic and immune changes. Puberty also marks a shift in sex differences in susceptibility to asthma. Yet, little is known about the gene expression changes in immune cells that occur during pubertal development. Here we assess pubertal development and leukocyte gene expression in a longitudinal cohort of 251 children with asthma. We identify substantial gene expression changes associated with age and pubertal development. Gene expression changes between pre- and post-menarcheal females suggest a shift from predominantly innate to adaptive immunity. We show that genetic effects on gene expression change dynamically during pubertal development. Gene expression changes during puberty are correlated with gene expression changes associated with asthma and may explain sex differences in prevalence. Our results show that molecular data used to study the genetics of early onset diseases should consider pubertal development as an important factor that modifies the transcriptome.

Examining mGlu5 Receptor Availability as a Predictor of Vulnerability to PTSD: An [18F]FPEB and PET Study in Male and Female Rats

Background Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females. Methods Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [18F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female). Results Overall, FE rats displayed greater fear generalization as compared with CON (p < .001). Further, greater mGlu5 receptor availability at baseline (p = .003) and post-test (p = .005) was significantly associated with expression of the SEFL phenotype. Notably, FE female rats displayed a shift to more passive coping (ie, freezing), and displayed greater SEFL susceptibility (p = .01), and had lower baseline mGlu5 availability (p = .03) relative to their FE male rat counterparts. Conclusion Results are consistent with clinical findings of higher mGlu5 receptor availability in PTSD, and add to growing evidence implicating these receptors in the pathophysiology of PTSD and sex-differences in susceptibility for this disorder.

Network medicine‐based multimodal omics analytic framework identifies immunometabolism endophenotypes underlying sex difference of Alzheimer’s disease

AbstractBackgroundAlthough Alzheimer’s disease (AD) is sexually dimorphic in prevalence, incidence, symptomology, and neuropathology, the molecular mechanisms underlying these sex differences are not well understood.MethodWe presented a multimodal omics analytic framework to inspect sex differences in susceptibility to inflammation, cellular metabolism, and disease pathophysiology of AD. Specifically, we investigated the interplay between cellular metabolism and immune responses, termed the “immunometabolism endophenotype,” by unique integration of transcriptomics (single‐cell/nuclei RNA‐seq), proteomics (inflammatory biomarker expression), and metabolomics from the AD knowledge portal, the Alzheimer’s Disease Metabolomics Consortium, and the Cleveland Alzheimer's Disease Research Center (CADRC).ResultWe identified sex‐specific, elevated pro‐inflammatory gene/protein expression in blood (including myeloid‐derived suppressor cells [MDSCs]) and cerebrospinal fluid of phenotypically characterized subjects by AD biomarkers of Amyloid deposition, pathologic Tau, and Neurodegeneration (ATN). We also identified sex‐specific microglial gene signatures in AD patient brains from single‐cell/nuclei RNA‐seq (sc/snRNA‐seq) data analyses. We further found that women lost gene expression of innate and adaptive pathways (i.e., NF‐kappa B signaling, Toll‐like receptor signaling, and HIF signaling) in microglia compared to men with amyloid and tau neuropathology. However, women have elevated expression of innate and adaptive pathways (i.e., IL‐17 signaling and antigen processing and presentation) in excitatory neurons compared to men with tau neuropathology. Integrative sc/snRNA‐seq data analyses showed sex‐specific ligand‐receptor interactions among microglia, astrocytes, and neurons. We also found that women with AD have elevated metabolites of glycerophospholipids and sphingolipids compared to men with AD. A microglia‐specific male‐biased metabolite‐enzyme network is enriched in immune pathways of Type I and II IFN signaling and fructose, mannose, and HIF‐1 metabolic pathways. By contrast, the female‐biased metabolite‐enzyme network is significantly enriched in glycerophospholipids. These findings were further validated by the female‐biased expression of pro‐inflammatory cytokines (i.e., IFNγ, GM‐CSF, IL‐8, and IL‐15) from ATN‐characterized cohorts from our CADRC.ConclusionThis study establishes proof‐of‐concept of sex‐specific immune responses, cellular metabolism, and microglial immunometabolism underlying sex differences in AD.

Sex differences in susceptibility to influenza A virus infection depend on host genotype.

Infection with the respiratory pathogen influenza A virus (IAV) causes significant morbidity and mortality each year. While host genotype is thought to contribute to severity of disease, naturally occurring genetic determinants remain mostly unknown. Moreover, more severe disease is seen in women compared with men, but genetic mechanisms underlying this sex difference remain obscure. Here, using IAV infection in a mouse model of naturally selected genetic diversity, namely C57BL6/J (B6) mice carrying chromosomes (Chr) derived from the wild-derived and genetically divergent PWD/PhJ (PWD) mouse strain (B6.ChrPWD consomic mice), we examined the effects of genotype and sex on severity of IAV-induced disease. Compared with B6, parental PWD mice were completely protected from IAV-induced disease, a phenotype that was fully recapitulated in the B6.Chr16PWD strain carrying the PWD-derived allele of Mx1. In contrast, several other consomic strains, including B6.Chr3PWD and B6.Chr5PWD, demonstrated greatly increased susceptibility. Notably, B6.Chr5PWD and B6.ChrX.3PWD strains, the latter carrying the distal one-third of ChrX from PWD, exhibited increased morbidity and mortality specifically in male but not female mice. Follow up analyses focused on B6 and B6.ChrX.3PWD strains demonstrated moderately elevated viral load in B6.ChrX3PWD male, but not female mice. Transcriptional profiling demonstrated genotype- and sex-specific gene expression profiles in the infected lung, with male B6.ChrX.3 mice exhibiting the most significant changes, including upregulation of a proinflammatory gene expression program associated with myeloid cells, and altered sex-biased expression of several X-linked genes that represent positional candidates, including Tlr13 and Slc25a53. Taken together, our results identify novel loci on autosomes and the X chromosome regulating IAV susceptibility and demonstrate that sex differences in IAV susceptibility are genotype-dependent, suggesting that future genetic association studies need to consider sex as a covariate.

Acute immobilization stress evokes sexually dimorphic peripheral and hippocampal neuroimmune responses in adult rats

Stress perception and response vary across sexes and may contribute to the sex differences in susceptibility to psychopathology. Stress also engages the immune system and baseline immune system markers are known to be sexually dimorphic. Here, we investigated if the neuroimmune consequences following a single episode of acute immobilization stress (AIS) are sexually dimorphic in male and female Sprague-Dawley rats. We analyzed immune parameters in the periphery, and markers of neuroinflammation in the hippocampus, a key target of stress effects in the brain. We observed sexual dimorphism in the pattern of regulation of peripheral cytokines following stress, with males showing a significant increase in the levels of specific cytokines compared to females. Hippocampal cytokine and neuroinflammation-associated gene expression level analysis did not reveal any sexually dimorphic effects of AIS. However, we noted lower baseline expression levels for specific cytokines and many of the genes analyzed in the hippocampus of control females compared to control males. Finally, we assessed the levels of components of the NLRP3 inflammasome in the hippocampus and observed increased NLRP3 protein levels at baseline in females. We further noted that while males showed an increase in NLRP3 levels following AIS, females failed to show a similar change. Together, our results highlight a sexual dimorphism in neuroimmune consequences following AIS, both in the periphery and within the hippocampus, with males displaying robust proinflammatory changes and similar changes not observed in females. Our study underlines the importance of investigating the effect of sex on neuroimmune consequences following acute stress.

Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure.

Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions.

Sex differences in the intergenerational inheritance of metabolic traits.

Strong evidence suggests that early-life exposures to suboptimal environmental factors, including those in utero, influence our long-term metabolic health. This has been termed developmental programming. Mounting evidence suggests that the growth and metabolism of male and female fetuses differ. Therefore, sexual dimorphism in response to pre-conception or early-life exposures could contribute to known sex differences in susceptibility to poor metabolic health in adulthood. However, until recently, many studies, especially those in animal models, focused on a single sex, or, often in the case of studies performed during intrauterine development, did not report the sex of the animal at all. In this review, we (a) summarize the evidence that male and females respond differently to a suboptimal pre-conceptional or in utero environment, (b) explore the potential biological mechanisms that underlie these differences and (c) review the consequences of these differences for long-term metabolic health, including that of subsequent generations.