Role In Sexual Dimorphism Research Articles

Endothelial Reactive Oxygen Species: Key Players in Cardiovascular Health and Disease.

Significance: Endothelial cells (ECs) line the entire vasculature system and serve as both barriers and facilitators of intra- and interorgan communication. Positioned to rapidly sense internal and external stressors, ECs dynamically adjust their functionality. Endothelial dysfunction occurs when the ability of ECs to react to stressors is impaired, which precedes many cardiovascular diseases (CVDs). While EC reactive oxygen species (ROS) have historically been implicated as mediators of endothelial dysfunction, more recent studies highlight the central role of ROS in physiological endothelial signaling. Recent Advances: New evidence has uncovered that EC ROS are fundamental in determining how ECs interact with their environment and respond to stress. EC ROS levels are mediated by external factors such as diet and pathogens, as well as inherent characteristics, including sex and location. Changes in EC ROS impact EC function, leading to changes in metabolism, cell communication, and potentially disrupted signaling in CVDs. Critical Issues: Current endothelial biology concepts integrate the dual nature of ROS, emphasizing the importance of EC ROS in physiological stress adaptation and their contribution to CVDs. Understanding the discrete, localized signaling of EC ROS will be critical in preventing adverse cardiovascular outcomes. Future Directions: Exploring how the EC ROS environment alters EC function and cross-cellular communication is critical. Considering the inherent heterogeneity among EC populations and understanding how EC ROS contribute to this diversity and the role of sexual dimorphism in the EC ROS environment will be fundamental for developing new effective cardiovascular treatment strategies.

#2145 Sexual dimorphism in kidney regenerative capacity decline and in progressive tubular cell polyploidization during aging

Abstract Background and Aims Aging is characterized by a progressive kidney function decline, resulting in chronic kidney disease (CKD), which is steeper in men than in women. However, sex-related differences in mechanisms underpinning CKD development during aging still remain to be clarified. In most organs regenerative capacity declines overtime from a pool of resident stem cells leading to tissue aging. In the kidney, we have revealed that two adaptive responses co-exist to recover kidney function after injury. On one hand a population of renal progenitors (RPC), which is interspersed among parietal epithelial cells of Bowman's capsule and tubular cells (TC) of nephron segments, proliferate and generate new podocytes and TC to recover structural integrity during the regenerative processes occurring in glomerular and tubular diseases. On the other, TC enter the alternative cell cycles to become polyploid in order to increase their functional capacity and maintain the residual kidney function after injury. However, a continuous TC polyploidization comes with the long term trade-offs (fibrosis and senescence), driving CKD. Here, we aimed to investigate the role of sexual dimorphism in these two different adaptive responses during aging. Method To trace RPC (Pax2+cells) we used the inducible Pax2/Confetti or Pax2/mTmG mice (RPC are randomly labelled by one of the four fluorescent reporter genes or with GFP respectively). To study polyploid TC, we used the inducible Pax8/FUCCI2aR mice (polyploid TC are identified by expression of cell cycle fluorescent proteins in combination with DNA content analysis). Mice were analyzed at 2, 5, 12 and 20 months of age. scRNA sequencing was performed at 2 and 20 months of age. Results Pax2/Confetti mice revealed that the number of Pax2+RPC either of the Bowman's capsule or in tubules was higher in female than in male mice at all ages. Specifically, tracing analysis during aging showed that in females Pax2+RPC of the Bowman's capsule generated new podocytes, resulting in glomeruli with a better integrity of the slit-diaphragm compared with aged males. Moreover, tubular Pax2+RPC in females clonally expanded, generating a higher number of clones, which were longer than those in males. scRNAseq analysis on kidneys showed that females were endowed with a greater number of Pax2+RPC with a higher expression of Pax2 than males, suggesting that RPC in females kept a higher regenerative capacity than males during aging. Simultaneously, analysis of tubular polyploidy demonstrated that, whereas in females the polyploid fraction progressively increased, it was drastically reduced in males during aging. These results suggested that whereas in females the increase of polyploid TC provided a better maintenance of kidney function overtime, loss of polyploid response in males made them more susceptible to develop CKD. Indeed, aged male mice showed a higher percentage of polyploid TC undergoing further cycles of polyploidization, which were associated with fibrosis and senescence. In agreement with these findings, we observed a progressive kidney function decline along with an increase of glomerulosclerosis, interstitial fibrosis and blood pressure, which were significantly greater in males than in females. Conclusion Female mice showed a higher regenerative and polyploid response compared to male mice, aimed likely to cope kidney function decline during aging. These results reveal the intriguing role of a new kidney adaptive response, which may explain the higher susceptibility of males to develop a more premature CKD during aging.

Costly conspicuousness reveals benefits of sexual dimorphism in brood parasitic diederik cuckoos.

The existence of adult sexual dimorphism is typically explained as a consequence of sexual selection, yet coevolutionary drivers of sexual dimorphism frequently remain untested. Here, I investigate the role of sexual dimorphism in host-parasite interactions of the brood parasitic diederik cuckoo, Chrysococcyx caprius. Female diederik cuckoos are more cryptic in appearance and pose a threat to the clutch, while male diederik cuckoos are conspicuous and not a direct threat. Specifically, I examine whether sexual dimorphism in diederik cuckoos provokes threat-level sensitive responses in Southern red bishop, Euplectes orix, hosts. I use experimentally simulated nest intrusions to test whether hosts have the capacity to differentially (i) detect, and/or (ii) discriminate between, male and female diederik cuckoos, relative to harmless controls. Overall, I found no evidence that diederik cuckoos differ in detectability, since both sexes are comparable to controls in the probability and speed of host detection. Furthermore, neither male nor female hosts discriminate between sexually dimorphic diederik cuckoos when engaging in frontline nest defences. However, hosts that witnessed a male diederik cuckoo during the trial were more likely to reject odd eggs. Moreover, experimental eggs were significantly more likely to be rejected when female bishops observed a male compared to a female diederik cuckoo. While the cryptic appearance of female diederik cuckoos does not reduce detection by hosts, it does provide the benefit of anonymity given the egg rejection costs of conspicuous male-like appearance in the nest vicinity. These findings have implications for the evolution and maintenance of sexual dimorphism across the Cuculidae, and highlight the value of testing assumptions about the ecological drivers of sexual dimorphism.

Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury.

It is well established that females are more susceptible to the toxic effects of alcohol, although the exact mechanisms are still poorly understood. Previous studies noted that alcohol reduces the expression of mitogen-activated protein kinase phosphatase 1 (MKP1), a negative regulator of mitogen-activated protein kinases (MAPK) in the liver. However, the role of hepatocyte- specific MKP1 in the pathogenesis of alcohol-associated liver disease (ALD) remains uncharacterized. This study aimed to evaluate the role of hepatocyte-specific MKP1 in the susceptibility and sexual dimorphism in alcohol-induced liver injury. C57Bl/6 mice were used in an intragastric ethanol feeding model of alcohol-associated steatohepatitis (ASH). Hepatocyte-specific Mkp1-/- knockout and (Mkp1+/+ "f/f" male and female mice were subjected to the NIAAA chronic plus binge model. Primary mouse hepatocytes were used for in vitro studies. Liver RNA sequencing was performed on an Illumina NextSeq 500. Liver injury was evaluated by plasma alanine transaminase (ALT), hepatic ER stress and inflammation markers. Statistical analysis was carried out using ANOVA and the unpaired Student's t-test. ASH was associated with the severe injury accompanied by increased endoplasmic reticulum (ER) stress and significant downregulation of Dusp1 mRNA expression. In vitro, ethanol treatment resulted in a time-dependent decrease in Dusp1 mRNA and protein expression in primary hepatocytes in both males and females; however, this effect was significantly more pronounced in hepatocytes from females. In vivo, female mice developed more liver injury in a chronic plus binge model which was accompanied by a significant decrease in liver Dusp1 mRNA expression. In comparison, liver Dusp1 was not changed in male mice, while they developed milder injury to alcohol. Mkp1 deletion in hepatocytes led to increased alcohol induced liver injury, ER stress and inflammation in both sexes. Hepatocyte Mkp1 plays a significant role in alcohol induced liver injury. Alcohol downregulates Mkp1 expression in hepatocytes in a sex dependent manner and could play a role in sexual dimorphism in increased female susceptibility to alcohol.

Analysis of immune-related genes (IRGs) and their potential role in sexual dimorphism in patients (pts) with metastatic colorectal cancer (mCRC).

182 Background: Sex-based disparities have been reported for mCRC both in incidence, males having higher incidence than females, and in outcome, younger females having better outcome than males of same age or older females. Tumor immune microenvironment is hypothesized to have role in this sexual dimorphic pattern. Herein, we explored the role of gene expression (exp) and genetic variation of IRGs on progression-free (PFS) and overall survival (OS) in mCRC pts. Methods: 21 IRGs with potential roles in CRC were identified from literature review. The association of tumor gene exp with PFS and OS was evaluated in pts with mCRC (433 pts, RNA seq) from CALGB/SWOG 80405. Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) / cetuximab [cet] (N = 207)) and sex (male (N = 271) / female (N = 162)). Further, the impact on outcome of 5 selected germline single nucleotide polymorphisms (SNPs) in 3 significant IRGs, SCG2 (rs600257, rs9283537), CRIP2 rs66717274, and AXIN2 (rs7591, rs2240308), was evaluated in genotyped (OncoArray, Illumina) samples of 451 pts from 2 clinical trials: FIRE-3 (FOLFIRI-bev, N = 107; FOLFIRI-cet, N = 129) and TRIBE (FOLFIRI-bev, N = 215). Unadjusted associations were evaluated using log-rank (lr) tests; covariate-adjusted analyses were performed using Cox models for hazard ratio (HR) estimation and likelihood ratio testing. Results: Of 21 analyzed IRGs, SCG2, CRIP2 and AXIN2 significantly associated with PFS and OS in mCRC pts in CALGB/SWOG 80405 divided into tertiles of high, medium and low exp. Among pts receiving cet treatment, SCG2high (PFS: median 9.0 vs 13.0 months (mo), lrP = 0.015; OS: 20.4 vs 37.4 mo, lrP = 2.9e-05) and CRIP2high (PFS: 9.2 vs 14.2 mo, lrP = 0.00076; OS: 20.9 vs 36.3 mo, lrP = 8.3e-05) were significantly associated with shorter PFS and OS, whereas AXIN2high (PFS: 14.1 vs 7.3 mo, lrP = 2.4e-06; OS: 37.1 vs 15.6 mo, lrP = 4.9e-05) correlated with longer PFS and OS. Sex-based differences were observed, SCG2high exp associated with shorter PFS (10.0 vs 13.1 mo, lrP = 0.0054) and OS (22.3 vs 36.0 mo, lrP = 7.7e-05), and similarly CRIP2high associated with shorter PFS (9.8 vs 14.2 mo, lrP = 0.012) and OS (23.6 vs 35.8 mo, lrP = 4e-04), in males but not in females. In univariate SNP analysis, SCG2 rs9283537 any A allele showed shorter PFS (HR = 0.62, 95% Confidence interval [CI] = 0.40-0.98, P = 0.039) in females but longer PFS (HR = 2.37, 95% CI = 1.07-5.22, P = 0.028) in males compared to G/G carriers in the FIRE-3 cet cohort and interaction analysis showed significant p-values for PFS and OS (P<0.005). Conclusions: Our results highlight important role for SCG2, CRIP2, and AXIN2 as prognostic and predictive biomarkers for first-line treatment in mCRC, with potential targeted agent- and pt’s sex-based differences. These biomarkers with further validation may contribute to personalized treatment strategies for mCRC pts.

Integrating microbial 16S rRNA sequencing and non-targeted metabolomics to reveal sexual dimorphism of the chicken cecal microbiome and serum metabolome.

The gut microbiome plays a key role in the formation of livestock and poultry traits via serum metabolites, and empirical evidence has indicated these traits are sex-linked. We examined 106 chickens (54 male chickens and 52 female chickens) and analyzed cecal content samples and serum samples by 16S rRNA gene sequencing and non-targeted metabolomics, respectively. The cecal microbiome of female chickens was more stable and more complex than that of the male chickens. Lactobacillus and Family XIII UCG-001 were enriched in male chickens, while Eubacterium_nodatum_group, Blautia, unclassified_Anaerovoraceae, Romboutsia, Lachnoclostridium, and norank_Muribaculaceae were enriched in female chickens. Thirty-seven differential metabolites were identified in positive mode and 13 in negative mode, showing sex differences. Sphingomyelin metabolites possessed the strongest association with cecal microbes, while 11β-hydroxytestosterone showed a negative correlation with Blautia. These results support the role of sexual dimorphism of the cecal microbiome and metabolome and implicate specific gender factors associated with production performance in chickens.

Influence of sexual dimorphism on satellite cell regulation and inflammatory response during skeletal muscle regeneration.

After injury, skeletal muscle regenerates thanks to the key role of satellite cells (SC). The regeneration process is supported and coordinated by other cell types among which immune cells. Among the mechanisms involved in skeletal muscle regeneration, a sexual dimorphism, involving sex hormones and more particularly estrogens, has been suggested. However, the role of sexual dimorphism on skeletal muscle regeneration is not fully understood, likely to the use of various experimental settings in both animals and human. This review aims at addressing how sex and estrogens regulate both the SC and the inflammatory response during skeletal muscle regeneration by considering the different experimental designs used in both animal models (i.e., ovarian hormone deficiency, estrogen replacement or supplementation, treatments with estrogen receptors agonists/antagonists and models knockout for estrogen receptors) and human (hormone therapy replacement, pre vs. postmenopausal, menstrual cycle variation…).

Fundamental neurochemistry review: Old brain stories - Influence of age and sex on the neurodegeneration-associated lipid changes.

Brain aging is a naturally occurring process resulting in the decline of cognitive functions and increased vulnerability to develop age-associated disorders. Fluctuation in lipid species is crucial for normal brain development and function. However, impaired lipid metabolism and changes in lipid composition in the brain have been increasingly recognized to play a crucial role in physiological aging, as well as in several neurodegenerative diseases. In the last decades, the role of sexual dimorphism in the vulnerability to develop age-related neurodegeneration has increased. However, further studies are warranted for detailed assessment of how age, sex, and additional non-biological factors may influence the lipid changes in brains. The aim of this work is to address the presence of sex differences in the brain lipid changes that occur along aging, and in the two most common age-related neurodegenerative disorders (Alzheimer's and Parkinson's diseases). We included the studies that assessed lipid-related alterations in the brain of both humans and experimental models. Additionally, we explored the influence of sex on lipid-lowering therapies. We conclude that sex exerts a notable effect on lipid modifications occurring with age and neurodegeneration, and in lipid-reducing interventions. Therefore, the application of sex as an experimental variable is strongly encouraged for future research in the field of precision medicine approach.

Abstract 374: Sexual Dimorphism And Elabela Expression In Peripheral Artery Disease

Introduction: Elabela is a component of the apelinergic system known to regulate immune responses and has a cardiovascular protection role, including atherosclerosis. Peripheral artery disease (PAD) is the narrowing or blockage of larger arteries in the legs. Patients with PAD suffer from poor perfusion to their lower extremities, in addition to increased rates of cardiovascular complications. The role of sexual dimorphism in the immune system in the PAD is poorly understood. Our previous research suggests that Elabela may hold a gender-dependent protective role that can be used as immunotherapeutic. We hypothesized that in patients with PAD, expression of Elabela will be different between males and females, implicating in sexual dimorphism of the immune response, the disease outcome, and treatment. Methods: Blood samples were collected from PAD patients (n=8) and risk factor closely matched controls (n=8). PBMCs were isolated by gradient centrifugation. By flow cytometry, gating strategy on Elabela, and Elabela expressing leukocytes, using FlowJow software for analysis. Results: The results showed that there is a sexual difference in the expression of Elabela in both controls and patients with PAD. In general, males showed a high level of Elabela than females. PAD decreases Elabela expression in both males and females. Regarding Elabela expressing leukocytes, in female controls, there was no significant difference in leukocyte expression of Elabela as compared to PAD patients, while male controls demonstrated increased leukocyte expression of Elabela. Conclusions: Our findings suggest a potential role for Elabela in PAD. Importantly, these results also indicate a difference in Elabela expression based on sex dimorphism. Such differences could potentially be used as a biomarker in the diagnosis and prognosis of PAD along with therapeutic values.

CD4 co-receptor regulates sexual dimorphic NK cell responses to T. gondiiinfection.

Abstract Immunity to Toxoplasma gondiiis sexually dimorphic in humans and mice with females having higher morbidity and mortality during immune dysfunction and HIV/AIDS. The mechanisms underlying these sex differences are unclear. Since CD4+ T cells are very low during HIV/AIDS and females are more susceptible to Toxoplasmic encephalitis (TE) when they have AIDS, we investigated how a lack of CD4 co-receptor expression (CD4KO) and CD4+ T cells (MHCIIKO) impacted T. gondiisurvival and innate immune responses in mice. Female CD4KO mice succumbed to T. gondiimuch faster than male CD4KO mice. To dissect why female CD4KO mice died faster we tested their NK cell responses to acute T. gondiiinfection compared to male CD4KO mice. Although in wild type (WT) animals both sexes had similar increases in NK cell numbers and IFNg production, infected CD4KO female mice had 50% fewer IFNg+ NK cells than infected WT female mice. However, infected male CD4KO had the same number of NK cells producing IFNg compared to WT male mice. Since CD4 co-receptor deficient mice still have functional helper T cells that are CD4-we next tested survival and NK cell responses in female and male MHCII deficient (MHCIIKO) animals, which have very few helper CD4+T cells. To our surprise survival, NK cell numbers, and IFNg+ NK cells were not significantly different between WT or MHCIIKO female and male mice. These results suggest only in female mice and not in male mice, CD4 co-receptor expression is required for survival via optimal NK cell responses during acute T. gondiiinfection. Our findings reveal an unappreciated sexual dimorphic role of CD4 co-receptor expression in regulation of NK cell responses to acute T. gondiiinfection. National Institute of General Medical Sciences (P20GM103432)

Abstract 2741: Sexual dimorphism induces differential immunomodulatory outcomes from local nanoparticle and focused ultrasound therapy in murine model of head and neck cancer

Abstract Nanoparticles (NPs) and therapeutic devices are increasingly being investigated to re-engineer poorly immunogenic tumors into activated ′hot′ targets. Innate & adaptive immunological responses in females are known to be relatively superior to males. However, the development of NPs and therapeutic devices generally lacks attention to the impact of sex on therapeutic outcomes. Herein, we evaluated the role of sexual dimorphism in the immune-mediated remission of murine head & neck (MOC2) tumors following in-situ therapy with immunogenic cell death-enhancing calreticulin nanoparticle (CRT-NP) and focused ultrasound-based histotripsy (HT). CRT-NP was synthesized with DOTAP and cholesterol lipids using the thin film and extrusion methodology and loaded with a full-length clone CRT-expressing vector. CRT-NP was characterized for size and Ζ potential (ZP) using dynamic light scattering. To assess in vivo efficacy, male & female mice bearing MOC2 tumor xenografts were randomized into the following groups (n=6mice/group)¦ 1) Control, 2) CRT-NP, & 3) HT. Three intratumoral CRT-NP injections (20µg CRT-DNA/injection) were given 2 days apart 7-days post-inoculation. For comparing gender-mediated tumor immunomodulation, two local HT treatments were similarly administered in male & female MOC2 cohorts. Mice were sacrificed on day 20-post inoculation & the tumors, tumor-draining lymph nodes, spleen, & serum were processed for assessing inflammatory signatures using flow cytometry, & cytokine analysis. CRT-NPs demonstrated a hydrodynamic diameter of ≈260nm, ΖP of +17mv & a PDI ≤0.3. Compared to the untreated controls that showed a pronounced increase in tumor volumes, male & female mice treated with CRT-NP showed a ≈65% reduction in tumor growth post-treatment. HT treatment of female mice similarly suppressed the MOC2 tumor growth rates ≈64% vs. corresponding untreated control, however, it was ineffective in inducing remission of male mice tumors. The reduced HT efficacy in male mice correlated with increased infiltration of immunosuppressive NK+PD1+ cells & CD11b+PDL1+ macrophage in tumors. In contrast, the improved efficacy in female mice with both CRT and HT treatments associated with increased infiltration of CD4+ cells, CD8+ cells, NK cells, macrophage (CD11b+CD86+MHCII+), & a reduction in the M-MDSC population in the treated tumors. An additional correlation of local immune cell immunomodulation with systemic serum cytokine responses is currently in the works. CRT-NP was effective in both male & female mice. HT-induced tumor remission in females, but male mice demonstrate immunoresistance. These suggest that immunomodulatory therapies should account for sexual dimorphism as a variable. A higher accumulation of immunosuppressive cells in male TME can impact the anti-tumor immunity of immunomodulatory therapies in preclinical and clinical settings. Citation Format: Sri Vidhya Chandrasekar, Akansha Singh, Ashish Ranjan. Sexual dimorphism induces differential immunomodulatory outcomes from local nanoparticle and focused ultrasound therapy in murine model of head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2741.

Comparative Evaluation of Nasal Index and its Role in Sexual Dimorphism in Central Indian Population: A Cross-sectional Study

Introduction: Nasal Index (NI) is a sensitive anthropometric index. It exhibits sexual difference and has become useful tool in forensic medicine and reconstructive surgery. It is an important anthropometric parameter for classification of gender of a person whose identity is not known. Aim: To determine the values of the nasal parameters such as Nasal Height (NH), Nasal Breadth (NB) and NI, clinically and radiographically for male and female and also to compare the NI and its role in sexual dimorphism. Materials and Methods: This cross-sectional study was conducted in the Department of Anatomy of a premium Medical College in Bhopal, Madhya Pradesh, India, between July 2017 and July 2019, study included total 392 subjects (196 males and 196 females), aged between 18 to 60 years. Posteroanterior (PA), Cephalogram (Ceph) was taken for all the study subjects. NH and NB were measured both clinically and radiographically. NI was then calculated as NB/NH×100. The data was analysed statistically using unpaired Student’s t-test. Results: As males and females were equally divided, major subjects belonged to the age group of 41-50 years (31.63%), followed by 51-60 years (27.04%). Radiographic findings of NH were found to be statistically higher in males (47.46±2.26 mm) while clinical findings of NH were found to be statistically higher in females (55.66±3.21 mm). Radiographic findings and clinical findings of NB were found to be statistically higher in males (33.95±2.41 mm, 37.19±2.44 mm) as compared to females (30.55±1.50 mm, 32.41±1.58 mm). Radiographic findings and clinical findings of the NI were found to be statistically higher in males (71.70±6.21, 69.94±5.87) as compared to females (67.02±5.21, 58.44±4.70). Conclusion: Nasal parameters showed significant differences between males and females in Central Indian population, suggesting sexual dimorphism and also serve as important clinical and radiographical tools useful in nasal surgeries, anthropometry and forensic medicine

Precision-cut rat placental slices as a model to study sex-dependent inflammatory response to LPS and Poly I:C.

Maternal inflammation in pregnancy represents a major hallmark of several pregnancy complications and a significant risk factor for neurodevelopmental and neuropsychiatric disorders in the offspring. As the interface between the mother and the fetus, the placenta plays a crucial role in fetal development and programming. Moreover, studies have suggested that the placenta responds to an inflammatory environment in a sex-biased fashion. However, placenta-mediated immunoregulatory mechanisms are still poorly understood. Therefore, we have developed a model of ex vivo precision-cut placental slices from the rat term placenta to study acute inflammatory response. Rat placental slices with a precise thickness of 200 µm were generated separately from male and female placentas. Inflammation was stimulated by exposing the slices to various concentrations of LPS or Poly I:C for 4 and 18 hours. Treatment of placental slices with LPS significantly induced the expression and release of proinflammatory cytokines TNF-α, IL-6, and IL-1β. In contrast, Poly I:C treatment resulted in a less-pronounced inflammatory response. Interestingly, the female placenta showed higher sensitivity to LPS than male placenta. Anti-inflammatory agents, curcumin, 1α,25- dihydroxyvitamin D3, and progesterone attenuated the LPS-induced proinflammatory cytokine response at both mRNA and protein levels. We conclude that rat placental slices represent a novel alternative model to study the role of sexual dimorphism in the acute inflammatory response and immune activation in pregnancy.

Sex‐specific impact of tooth wear on senescence in a low‐dimorphic mammal species: The European roe deer (Capreolus capreolus)

AbstractAmong ungulates, capital breeding males, especially in highly dimorphic species, support higher reproductive costs than females. Roe deer, a relatively monomorphic species, is defined as an ‘income breeder’, using a concurrent intake of energy from forage to pay for a reproductive attempt. In a Northern Apennines (Arezzo province, Tuscany, Central Italy) population, we detected sexual dimorphism in adult roe deer according to average body mass (males 11% heavier than females), mandible size (male mandibles are 2% longer than female ones), and tooth measurements (first lower molar 10% higher and mandible cheek teeth row 4% longer in males than in females, providing males with a larger surface for chewing). In our study, body mass and body condition of roe deer males decreased with increasing tooth wear as in females. However, males started losing weight at a lower tooth wear level than females; after losing about 15% (~3.2 kg) of body mass they had greater probability of death than females. For low‐dimorphic species like roe deer, these findings raise new considerations about the role of sexual dimorphism in feed intake efficiency.

Monocyte Trafficking and Polarization Contribute to Sex Differences in Meta-Inflammation.

Obesity is associated with systemic inflammation and immune cell recruitment to metabolic tissues. Sex differences have been observed where male mice challenged with high fat diet (HFD) exhibit greater adipose tissue inflammation than females demonstrating a role for sex hormones in differential inflammatory responses. Circulating monocytes that respond to dietary lipids and chemokines and produce cytokines are the primary source of recruited adipose tissue macrophages (ATMs). In this study, we investigated sexual dimorphism in biological pathways in HFD-fed ATMs from male and female mice by RNA-seq. We also conducted chemotaxis assays to investigate sex differences in the migration of monocytes isolated from bone marrow from male and female mice toward a dietary saturated lipid — palmitate (PA), and a chemokine — monocyte chemoattractant protein 1 (MCP1), factors known to stimulate myeloid cells in obesity. ATM RNA-Seq demonstrated sex differences of both metabolic and inflammatory activation, including pathways for chemokine signaling and leukocyte trans-endothelial migration. In vivo monocyte transfer studies demonstrated that male monocytes traffic to female adipose tissue to generate ATMs more readily. In chemotaxis assays, lean male monocytes migrated in greater numbers than females toward PA and MCP1. With short-term HFD, male and female monocytes migrated similarly, but in chronic HFD, male monocytes showed greater migration than females upon PA and MCP1 stimulation. Studies with monocytes from toll-like receptor 4 knockout mice (Tlr4-/- ) demonstrated that both males and females showed decreased migration than WT in response to PA and MCP1 implying a role for TLR4 in monocyte influx in response to meta-inflammation. Overall, these data demonstrate the role of sexual dimorphism in monocyte recruitment and response to metabolic stimuli that may influence meta-inflammation in obesity.

Comparison of the renal effects of bisphenol A in mice with and without experimental diabetes. Role of sexual dimorphism

Bisphenol-A (BPA), a chemical -xenoestrogen- used in the production of the plastic lining of food and beverage containers, is present in the urine of almost the entire population. Recent studies have shown that BPA exposure is associated with podocytopathy, increased urinary albumin excretion (UAE), and hypertension. Since these changes are characteristic of early diabetic nephropathy (DN), we explored the renal effects of BPA and diabetes including the potential role of sexual dimorphism. Male and female mice were included in the following animals' groups: control mice (C), mice treated with 21.2 mg/kg of BPA in the drinking water (BPA), diabetic mice induced by streptozotocin (D), and D mice treated with BPA (D + BPA). Male mice form the D + BPA group died by the tenth week of the study due probably to hydro-electrolytic disturbances.Although BPA treated mice did not show an increase in serum creatinine, as observed in D and D + BPA groups, they displayed similar alteration to those of the D group, including increased in kidney damage biomarkers NGAL and KIM-1, UAE, hypertension, podocytopenia, apoptosis, collapsed glomeruli, as well as TGF-β, CHOP and PCNA upregulation. UAE, collapsed glomeruli, PCNA staining, TGF-β, NGAL and animal survival, significantly impaired in D + BPA animals. Moreover, UAE, collapsed glomeruli and animal survival also displayed a sexual dimorphism pattern.In conclusion, oral administration of BPA is capable of promoting in the kidney alterations that resemble early DN. Further translational studies are needed to clarify the potential role of BPA in renal diseases, particularly in diabetic patients.

Роль статевого диморфізму у розвитку неалкогольної жирової хвороби печінки

Метаболічне ураження печінки часто супроводжує захворювання різних систем організму. Неалкогольна жирова хвороба печінки (НЖХП) — найбільш поширена патологія, що пов’язана з інсулінорезистентністю, цукровим діабетом та ожирінням. Поширеність НЖХП коливається залежно від різних факторів, серед яких — етнічне походження, вік, наявність метаболічного синдрому. Дані епідеміологічних досліджень останніх років свідчать, що жировий гепатоз майже в два рази частіше спостерігається у чоловіків порівняно з жінками дітородного віку. Відомо, що статеві гормони є важливими регуляторами обміну ліпідів і відповідають за гендерний диморфізм ліпідного профілю. У статті наведений огляд наукових досліджень щодо визначення ролі естрогенів у розвитку НЖХП на різних етапах її патогенезу: накопичення жирів, запалення та розвитку фіброзу.

Examining vocal attractiveness through articulatory working space.

Robust gender differences exist in the acoustic correlates of clearly articulated speech, with females, on average, producing speech that is acoustically and phonetically more distinct than that of males. This study investigates the relationship between several acoustic correlates of clear speech and subjective ratings of vocal attractiveness. Talkers were recorded producing vowels in /bVd/ context and sentences containing the four corner vowels. Multiple measures of working vowel space were computed from continuously sampled formant trajectories and were combined with measures of speech timing known to co-vary with clear articulation. Partial least squares regression (PLS-R) modeling was used to predict ratings of vocal attractiveness for male and female talkers based on the acoustic measures. PLS components that loaded on size and shape measures of working vowel space-including the quadrilateral vowel space area, convex hull area, and bivariate spread of formants-along with measures of speech timing were highly successful at predicting attractiveness in female talkers producing /bVd/ words. These findings are consistent with a number of hypotheses regarding human attractiveness judgments, including the role of sexual dimorphism in mate selection, the significance of traits signalling underlying health, and perceptual fluency accounts of preferences.

The role of sexual dimorphism in susceptibility to SARS-CoV-2 infection, disease severity, and mortality: facts, controversies and future perspectives

Former studies have revealed intersex variability in immune response to infectious diseases, including Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological surveillance of the ongoing pandemic has demonstrated a male vulnerability to morbidity and mortality, despite similar infection rates between the two sexes. Divergence in the frequency of comorbidities between males and females, differences in hormonal profile, chromosomal composition and gender behavior have all been proposed as potential causative factors. Data deriving from the immunization process indirectly support the existence of a sex-specific response to SARS-CoV-2, since females apparently produce higher numbers of antibodies while simultaneously exhibiting higher rates of side effects, indicating a stronger immune reactivity to the vaccine's elements. Interpreting intersex differences in immune response to SARS-CoV-2 could lead to a deeper understanding of the COVID-19 pathophysiology and enable healthcare professionals to conduct a more accurate patient risk assessment and better predict the clinical outcome of the disease. This narrative review aims to discuss the pathophysiological and behavioral basis of the disproportionate male morbidity and mortality observed in COVID-19, in the context of most research findings in the field.

The Role of the Androgen Receptor in Sexual Dimorphisms of Renal Ammonia Metabolism

Female mice excrete ~2x more ammonia than do male mice, and this appears to result from sex-differences in ammoniagenic enzyme expression in the proximal tubule (PT) and differences in ammonia transporter expression in the PT, TAL and collecting duct. Orchiectomy studies, with and without testosterone replacement, showed that many, but not all, of these sex-differences were mediated by testosterone. We showed recently that the androgen receptor (AR) is present in the PT in both male and female kidney, and not detectably in other renal epithelial cells. This study's objective was to determine AR's role in sexual dimorphisms in ammonia handling. To avoid known systemic effects of AR blockade/deletion, we generated mice with kidney-specific AR deletion (KS-AR-KO) using Cre/loxP techniques (AR floxed mice and Pax8-Cre mice); control (C) mice were Pax8-Cre-negative littermates. Plasma testosterone did not differ significantly between KO and C mice in either sex (M-C, 67±74 ng/dl; M-KO, 239±471; F-C, 27±10; F-KO, 29±11; P=NS; N= 8-11 in each group). In male mice, KS-AR-KO increased ammonia excretion significantly (M-C, 44±14 µmol/day; M-KO, 92±74; P < 0.05; N= 8-11 in each group); this occurred despite no significant difference in food intake, a major determinant of endogenous acid production; there was no significant difference in female mice. KS-AR-KO did not alter serum Na+, K+, or HCO3- significantly in either sex. Expression of phosphoenolpyruvate carboxykinase (PEPCK), a major proximal tubule (PT) ammonia generating protein, and NKCC2, the major mechanism of TAL ammonia reabsorption, were increased significantly by KS-AR-KO in male mice, but not in female mice. KS-AR-KO decreased expression of NHE-3, the major mechanism of PT ammonia secretion, and NBCe1-A, a basolateral PT transporter that regulates PT ammonia metabolism, in male mice, but not in female mice, and did not alter the sex-specific difference in collecting duct Rhbg and Rhcg expression in either sex. Renal structural analysis showed AR deletion decreased kidney size (M-C, 222±27 mg; M-KO, 175±23; P<0.05; N= 5-6 in each group) and cortical proximal tubule volume density (C, 61±2%; KO, 42±2; P<0.05; N= 5-6 in each group) in male mice, but did not alter either parameter in females. KS-AR-KO did not alter the sexual dimorphism of collecting duct volume density in either sex. We conclude that sex-differences in ammonia generation and excretion involve AR-dependent signaling pathways in male, but not female, kidney that lead to increased PT PEPCK and TAL NKCC2 expression. Adaptive responses in NHE-3 and NBCe1-A limit the magnitude of the effect on ammonia excretion, and the sex differences in the collecting duct are not mediated by AR. Since AR is not present in the TAL, the effect of KS-AR-KO on male NKCC2 expression likely involves PT-dependent paracrine signaling. Finally, the greater kidney size and PT volume density in male mice is the result of PT AR signaling.