Biological Sex Differences Research Articles

Biological sex and vessel specific relationships between cerebral pulsatility and white matter hyperintensities: a 4D flow MRI study

AbstractBackgroundBrain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex‐specific.Method407 cognitively healthy middle‐aged and older adults (45‐87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid‐attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume.ResultPI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P≤0.01, all male P≥0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P≤0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P≤0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (β = 0.39±0.09 a.u., R2 = 0.13) compared with females (β = 0.18±0.05 a.u., R2 = 0.05).ConclusionThese data suggest that, among cognitively healthy middle‐aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex‐ and vessel‐specific which may contribute to sex‐specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.

Biological sex and vessel specific relationships between cerebral pulsatility and white matter hyperintensities: a 4D flow MRI study

AbstractBackgroundBrain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex‐specific.Method407 cognitively healthy middle‐aged and older adults (45‐87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid‐attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume.ResultPI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P = 0.01, all male P = 0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P = 0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P = 0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (ß = 0.39±0.09 a.u., R2 = 0.13) compared with females (ß = 0.18±0.05 a.u., R2 = 0.05).ConclusionThese data suggest that, among cognitively healthy middle‐aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex‐ and vessel‐specific which may contribute to sex‐specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.

Heart Rate Variability in Concussed College Athletes: Follow-Up Study and Biological Sex Differences.

Finding reliable biomarkers to assess concussions could play a pivotal role in diagnosis, monitoring, and predicting associated risks. The present study aimed to explore the use of heart rate variability (HRV) in the follow-up of concussions among college athletes and to investigate the relationships between biological sex, symptomatology, and HRV values at baseline and after a concussion. Correlations between measures were also analyzed. A total of 169 (55 females) athletes aged 16 to 22 years old completed baseline testing, and 30 (8 females) concussion cases were followed. Baseline assessment (T1) included psychosocial and psychological questionnaires, symptoms report, and four minutes of HRV recording. In the event of a concussion, athletes underwent re-testing within 72 h (T2) and before returning to play (T3). Baseline findings revealed that girls had higher %VLF while sitting than boys, and a small negligible correlation was identified between %HF and total symptoms score as well as %HF and affective sx. Post-concussion analyses demonstrated a significant effect of time × position × biological sex for %HF, where girls exhibited higher %HF at T3. These findings suggest disruptions in HRV following a concussion and underscore biological sex as an important factor in the analysis of HRV variation in concussion recovery trajectory.

Developmental transcriptomic patterns can be altered by transgenic overexpression of Uty

The genetic material encoded on X and Y chromosomes provides the foundation by which biological sex differences are established. Epigenetic regulators expressed on these sex chromosomes, including Kdm6a (Utx), Kdm5c, and Ddx3x have far-reaching impacts on transcriptional control of phenotypic sex differences. Although the functionality of UTY (Kdm6c, the Y-linked homologue of UTX), has been supported by more recent studies, its role in developmental sex differences is not understood. Here we test the hypothesis that UTY is an important transcriptional regulator during development that could contribute to sex-specific phenotypes and disease risks across the lifespan. We generated a random insertion Uty transgenic mouse (Uty-Tg) to overexpress Uty. By comparing transcriptomic profiles in developmental tissues, placenta and hypothalamus, we assessed potential UTY functional activity, comparing Uty-expressing female mice (XX + Uty) with wild-type male (XY) and female (XX) mice. To determine if Uty expression altered physiological or behavioral outcomes, adult mice were phenotypically examined. Uty expression masculinized female gene expression patterns in both the placenta and hypothalamus. Gene ontology (GO) and gene set enrichment analysis (GSEA) consistently identified pathways including immune and synaptic signaling as biological processes associated with UTY. Interestingly, adult females expressing Uty gained less weight and had a greater glucose tolerance compared to wild-type male and female mice when provided a high-fat diet. Utilizing a Uty-overexpressing transgenic mouse, our results provide novel evidence as to a functional transcriptional role for UTY in developing tissues, and a foundation to build on its prospective capacity to influence sex-specific developmental and health outcomes.

Unraveling the Role of Sex in Endothelial Cell Dysfunction: Evidence From Lineage Tracing Mice and Cultured Cells.

Biological sex differences play a vital role in cardiovascular diseases, including atherosclerosis. The endothelium is a critical contributor to cardiovascular pathologies since endothelial cells (ECs) regulate vascular tone, redox balance, and inflammatory reactions. Although EC activation and dysfunction play an essential role in the early and late stages of atherosclerosis development, little is known about sex-dependent differences in EC. We used human and mouse aortic EC as well as EC-lineage tracing (Cdh5-CreERT2 Rosa-YFP [yellow fluorescence protein]) atherosclerotic Apoe-/- mice to investigate the biological sexual dimorphism of the EC functions in vitro and in vivo. Bioinformatics analyses were performed on male and female mouse aortic EC and human lung and aortic EC. In vitro, female human and mouse aortic ECs showed more apoptosis and higher cellular reactive oxygen species levels than male EC. In addition, female mouse aortic EC had lower mitochondrial membrane potential (ΔΨm), lower TFAM (mitochondrial transcription factor A) levels, and decreased angiogenic potential (tube formation, cell viability, and proliferation) compared with male mouse aortic EC. In vivo, female mice had significantly higher lipid accumulation within the aortas, impaired glucose tolerance, and lower endothelial-mediated vasorelaxation than males. Using the EC-lineage tracing approach, we found that female lesions had significantly lower rates of intraplaque neovascularization and endothelial-to-mesenchymal transition within advanced atherosclerotic lesions but higher incidents of missing EC lumen coverage and higher levels of oxidative products and apoptosis. RNA-seq analyses revealed that both mouse and human female EC had higher expression of genes associated with inflammation and apoptosis and lower expression of genes related to angiogenesis and oxidative phosphorylation than male EC. Our study delineates critical sex-specific differences in EC relevant to proinflammatory, pro-oxidant, and angiogenic characteristics, which are entirely consistent with a vulnerable phenotype in females. Our results provide a biological basis for sex-specific proatherosclerotic mechanisms.

How does the experience of shame impact body dysmorphic symptomatology? Exploring the role of mindfulness and body image-related cognitive fusion

Shame has been considered a core component of body dysmorphia-related symptomatology. However, literature concerning the emotion regulation processes that underlie the association between these two constructs seems to be scarce. Therefore, the main aim of this cross-sectional study was to explore the role that mindfulness and body image-related cognitive fusion has on the relationship between the experience of shame and body dysmorphia-related symptomatology Additionally, biological sex differences concerning the studied variables were explored. Three hundred and twenty-seven participants (male and female) above 18 years old completed an online survey with self-report measures to assess shame experiences, mindfulness, body image-related cognitive fusion and body dysmorphia-related symptoms. Results indicated that female participants presented higher body dysmorphia-related symptomatology when compared with males. A path analysis was conducted suggesting that, while controlling for the effect of age and BMI, the experience of shame had a direct effect on body dysmorphia-related symptomatology, as well as an indirect effect through mindfulness and body image-related cognitive fusion. This model presented a good fit, explaining 56% of the variance of body dysmorphia-related symptomatology. Also, findings from a multi-group path analysis revealed that the relationship between these variables is invariant across males and females. These findings have important research and clinical implications, supporting the importance of targeting mindfulness and cognitive defusion skills when working in the context of Body Dysmorphia.

Neurobiological metric of cortical delay discounting differentiates risk for self- and other-directed violence among trauma-exposed individuals.

Self- and other-directed violence (SDV/ODV) contribute to elevated rates of mortality. Early trauma exposure shows robust positive associations with these forms of violence but alone does not distinguish those at heightened risk for later engagement in SDV/ODV. Novel assessment metrics could aid early identification efforts for individuals with vulnerabilities to violence perpetration. This study examined a novel neurobiological measure of impulsive choice for reward as a potential moderator of associations between childhood trauma exposure and lifetime SDV/ODV. A high-risk community sample of 177 adults (89 men; 50.3%) were assessed for childhood trauma exposure, engagement in SDV (e.g., suicide attempts), and ODV (e.g., assault). A cortical delay discounting (C-DD) measure was created using a multivariate additive model of gray matter thickness across both hemispheres, previously found to be positively associated with susceptibility to impulsivity and externalizing disorders. Childhood trauma exposure was positively associated with ODV and SDV; however, these relationships differed as a function of C-DD. Engagement in ODV increased as scores on C-DD increased, and SDV increased as scores on C-DD decreased. Furthermore, moderation revealed biological sex differences, as the association between childhood trauma and SDV depended on C-DD for women but not for men. Findings from the present work demonstrate that risk conferred by childhood trauma exposure to violence varied as a function of a C-DD. Together, these findings point to the utility of neurobiological markers of impulsive decision-making for differentiating risk for violence among individuals with a history of trauma exposure. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Biological Sex Differences In Blood-Based Biomarkers After Physiological Exercise Testing In Endurance-Trained Athletes

Biological Sex Differences In Blood-Based Biomarkers After Physiological Exercise Testing In Endurance-Trained Athletes

Sex difference and immunosenescence affect transplantation outcomes.

Kidney transplantation is a well-established alternative to renal replacement therapy. Although the number of patients with end-stage renal disease (ESRD) is increasing, the availability of kidney for transplantation is still insufficient to meet the needs. As age increases, the prevalence of ESRD increases; thus, the population of aged donors and recipients occupies large proportion. Accumulated senescent cells secrete pro-inflammatory factors and induce senescence. Additionally, it is gradually becoming clear that biological sex differences can influence aging and cause differences in senescence. Here, we review whether age-related sex differences affect organ transplant outcomes and what should be done in the future.

Sex matters: the frequently overlooked importance of considering sex in computational models.

Personalised medicine and the development of a virtual human or a digital twin comprises visions of the future of medicine. To realise these innovations, an understanding of the biology and physiology of all people are required if we wish to apply these technologies at a population level. Sex differences in health and biology is one aspect that has frequently been overlooked, with young white males being seen as the "average" human being. This has not been helped by the lack of inclusion of female cells and animals in biomedical research and preclinical studies or the historic exclusion, and still low in proportion, of women in clinical trials. However, there are many known differences in health between the sexes across all scales of biology which can manifest in differences in susceptibility to diseases, symptoms in a given disease, and outcomes to a given treatment. Neglecting these important differences in the development of any health technologies could lead to adverse outcomes for both males and females. Here we highlight just some of the sex differences in the cardio-respiratory systems with the goal of raising awareness that these differences exist. We discuss modelling studies that have considered sex differences and touch on how and when to create sex-specific models. Scientific studies should ensure sex differences are included right from the study planning phase and results reported using sex as a biological variable. Computational models must have sex-specific versions to ensure a movement towards personalised medicine is realised.

The time-course of cancer cachexia onset reveals biphasic transcriptional disruptions in female skeletal muscle distinct from males

BackgroundCancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences.ResultsWe found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another during the later stages of cachexia development. The early phase was associated with the upregulation of extracellular-matrix pathways, while the later phase was characterized by the downregulation of oxidative phosphorylation, electron transport chain, and TCA cycle. When DEGs were compared to a known list of mitochondrial genes (MitoCarta), ~ 47% of these genes were differently expressed in females exhibiting global cachexia, suggesting transcriptional changes to mitochondrial gene expression happens concomitantly to functional impairments previously published. In contrast, the JAK-STAT pathway was upregulated in both the early and late stages of CC. Additionally, we observed a consistent downregulation of Type-II Interferon signaling genes in females, which was associated with protection in skeletal muscle atrophy despite systemic cachexia. Upregulation of Interferon signaling was noted in the gastrocnemius muscle of cachectic and atrophic male mice. Comparison of female tumor-bearing mice with males revealed ~ 70% of DEGs were distinct between sexes in cachectic animals, demonstrating dimorphic mechanisms of CC.ConclusionOur findings suggest biphasic disruptions in the transcriptome of female LLC tumor-bearing mice: an early phase associated with ECM remodeling and a late phase, accompanied by the onset of systemic cachexia, affecting overall muscle energy metabolism. Notably, ~ 2/3 of DEGs in CC are biologically sex-specific, providing evidence of dimorphic mechanisms of cachexia between sexes. Downregulation of Type-II Interferon signaling genes appears specific to CC development in females, suggesting a new biological sex-specific marker of CC not reliant on the loss of muscle mass, that might represent a protective mechanism against muscle loss in CC in female mice.

Sex differences in the renin-angiotensin-aldosterone system and its roles in hypertension, cardiovascular, and kidney diseases.

Cardiovascular disease is a pathology that exhibits well-researched biological sex differences, making it possible for physicians to tailor preventative and therapeutic approaches for various diseases. Hypertension, which is defined as blood pressure greater than 130/80 mmHg, is the primary risk factor for developing coronary artery disease, stroke, and renal failure. Approximately 48% of American men and 43% of American women suffer from hypertension. Epidemiological data suggests that during reproductive years, women have much lower rates of hypertension than men. However, this protective effect disappears after the onset of menopause. Treatment-resistant hypertension affects approximately 10.3 million US adults and is unable to be controlled even after implementing ≥3 antihypertensives with complementary mechanisms. This indicates that other mechanisms responsible for modulating blood pressure are still unclear. Understanding the differences in genetic and hormonal mechanisms that lead to hypertension would allow for sex-specific treatment and an opportunity to improve patient outcomes. Therefore, this invited review will review and discuss recent advances in studying the sex-specific physiological mechanisms that affect the renin-angiotensin system and contribute to blood pressure control. It will also discuss research on sex differences in hypertension management, treatment, and outcomes.

Cognitive disturbances during perimenopause: are they linked to dementia?

Women have a greater risk of developing Alzheimer's disease (AD) compared to men. This biological sex difference is primarily due to the greater longevity of women compared to men, but other factors also contribute to this difference, including a greater risk of AD among those with the apolipoprotein epsilon 4 (APOE4) genetic risk factor. Sex steroid hormones have myriad effects on the central nervous system, and other bodily systems that play an important role in brain health, including immune, metabolic and cardiovascular systems. Knowledge of the brain changes that occur in menopause is limited by the lack of large-scale longitudinal neuroimaging studies of women transitioning through the menopause, though such studies are currently underway. Initial evidence from cross-sectional studies and small longitudinal studies suggest that both brain structure and function may undergo changes, and that AD biomarkers may accumulate more rapidly during the menopause. Clearly the menopause is not a universal trigger for the development of AD, as all women who live into late life transition through the menopause and only a minority of women with develop AD. One of the factors that may make certain women more vulnerable to AD is vasomotor symptoms (VMS). Although a causal role of VMS is not established, correlational studies link objectively measured VMS with memory deficits, disruptions in brain function and the accumulation of white matter hyperintensities, small ischemic lesions that increase the risk of both vascular dementia and AD. Mood symptoms and sleep disruption also contribute to cognitive changes and alterations in brain health. Some evidence indicates that hormone therapy (HT) may be associated with lower levels of AD biomarkers, but more clinical trial data is needed, particularly in women with VMS. Medical societies reliably conclude based on the evidence to date that HT should not be used for the treatment of cognitive issues or the prevention of dementia. The use of HT for the treatment of VMS, however, is indicated and may help women to maintain more optimal brain health as they age.

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury.

Introduction: In experimental animal models, biological sex-differences in the manifestation and severity of normal tissue radiation injury have been well-documented. Previously we demonstrated male and female rats have differential and highly reproducible responses to high-dose partial body irradiation (PBI) with male rats having greater susceptibility to both gastrointestinal acute radiation syndrome (GI-ARS) and radiation pneumonitis than female rats. Methods: In the current study, we have investigated whether differential expression of the renin-angiotensin system (RAS) enzymes angiotensin converting enzyme (ACE) and ACE2 contribute to the observed sex-related differences in radiation response. Results: During the period of symptomatic pneumonitis, the relative ratio of ACE to ACE2 (ACE/ACE2) protein in the whole lung was significantly increased by radiation in male rats alone. Systemic treatment with small molecule ACE2 agonist diminazene aceturate (DIZE) increased lung ACE2 activity and reduced morbidity during radiation pneumonitis in both sexes. Notably DIZE treatment also abrogated morbidity in male rats during GI-ARS. We then evaluated the contribution of the irradiated bone marrow (BM) compartment on lung immune cell infiltration and ACE imbalance during pneumonitis. Transplantation of bone marrow from irradiated donors increased both ACE-expressing myeloid cell infiltration and immune ACE activity in the lung during pneumonitis compared to non-irradiated donors. Discussion: Together, these data demonstrate radiation induces a sex-dependent imbalance in the renin-angiotensin system enzymes ACE and ACE2. Additionally, these data suggest a role for ACE-expressing myeloid cells in the pathogenesis of radiation pneumonitis. Finally, the observed sex-differences underscore the need for consideration of sex as a biological variable in the development of medical countermeasures for radiation exposure.

Neural responses to reward valence and magnitude from pre- to early adolescence

BackgroundNeural activation during reward processing is thought to underlie critical behavioral changes that take place during the transition to adolescence (e.g., learning, risk-taking). Though literature on the neural basis of reward processing in adolescence is booming, important gaps remain. First, more information is needed regarding changes in functional neuroanatomy in early adolescence. Another gap is understanding whether sensitivity to different aspects of the incentive (e.g., magnitude and valence) changes during the transition into adolescence. We used fMRI from a large sample of preadolescent children to characterize neural responses to incentive valence vs. magnitude during anticipation and feedback, and their change over a period of two years. MethodsData were taken from the Adolescent Cognitive and Brain DevelopmentSM (ABCD®) study release 3.0. Children completed the Monetary Incentive Delay task at baseline (ages 9–10) and year 2 follow-up (ages 11–12). Based on data from two sites (N = 491), we identified activation-based Regions of Interest (ROIs; e.g., striatum, prefrontal regions, etc.) that were sensitive to trial type (win $5, win $0.20, neutral, lose $0.20, lose $5) during anticipation and feedback phases. Then, in an independent subsample (N = 1470), we examined whether these ROIs were sensitive to valence and magnitude and whether that sensitivity changed over two years. ResultsOur results show that most ROIs involved in reward processing (including the striatum, prefrontal cortex, and insula) are specialized, i.e., mainly sensitive to either incentive valence or magnitude, and this sensitivity was consistent over a 2-year period. The effect sizes of time and its interactions were significantly smaller (0.002≤η2≤0.02) than the effect size of trial type (0.06≤η2≤0.30). Interestingly, specialization was moderated by reward processing phase but was stable across development. Biological sex and pubertal status differences were few and inconsistent. Developmental changes were mostly evident during success feedback, where neural reactivity increased over time. ConclusionsOur results suggest sub-specialization to valence vs. magnitude within many ROIs of the reward circuitry. Additionally, in line with theoretical models of adolescent development, our results suggest that the ability to benefit from success increases from pre- to early adolescence. These findings can inform educators and clinicians and facilitate empirical research of typical and atypical motivational behaviors during a critical time of development.

Making a 'sex-difference fact': Ambien dosing at the interface of policy, regulation, women's health, and biology.

The U.S. Food and Drug Administration's (FDA) 2013 decision to lower recommended Ambien dosing for women has been widely cited as a hallmark example of the importance of sex differences in biomedicine. Using regulatory documents, scientific publications, and media coverage, this article analyzes the making of this highly influential and mobile 'sex-difference fact'. As we show, the FDA's decision was a contingent outcome of the drug approval process. Attending to how a contested sex-difference fact came to anchor elite women's health advocacy, this article excavates the role of regulatory processes, advocacy groups, and the media in producing perceptions of scientific agreement while foreclosing ongoing debate, ultimately enabling the stabilization of a binary, biological sex-difference fact and the distancing of this fact from its conditions of construction.

Sex-specific differences in the circulatory response to postural stress among young adults with adverse childhood experiences (ACEs)

Adverse childhood experiences (ACEs)—a highly prevalent assortment of traumatic childhood events (e.g., abuse)—are strongly linked to adult cardiovascular disease (CVD), though differently among males and females. Biological sex differences in the circulatory response to physiological stress (e.g., postural stress) have been well-characterized; however, whether ACEs affect this response differently among males and females remains unclear. This study tested the hypothesis that ACEs affect the circulatory response to head-up tilt (HUT; postural stress) differently among males and females. Three hundred ( n = 156 female; 22.4 ± 1.8 years) young adults recruited through the Niagara Longitudinal Heart Study (NLHS) were included in the current analyses. ACEs were assessed (Childhood Trust Events Survey 2.0) and participants were dichotomized into high (≥4 ACEs) and low (<4 ACEs) exposure groups. Beat-by-beat mean arterial pressure (MAP; finger photoplethysmography) and heart rate (HR; electrocardiogram) were recorded during 10-minutes of supine rest and 5-minutes of 60° HUT. Sex-stratified, mixed-model regression analyses assessed the effect of ACEs on changes (Δ) in MAP and HR from supine rest to HUT, adjusting for age, body mass index, physical activity, and smoking status. During HUT, MAP increased to a similar extent in males with high and low ACEs exposure (ΔMAP: 11.5 ± 10.8 mmHg vs. 10.1 ± 10.9 mmHg, respectively; p > 0.05). In contrast, MAP increased to a greater extent in females with high ACEs exposure compared to females with low ACEs exposure (ΔMAP: 11.3 ± 10.4 mmHg vs. 5.9 ± 9.8 mmHg, respectively; p = 0.003). HR increased during HUT in males with both high and low ACEs exposure; however, it increased to a lesser extent in males with high ACEs exposure compared to males with low ACEs exposure (ΔHR: 14.7 ± 7.5 bpm vs. 18.7 ± 8.1 bpm, respectively; p = 0.015). In females, HR increased to a similar extent during HUT in those with high and low ACEs exposure (ΔHR: 16.5 ± 8.1 bpm vs. 17.6 ± 8.9 bpm, respectively; p > 0.05). These data suggest that ACEs affect the circulatory response to postural stress differently in males and females. Further, these data imply that sex-specific differences in circulatory regulation can be observed as early as young adulthood in those reporting high ACEs exposure. This work was supported by the Canadian Institute of Health Research (CIHR) and Brock University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PO-2219 Radiosensitivity Index as potential marker of biological sex differences to radiation response

PO-2219 Radiosensitivity Index as potential marker of biological sex differences to radiation response

Potential biological contributers to the sex difference in multiple sclerosis progression.

Multiple sclerosis (MS) is an immune-mediated disease that targets the myelin sheath of central nervous system (CNS) neurons leading to axon injury, neuronal death, and neurological progression. Though women are more highly susceptible to developing MS, men that develop this disease exhibit greater cognitive impairment and accumulate disability more rapidly than women. Magnetic resonance imaging and pathology studies have revealed that the greater neurological progression seen in males correlates with chronic immune activation and increased iron accumulation at the rims of chronic white matter lesions as well as more intensive whole brain and grey matter atrophy and axon loss. Studies in humans and in animal models of MS suggest that male aged microglia do not have a higher propensity for inflammation, but may become more re-active at the rim of white matter lesions as a result of the presence of pro-inflammatory T cells, greater astrocyte activation or iron release from oligodendrocytes in the males. There is also evidence that remyelination is more efficient in aged female than aged male rodents and that male neurons are more susceptible to oxidative and nitrosative stress. Both sex chromosome complement and sex hormones contribute to these sex differences in biology.

The sweet side of sex as a biological variable.

Glycobiology as a field holds enormous potential for understanding human health and disease. However, few glycobiology studies adequately address the issue of sex differences in biology, which severely limits the conclusions that can be drawn. Numerous CAZymes, lectins, and other carbohydrate-associated molecules have the potential to be differentially expressed and regulated with sex, leading to differences in O-GlcNAc, N-glycan branching, fucosylation, sialylation, and proteoglycan structure, among others. Expression of proteins involved in glycosylation is influenced through hormones, miRNA, and gene dosage effects. In this review, we discuss the benefits of incorporating sex-based analysis in glycobiology research and the potential drivers of sex differences. We highlight examples of where incorporation of sex-based analysis has led to insights into glycobiology. Finally, we offer suggestions for how to proceed moving forward, even if the experiments are already complete. Properly incorporating sex based analyses into projects will substantially improve the accuracy and reproducibility of studies as well as accelerate the rate of discovery in the glycosciences.