Driving Sex Differences Research Articles

Sex Differences in Antipsychotic and Benzodiazepine Prescribing Patterns: A Cohort Study of Newly Admitted Nursing Home Residents with Dementia in Ontario, Canada.

In nursing homes, residents with dementia frequently receive potentially inappropriate medications that are associated with an increased risk of adverse events. Despite known sex differences in clinical presentation and sociodemographic characteristics among persons with dementia, few studies have examined sex differences in patterns and predictors of potentially inappropriate medicationuse. The objectives of this study were to examine sex differences in the patterns of antipsychotic and benzodiazepine use in the 180days following admission to a nursing home, estimate clinical and sociodemographic predictors of antipsychotic and benzodiazepine use in male and female residents, and explore the effects of modification by sex on the predictors of using these drug therapies. We conducted a retrospective cohort study of 35,169 adults aged 66years and older with dementia who were newly admitted to nursing homes in Ontario, Canada between 2011 and 2014. Health administrative databases were linked to detailed clinical assessment data collected using the Resident Assessment Instrument (RAI-MDS 2.0). Cox proportional hazards models were adjusted for clinical and sociodemographic covariates to estimate the rate of antipsychotic and benzodiazepine initiation and discontinuation in the 180days following nursing home admission in the total sample and stratified by sex. Sex-covariate interaction terms were used to assess whether sex modified the association between covariates and the rate of drug therapy initiation or discontinuation following nursing home entry. Across 638 nursing homes, our analytical sample included 22,847 females and 12,322 males. At admission, male residents were more likely to be prevalent antipsychotic users than female residents (33.8% vs 28.3%; p < 0.001), and female residents were more likely to be prevalent benzodiazepine users than male residents (17.2% vs 15.3%, p < 0.001). In adjusted models, female residents were less likely to initiate an antipsychotic after admission (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.73-0.86); however, no sex difference was observed in the rate of benzodiazepine initiation (HR 1.04, 95% CI 0.96-1.12). Female residents were less likely than males to discontinue antipsychotics (HR 0.89, 95% CI 0.81-0.98) and benzodiazepines (HR 0.82, 95% CI 0.75-0.89). Sex modified the association between some covariates and the rate of changes in drug use (e.g., widowed males exhibited an increased rate of antipsychotic discontinuation (p-interaction = 0.03) compared with married males), but these associations were not statistically significant among females. Sex did not modify the effect of frailty on the rates of initiation and discontinuation. Males and females with dementia differed in their exposure to antipsychotics and benzodiazepines at nursing home admission and their patterns of use following admission. A greater understanding of factors driving sex differences in potentially inappropriate medication use may help tailor interventions to reduce exposure in this vulnerable population.

Distal convoluted tubule sexual dimorphism revealed by advanced 3D imaging.

The thiazide-sensitive Na+-Cl- cotransporter (NCC) is more abundant in kidneys of female subjects than of male subjects. Because morphological remodeling of the distal convoluted tubule (DCT) is dependent on NCC activity, it has been generally assumed that there is a corresponding sexual dimorphism in the structure of the DCT, leading to a larger female DCT. Until now, this has never been directly examined. Here, optical clearing techniques were combined with antibody labeling of DCT segment markers, state-of-the-art high-speed volumetric imaging, and analysis tools to visualize and quantify DCT morphology in male and female mice and study the DCT remodeling response to furosemide. We found an unexpected sex difference in the structure of the DCT. Compared with the male mice, female mice had a shorter DCT, a higher cellular density of NCC, and a greater capacity to elongate in response to loop diuretics. Our study revealed a sexual dimorphism of the DCT. Female mice expressed a greater density of NCC transporters in a shorter structure to protect Na+ balance in the face of greater basal distal Na+ delivery yet have a larger reserve and structural remodeling capacity to adapt to unique physiological stresses. These observations provide insight into mechanisms that may drive sex differences in the therapeutic responses to diuretics.

Sex effects in the association between airway microbiome and asthma

BackgroundSex differences exist in asthma susceptibility and severity. Accumulating evidence has linked airway microbiome dysbiosis to asthma, and airway microbial communities have been found to differ by sex. However, whether sex modifies the link between airway microbiome and asthma has not been investigated. ObjectiveTo evaluate sex effects in the association between airway microbiome and asthma. MethodsWe analyzed induced sputum samples from 47 subjects (n = 23 patients with asthma and n = 24 normal controls) using 16S ribosomal RNA gene sequencing methods. The bacterial composition was analyzed for sex differences. Bacterial associations with asthma were assessed for each sex at the core taxa and genus levels. ResultsThe microbiome in induced sputum differed in women vs men at the community level. A total of 5 core bacterial taxa were found in all samples. No sex-specific core taxa were detected. The most abundant core taxon, Streptococcus salivarius, was significantly enriched in women than in men (P = .02). Within each sex, individuals with relatively lower abundance of S salivarius were more likely to have asthma (P = .006). For both sexes, increased Lactobacillus species were found in sputum samples of patients with patients compared with normal controls (adjusted P = .01). Haemophilus species were associated with asthma in men and not in women. ConclusionThe airway microbiome differed by sex, and sex effects exist in the association of airway microbial markers and asthma. Future airway microbiome studies may yield better resolution if the context of specific sex is considered. The airway microbiome is a potential mechanism driving sex differences in asthma.

Sex-specific effects of wind on the flight decisions of a sexually dimorphic soaring bird.

In a highly dynamic airspace, flying animals are predicted to adjust foraging behaviour to variable wind conditions to minimize movement costs. Sexual size dimorphism is widespread in wild animal populations, and for large soaring birds which rely on favourable winds for energy-efficient flight, differences in morphology, wing loading and associated flight capabilities may lead males and females to respond differently to wind. However, the interaction between wind and sex has not been comprehensively tested. We investigated, in a large sexually dimorphic seabird which predominantly uses dynamic soaring flight, whether flight decisions are modulated to variation in winds over extended foraging trips, and whether males and females differ. Using GPS loggers we tracked 385 incubation foraging trips of wandering albatrosses Diomedea exulans, for which males are c. 20% larger than females, from two major populations (Crozet and South Georgia). Hidden Markov models were used to characterize behavioural states-directed flight, area-restricted search (ARS) and resting-and model the probability of transitioning between states in response to wind speed and relative direction, and sex. Wind speed and relative direction were important predictors of state transitioning. Birds were much more likely to take off (i.e. switch from rest to flight) in stronger headwinds, and as wind speeds increased, to be in directed flight rather than ARS. Males from Crozet but not South Georgia experienced stronger winds than females, and males from both populations were more likely to take-off in windier conditions. Albatrosses appear to deploy an energy-saving strategy by modulating taking-off, their most energetically expensive behaviour, to favourable wind conditions. The behaviour of males, which have higher wing loading requiring faster speeds for gliding flight, was influenced to a greater degree by wind than females. As such, our results indicate that variation in flight performance drives sex differences in time-activity budgets and may lead the sexes to exploit regions with different wind regimes.

Perinatal androgen exposure impacts mast cell development and sex differences in mast cell-mediated pathophysiology

Abstract Mast cell (MC)-associated diseases exhibit a sex bias with females often exhibiting more severe symptoms. Further, these sex biases exist in both prepubertal children and adults indicating that mechanisms other than adult sex hormones are involved. In previous studies, we showed that, compared with female MCs, male MCs store and release less histamine which coincided with reduced severity of MC-mediated anaphylaxis, and that these sex differences emerge prior to puberty. The early life mechanisms responsible for the emergence of sex differences in MC-associated disease remain poorly understood. Here we tested the hypothesis that perinatal androgen exposure, a major sexual organization event in males, drives sex differences in MC-mediated pathophysiology. Adult female mice that were previously exposed to high levels of androgens in the perinatal period (E16-PN7) via perinatal testosterone propionate administration had reduced IgE-mediated serum histamine levels and hypothermic responses compared with control females. In contrast, perinatal exposure of males to the endocrine disruptor DEHP, with known anti-androgenic effects, exacerbated IgE-mediated histamine levels and hypothermia. MC-deficient sash mice engrafted with BMMCs from adult perinatally androgenized females, exhibited reduced serum histamine and hypothermia responses compared with WT BMMC engrafted sash controls. Together, these data demonstrate that androgen exposure during the perinatal period shapes MC phenotype and MC-mediated anaphylaxis and thus could be an important determinant of differences in later life MC disease risk between the sexes.

Perinatal androgen exposure impacts mast cell development and mediator storage

Abstract Mast cell (MC)-associated diseases often exhibit a female sex bias in both prepubertal children and adults. We have shown that female MCs store and release greater amounts of histamine which correlates with heightened anaphylaxis in both prepubertal and adult mice. Further, perinatal androgen exposure, a major organizing event in sex biology, reduced MC histamine storage and release, and the severity of anaphylaxis in prepubertal and adult female mice, thus demonstrating that perinatal androgens are critical early life drivers of MC sex differences, but the mechanisms remain poorly understood. The objective of this study was to determine how perinatal androgens impact MC development. RNA sequencing analysis of BMMCs derived from adult female and male mice that were previously exposed to perinatal androgens revealed significant down-regulation of a number of genes related to granule biogenesis and mediator storage of which included lactotransferrin (by −2.6 fold), proteoglycan 2 (by −3.9 fold), lipocalin 2 (by −1.4-fold), elastase (by −2.5 fold) and myeloperoxidase (by 1.4 fold). Current studies aim to confirm RNA seq data with qPCR and protein expression analysis and to define the critical period of androgen programming on MC development and function. Understanding the mechanisms by which early life androgens drive sex differences in MCs will be critical in understanding the origins of sex differences in MC and its role in health and disease.

Sex differences in vasopressin 1a receptor regulation of social communication within the lateral habenula and dorsal raphe of mice

The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication in diverse taxa, often through its actions on the V1a receptor (V1aR) and in a sex-different and steroid-dependent way. One source of sex-different brain AVP is the steroid-sensitive and sexually-dimorphic AVP neurons in the bed nucleus of the stria terminalis (BNST), a cell population that regulates social behavior in a sex-dependent manner. Potential targets of these BNST-AVP cells include the lateral habenula (LHb) and dorsal raphe (DR), areas known to be important for social behavior, yet few studies have investigated AVP action within these regions. Consequently, to test if V1aR action in the LHb or DR controls social behavior in a sexually dimorphic manner, we administered a highly-specific V1aR antagonist (or saline vehicle) in the LHb or DR of C57BL/6 male and female mice and tested its effects on social investigation, social communication (urine marking, ultrasonic vocalizations), and territorial aggression. V1aR antagonism of the LHb or DR decreased male urine marking toward unfamiliar males, but not toward unfamiliar females. Additionally, V1aR blockade of the LHb decreased ultrasonic vocalizations generated in the presence of females. Social investigation, locomotion and aggressive behavior were not altered by V1aR antagonism in either area. Blocking V1aR in the LHb or DR of females had no effect, indicating V1aR action in the DR and LHb drives sex differences in social communication.

The demography of human warfare can drive sex differences in altruism.

Recent years have seen great interest in the suggestion that between-group aggression and within-group altruism have coevolved. However, these efforts have neglected the possibility that warfare - via its impact on demography - might influence human social behaviours more widely, not just those directly connected to success in war. Moreover, the potential for sex differences in the demography of warfare to translate into sex differences in social behaviour more generally has remained unexplored. Here, we develop a kin-selection model of altruism performed by men and women for the benefit of their groupmates in a population experiencing intergroup conflict. We find that warfare can promote altruistic, helping behaviours as the additional reproductive opportunities winners obtain in defeated groups decrease harmful competition between kin. Furthermore, we find that sex can be a crucial modulator of altruism, with there being a tendency for the sex that competes more intensely with relatives to behave more altruistically and for the sex that competes more intensely with non-relatives in defeated groups to receive more altruism. In addition, there is also a tendency for the less-dispersing sex to both give and receive more altruism. We discuss implications for our understanding of observed sex differences in cooperation in human societies.

Fight or flight trade-offs and the defensive behaviour of the mountain katydid, Acripeza reticulata

The defensive repertoires of prey are shaped by diverse ecological and evolutionary demands. This can generate trade-offs between the components of defences, as in the classic ‘fight or flight’ dichotomy, or dedicated investment in a singular end, allowing individuals in better condition to mount a more effective defence all round. Further, sexual dimorphism may drive sex differences in such responses, although our understanding of the interaction between sexual selection and defensive behaviour is in its infancy. Deimatic, or ‘startle’, defences typically combine multiple protective strategies, such as camouflage and aposematism, with a rapid transition between them, and thus offer unique opportunities for studying the dynamics of suites of defensive behaviours. Here we examined the display of the sexually dimorphic mountain katydid, with the goal of identifying the factors influencing individuals' escape response and display intensity. In experimental assays designed to simulate encounters with predators, we found that sex and repeated exposure to predation attempts affected components of the defensive behaviour of individuals in diverse ways. Both short-distance (sprint) and longer-distance (endurance) speeds differed between the sexes, primarily via an interaction between the intensity of displays and exposure to repeated predation attempts. Display intensity was best explained by an interaction between experience and sex: males maintained their intensity across 3 days of repeated attacks, while females decreased it. These results reveal complex influences on the expression of antipredator behaviour, and identify potential trade-offs mediating individual responses which differ between the sexes. Our findings also highlight the need to consider sexual dimorphism and the effect of individual condition when studying complex behavioural defences.

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors.

Microglia, the innate immune cells of the brain, have recently been removed from the position of mere sentinels and promoted to the role of active sculptors of developing circuits and cells. Alongside their functions in normal brain development, microglia coordinate sexual differentiation of the brain, a set of processes which vary by region and endpoint like that of microglia function itself. In this review, we highlight the ways microglia are both targets and drivers of brain sexual differentiation. We examine the factors that may drive sex differences in microglia, with a special focus on how changing microenvironments in the developing brain dictate microglia phenotypes and discuss how their diverse functions sculpt lasting sex-specific changes in the brain. Finally, we consider how sex-specific early life environments contribute to epigenetic programming and lasting sex differences in microglia identity.

Sex differences in mechanisms of arterial stiffness.

Arterial stiffness progressively increases with aging and is an independent predictor of cardiovascular disease (CVD) risk. Evidence supports that there are sex differences in the time course of aging-related arterial stiffness and the associated CVD risk, which increases disproportionately in postmenopausal women. The association between arterial stiffness and mortality is almost twofold higher in women versus men. The differential clinical characteristics of the development of arterial stiffness between men and women indicate the involvement of sex-specific mechanisms. This review summarizes the current literature on sex differences in vascular stiffness induced by aging, obesity, hypertension, and sex-specific risk factors as well as the impact of hormonal status, diet, and exercise on vascular stiffness in males and females. An understanding of the mechanisms driving sex differences in vascular stiffness has the potential to identify novel sex-specific therapies to lessen CVD risk, the leading cause of death in males and females. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

Perinatal androgens drive sex differences in mast cell phenotype and severity of mast cell disease

Abstract Highly prevalent and debilitating mast cell (MC)-associated immune disorders, such as allergy and irritable bowel syndrome exhibit a female sex bias in childhood and adulthood. The mechanisms underlying sex differences in MC disorders are unknown. Previously, we found adult female mice exhibited greater serum histamine and more severe MC-associated pathophysiology that coincided with an increased capacity to synthesize and store immune mediators, compared with males. Further, recent data showed sex differences in the MC exist prior to puberty, suggesting a mechanism independent of adult sex hormones. Here, we investigated the role of perinatal androgens, a key early life component of sexual differentiation, in sex differences in MC phenotype and MC disease. Testosterone proprionate (100 μg sc qd) or vehicle was given to pregnant female mice E16-P0 and directly to pups PN1-7. IgE-mediated anaphylaxis was performed in gonadectomized control male (CM), control female (CF) and perinatally androgenized female (AF) offspring at 8 wk of age. Serum histamine levels (CM 768 ± 106, CF 1406 ± 200, AF 676 ± 110 ng/mL) and hypothermia responses (Δ temp: CM −4.87 ± 0.45, CF − 7.28 ± 0.48, AF − 4.8 ± 0.39 °C) were ~2x lower in AF than CF mice, while AF and CM mice had similar responses. Further, bone marrow MC from AF mice had lower histamine content (AF 1305 ± 82: CF 2082 ± 94 ng/106cells) and 47% lower histamine release to IgE-FcɛRI stimulus compared to CF mice. Together, we demonstrate that sex differences in MC phenotype and disease susceptibility are established early in life by perinatal androgens. These findings provide insight into the mechanisms of sex differences in MC-associated immune disorders that could lead to new therapeutic targets for MC diseases.

S194. Does Cognitive Control of Emotion Drive Sex Differences in the Clinical Presentation of Schizophrenia?

In females with schizophrenia (SZ) psychotic symptom severity relates to mood symptom severity, indicating a link between psychosis and emotion processing not observed in SZ males. Sex differences in cognitive control of emotion (CCoE), mediated by the frontal-limbic network, may drive this but have not been examined. This study investigates sex differences in the frontal-limbic network during CCoE and its relationship to SZ symptoms.

Sex and Estrous Cycle Effects on Anxiety- and Depression-Related Phenotypes in a Two-Hit Developmental Stress Model.

Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology. To examine potential developmental mechanisms driving sex disparity in risk for anxiety and depression, we established a two-hit developmental stress model including maternal separation in early life followed by social isolation in adolescence. Our study shows complex interactions between early-life and adolescent stress, between stress and sex, and between stress and female estrogen status in shaping behavioral phenotypes of adult animals. In general, increased locomotor activity and body weight reduction were the only two phenotypes where two stressors showed synergistic activity. In terms of anxiety- and depression-related phenotypes, single exposure to early-life stress had the most significant impact and was female-specific. We show that early-life stress disrupts the protective role of estrogen in females, and promotes female vulnerability to anxiety- and depression-related phenotypes associated with the low-estrogenic state. We found plausible transcriptional and epigenetic alterations in psychiatric risk genes, Nr3c1 and Cacna1c, that likely contributed to the stress-induced behavioral effects. In addition, two general transcriptional regulators, Egr1 and Dnmt1, were found to be dysregulated in maternally-separated females and in animals exposed to both stressors, respectively, providing insights into possible transcriptional mechanisms that underlie behavioral phenotypes. Our findings provide a novel insight into developmental risk factors and biological mechanisms driving sex differences in depression and anxiety disorders, facilitating the search for more effective, sex-specific treatments for these disorders.

Transcriptome Analysis of the Human Tibial Nerve Identifies Sexually Dimorphic Expression of Genes Involved in Pain, Inflammation, and Neuro-Immunity.

Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women vs. men. Large transcriptomic resources are now available and can be used to mine for sex differences to gather insight from molecular profiles using donor cohorts. We performed in-depth analysis of 248 human tibial nerve (hTN) transcriptomes from the GTEx Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential gene expression. Many of the more abundant genes in men are associated with inflammation and appear to be primarily expressed by glia or immune cells, with some genes downstream of Notch signaling. In women, we find the differentially expressed transcription factor SP4 that is known to drive a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 differentially expressed (DE) genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTEx database, we identify a subset of DE, sexually dimorphic genes in diseases associated with chronic pain: arthritis and Type II diabetes. Our work creates a unique resource that identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.

Sex differences in aggression: Differential roles of 5-HT2, neuropeptide F and tachykinin.

Despite the conserved function of aggression across taxa in obtaining critical resources such as food and mates, serotonin’s (5-HT) modulatory role on aggressive behavior appears to be largely inhibitory for vertebrates but stimulatory for invertebrates. However, critical gaps exist in our knowledge of invertebrates that need to be addressed before definitively stating opposing roles for 5-HT and aggression. Specifically, the role of 5-HT receptor subtypes are largely unknown, as is the potential interactive role of 5-HT with other neurochemical systems known to play a critical role in aggression. Similarly, the influence of these systems in driving sex differences in aggressive behavior of invertebrates is not well understood. Here, we investigated these questions by employing complementary approaches in a novel invertebrate model of aggression, the stalk-eyed fly. A combination of altered social conditions, pharmacological manipulation and 5-HT2 receptor knockdown by siRNA revealed an inhibitory role of this receptor subtype on aggression. Additionally, we provide evidence for 5-HT2’s involvement in regulating neuropeptide F activity, a suspected inhibitor of aggression. However, this function appears to be stage-specific, altering only the initiation stage of aggressive conflicts. Alternatively, pharmacologically increasing systemic concentrations of 5-HT significantly elevated the expression of the neuropeptide tachykinin, which did not affect contest initiation but instead promoted escalation via production of high intensity aggressive behaviors. Notably, these effects were limited solely to males, with female aggression and neuropeptide expression remaining unaltered by any manipulation that affected 5-HT. Together, these results demonstrate a more nuanced role for 5-HT in modulating aggression in invertebrates, revealing an important interactive role with neuropeptides that is more reminiscent of vertebrates. The sex-differences described here also provide valuable insight into the evolutionary contexts of this complex behavior.

The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility.

Sex differences in immunity are well described in the literature and thought to be mainly driven by sex hormones and sex-linked immune response genes. The gastrointestinal tract (GIT) is one of the largest immune organs in the body and contains multiple immune cells in the GIT-associated lymphoid tissue, Peyer's patches and elsewhere, which together have profound effects on local and systemic inflammation. The GIT is colonised with microbial communities composed of bacteria, fungi and viruses, collectively known as the GIT microbiota. The GIT microbiota drives multiple interactions locally with immune cells that regulate the homeostatic environment and systemically in diverse tissues. It is becoming evident that the microbiota differs between the sexes, both in animal models and in humans, and these sex differences often lead to sex-dependent changes in local GIT inflammation, systemic immunity and susceptibility to a range of inflammatory diseases. The sexually dimorphic microbiome has been termed the 'microgenderome'. Herein, we review the evidence for the microgenderome and contemplate the role it plays in driving sex differences in immunity and disease susceptibility. We further consider the impact that biological sex might play in the response to treatments aimed at manipulating the GIT microbiota, such as prebiotics, live biotherapeutics, (probiotics, synbiotics and bacteriotherapies) and faecal microbial transplant. These alternative therapies hold potential in the treatment of both psychological (e.g., anxiety, depression) and physiological (e.g., irritable bowel disease) disorders differentially affecting males and females.

Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism.

Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. We then inferred patient-specific gene regulatory networks and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset of 1,193 patients from five independent studies. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% [95% confidence interval (CI), 78-100] survival compared with 61% (95% CI, 45-82) for women with lower targeting, respectively (P = 0.034). Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.Significance: A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to understand how sex influences progression and response to therapies in other cancers. Cancer Res; 78(19); 5538-47. ©2018 AACR.

Female Spontaneous Hypertensive Rats (SHR) Have Better Recovery In Response To Renal Ischemia Reperfusion Injury Than Males

Hypertension is a known risk factor for acute kidney injury (AKI) but there is little research on the link between the two. Normotensive males are considered to be more susceptible to AKI compared with females. However, how hypersensitive males and females respond to AKI is not well understood. The purpose of the present study is to test the hypothesis that male SHR have worse outcomes than females following renal ischemia reperfusion (IR). 13 week old male and female SHR were subjected to sham‐operated or 25‐minute warm bilateral ischemia followed by 7 days of reperfusion (n=5–6). Renal injury and function were assessed by the following methods: 1) plasma creatinine quantified by Quantichrome creatinine kit, 2) peritubular capillary congestion by Masson's trichrome staining, and 3) tubular damage by hematoxylin and eosin staining of kidney sections and Western blot analysis of kidney injury molecule‐1 (KIM‐1). 24 hours following IR, both male and female SHR showed a significant increase in plasma creatinine compared to respective sham‐operated controls, although the increase in creatinine was greater in males (males: 0.55±0.22 vs. 0.25 ±0.06 mg/dl; females: 0.45±0.06 vs. 0.26±0.06 mg/dl; PIR=0.02; Psex=0.3; Psex*IR=0.03). After 7 days of reperfusion, plasma creatinine remained elevated in male SHR compared to baseline (0.46±0.21 mg/dl vs 0.26±0.065), whereas plasma creatinine in female SHR returned to baseline levels (0.27±0.06 vs 0.26±0.06 mg/dl; PIR=0.03; Psex=0.05; Psex*IR=0.04). Further, histological examination of kidneys following 7 days of reperfusion showed a significant increase in the percentage of peritubular capillary congestion (male: 20±6% increase; female: 0% increase: PIR=0.642; Psex=0.018; Psex*IR=0.002) and damaged tubules (male: 42±13% increase; female: 6±3% increase; PIR=0.0001; Psex=0.0019; Psex*IR=0.0019) compared to sham controls only in males. KIM‐1 protein expression also remained significantly elevated in the outer medulla of both male and female SHR following 7 days of reperfusion, although levels were higher in males compared to female SHR (male: 0.779±0.012 vs 0.073±0.006; female: 0.240±0.147 vs 0.0374±0.038; PIR=0.0002; Psex=0.0092; Psex*IR=0.019). In conclusion, our data support the hypothesis that there is a sex difference in recovery from IR where female SHR recovered faster than male SHR. Further studies are ongoing in SHR to dissect the molecular mechanism(s) driving sex differences in IR outcomes.Support or Funding InformationThis work was supported by National Institute of Health (1P01HL134604‐01 to J.C. Sullivan)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex differences in cancer risk and survival.

e13074 Background: The ongoing global cancer increase poses immense challenges for cancer care. Few comprehensive analyses of sex differences in cancer risk and survival based on robust data have been conducted. Methods: We performed a large cohort study using nationwide Swedish Cancer Register data for years 1970-2014, including all adult incident, non-breast, non-genital cancer cases (504,379 male, 368,018 female). To assess the strength of association between sex and cancer we estimated male-to-female incidence rate ratios†. Relative survival models were used to quantify differences in survival and were expressed as excess mortality ratios*. We applied Poisson regression and adjusted for age and calendar year in both. Results: Men were at significantly increased risk for 34 of 39 sites, and had significantly poorer prognosis for 27 of 39, compared to increased risk for 5 of 39 sites and poorer survival for 2 of 39, in women. Incidence rate ratios in male predominant sites ranged from 1.05; 95% CI, 1.03-1.08 (lung adenocarcinoma) to 8.00; 95% CI, 7.50-8.53 (larynx), corresponding to 0.38; 95% CI, 0.36-0.39 (thyroid well-differentiated) to 0.69; 95% CI, 0.63-0.75 (thyroid anaplastic) in female predominant sites. In sites with poorer survival in men, excess mortality ratios ranged from 1.07; 95% CI, 1.03-1.10 (colon) to 2.08; 95% CI, 1.53-2.84 (well-differentiated thyroid). Conclusions: Male sex is an independent risk factor and associated with poorer survival for a large majority of cancer sites. The excess risk in men remains elevated over time for most sites. Identifying and eliminating factors driving sex differences may reduce global cancer burden considerably. [Table: see text]