Biology of Sex Differences最新文献

Background: Biological sex is a critical determinant in cardiovascular and renal disease outcomes. Although angiotensin II (Ang II) infusion is widely used to model hypertension in mice and rats, little is known about its effects in the Syrian hamster, a small rodent increasingly used for translational research. This study aimed to develop a model of chronic Ang II-induced hypertension in Syrian hamsters and investigate sex-specific differences in blood pressure, renal pathology, and components of the renin-angiotensin system (RAS).

Methods: Male and female Syrian hamsters (8-9 weeks old) were infused subcutaneously with Ang II (200 ng/kg/min) or saline via osmotic minipumps for four weeks. Mean arterial pressure (MAP) and kidney wet weight were determined on the euthanasia day. The kidneys were analyzed for renal pathology; renal RAS enzymes (ACE and ACE2) were measured by colorimetric assay and qPCR; cytokines (IL-6 and IL-1β) were measured by qPCR; and the angiotensin receptor type 1 (AT1R) was measured by radioligand binding and qPCR.

Results: Ang II infusion increased MAP in both sexes but elicited a significantly greater response in females (+ 50 mmHg) than males (+ 27 mmHg, p < 0.005). Female hamsters exhibited pronounced kidney injury, including acute tubular necrosis, glomerular sclerosis, and vascular fibrinoid necrosis, along with a 2-fold increase in kidney weight normalized to body weight. Ang II significantly downregulated renal ACE, ACE2, and AT₁R expression and activity in females but not in males. Renal IL-6 and IL-1β mRNA levels were elevated 20-fold and 3.9-fold, respectively, in females, compared to modest increases in males.

Conclusions: Female Syrian hamsters exhibit heightened vulnerability to Ang II-induced hypertension and renal damage compared to males, marked by exaggerated blood pressure elevation, enhanced renal inflammation, and suppression of classical RAS components. This novel hamster model provides a unique platform for studying sex-specific mechanisms of hypertension and renal pathology, with translational relevance for subpopulations of women who are at increased risk of Ang II-dependent hypertension-associated renal disease.

When used as variables in biomedical research, sex and gender can be difficult to operationalize and measure. Questions have arisen about whether either category is stable or causally meaningful in a research context. Here, we discuss some of the limitations of using both or even one of these categories in correlational or experimental work. We argue that attempting to draw a distinction between sex and gender can reignite the nature/nurture debate, inadvertently bringing outdated metaphors and assumptions about innateness and causation into our research. Many researchers, including ourselves, have described sex and gender as separate collections of causal factors (which we describe as a "bucket" metaphor) or as entangled (a "knot" metaphor). Because they regard sex and gender as conceptually separable and internally consistent, such metaphors have limited value for understanding the drivers of diversity in our data. Rather than continuing to reify sex and gender as distinct buckets or threads of explanatory variables, we call for deconstruction of these categories by focusing instead on clearly operationalized, instantiating variables that researchers can manipulate or measure. Our proposed approach differs from recent, similar calls in that we are not suggesting the exclusion of a sex/gender category from statistical models; instead, we recommend keeping it-not as a representation of biological reality, but as a tool used under a careful set of assumptions. We provide example datasets to illustrate how a sex/gender category can, when thoughtfully operationalized, be used to improve statistical rigor and inferential precision. In addition, we advocate for attention to variation within sex/gender, which is more informative in investigations of mechanism than comparing means across sex/gender categories.

Background: Plectropomus leopardus is a hermaphrodite fish with a unique pattern of gonadal development. However, the molecular mechanism of sexual differentiation in this species remains unclear. The Doublesex and Mab-3 related transcription factor (dmrt) gene family are known to play a crucial role in gonad differentiation and development. Notably, systematic investigations into the composition and function of the dmrt gene family in this hermaphrodite fish remain conspicuously lacking.

Methods: In this study, we systematically identified members of the dmrt gene family through genomic database mining in P. leopardus. Tissue and stage-specific expression profiles of dmrt paralogs were quantitatively analyzed using reverse transcription quantitative PCR (qPCR), revealing sexually dimorphic expression patterns in the gonads at various developmental stages. Furthermore, the expression distribution of dmrt2a at different developmental stages was explored using fluorescence in situ hybridization (FISH). Subsequently, dmrt2a was interfered with using RNAi technology, and the regulatory effect of dmrt2a on oocytes was verified by combining FISH and TUNEL assays.

Results: In this study, we identified six members of the dmrt gene family in P. leopardus and designated them as dmrt1, dmrt2a, dmrt2b, dmrt3, dmrta1 and dmrta2 based on the homology analysis results, respectively. Whole-tissue expression analysis revealed that the dmrt genes exhibit tissue-specific expression pattern in P. leopardus. Notably, dmrt1 and dmrt2a are highly expressed in the gonads, suggesting their potential role in gonadal development. Further qPCR results showed that dmrt genes are differentially expressed between males and females at different developmental stages. Among them, dmrt2a is highly expressed in the ovary at different developmental stages and is found to be a pivotal factor in ovarian development. FISH was used to further verify the expression of dmrt2a in oocytes. In addition, knockdown of dmrt2a in gonads caused oocyte apoptosis and decreased oocyte number, demonstrating the critical role of dmrt2a in oocyte development.

Conclusions: This study demonstrates that dmrt2a plays a crucial regulatory role in the development of the oocytes in P. leopardus, supplementing the understanding of the functional roles of the dmrt gene family in vertebrate sex differentiation. These findings will help to understand the properties and functions of the dmrt genes in P. leopardus and provide a solid basis for further studies on the functional mechanisms of dmrt genes in hermaphroditic fish.

To explain observed disparities in health outcomes between men and women, sex essentialist approaches assign causal primacy to sex-related biology. In this essay, we present three case studies to illustrate how sex essentialism can distort human biomedical research and distill three maxims for countering this distortion: (1) engage in responsible citation practices; (2) generate and weigh alternative hypotheses for apparent observations of sex differences; (3) take care in constructing the appropriate denominator when making sex comparisons. We offer these maxims as broadly applicable standards of evidence to guide biomedical research that includes analysis of potential sex differences, as well as to support Institutional Review Boards (IRBs), funders, publishers, and peer reviewers in evaluating sex difference findings. If widely applied, these maxims would substantially improve the rigor, precision, and utility of the knowledge base of sex and gender science.

Despite a substantial therapeutic arsenal to treat patients affected by heart failure (HF), no treatment specifically targets alterations of cardiac energy metabolism described in HF. Based on the results of previous studies demonstrating the cardiac preventive effects of B vitamins when introduced before inducing cardiac pressure overload in mice, we investigated the efficacy of a diet supplemented with a B vitamin cocktail (B3, B9 and B12 (3VitB)) to restore energy metabolism and improve cardiac function in an animal model of established HF. Four weeks after transverse aortic constriction (TAC) induction, male and female mice were treated with 3VitB. 3VitB increased life expectancy and reduced the TAC-induced alterations of cardiac parameters in males. Although these effects on survival and cardiac function were less clear in females due to their higher resistance to TAC, the 3VitB cocktail was beneficial in females as 8 weeks of treatment improved physical capacities and led to milder cardiomyocyte stress-induced hypertrophy in similar ways to those observed in males. In both sexes, 3VitB protected cardiac mitochondrial oxidative capacities, at least by supporting the process of mitochondrial biogenesis. Interestingly, our results revealed sex-specificities not only in response to cardiac pressure overload but also in response to 3VitB treatment. Overall, this study demonstrated the efficacy of 3VitB to preserved cardiac function and energy metabolism in an established HF model, especially in males that are more sensitive to cardiac pressure overload. This confers credit to vitamin supplementations and to metabolic therapy as new strategies to treat HF.

Background: The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to rising obesity rates. Maternal obesity (MO) is associated with increased susceptibility to metabolic disorders, including MASLD, in the offspring. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a hallmark of heterochromatin, plays a vital role in development by silencing gene programs dispensable for differentiated cell types. This study investigated how MO influences gene expression and chromatin architecture in male and female offspring liver, in early postnatal live and upon sexual maturity.

Methods: Female mice were fed a Western-style diet or a control diet before and throughout pregnancy and lactation. The offspring were weaned at 3 weeks and subsequently transitioned to a standard chow diet for 5 weeks.

Results: At 3 weeks, the liver transcriptomes of control offspring were similar between sexes. However, MO disrupted hepatic gene expression in both sexes, leading to the dysregulation of hundreds of genes and alterations in H3K9me3 binding patterns. By 8 weeks, as the mice reached sexual maturity, control offspring showed considerable sex-based gene expression divergence, with over 1,800 genes showing differential expression. These genes were predominantly involved in immune response regulation, cell adhesion and extracellular matrix organization, xenobiotic and glutathione-mediated detoxification, cholesterol metabolism, and lipid partitioning. Furthermore, thousands of differentially bound H3K9me3 peaks were observed between the 3- and 8-week time points. A significant fraction of these peaks were located on the X chromosome in females, suggesting a role in X inactivation. Remarkably, MO offspring displayed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes by week 8, underscoring the long-term impact of maternal diet on the genomic and metabolic landscape.

Conclusions: Collectively, this study highlights inherent sex differences in liver gene expression, and suggests that H3K9me3 plays a role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by 5 weeks of postnatal dietary normalization.

Background: βeta-2 glycoprotein I (β2GPI, Apolipoprotein H) is a plasma glycoprotein best known as a major autoantigen in autoimmune disorders such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), both of which confer elevated cardiovascular risk. Despite its prominence in autoimmunity, its role in lipid metabolism and potential sex-specific effects remain poorly understood.

Methods: We investigated β2GPI's influence on lipoprotein profiles using β2GPI knockout (KO) and wild-type (WT) mice subjected to normal chow (NC) and high-fat (HF) diets, as well as plasma from β2GPI-deficient patients and aged and sex matched controls. Lipoprotein fractions were analyzed for cholesterol and apolipoprotein content, and protein interactions were assessed by co-immunoprecipitation.

Results: In animal studies, female β2GPI KO mice-but not males-displayed significantly increased total plasma cholesterol on a HF diet and greater cholesterol content within HDL fractions. Apo E was enriched in HDL fractions from female KO mice under both NC and HF diets, and plasma Apo E was elevated in HF-fed female KOs. In WT females on HF diet, β2GPI was enriched in HDL fractions, and β2GPI co-immunoprecipitated with Apo E. In human studies, the β2GPI-deficient female patient exhibited increased HDL cholesterol, a shift toward larger HDL particles, and enriched Apo E in HDL fractions relative to controls. Co-immunoprecipitation confirmed β2GPI-Apo E interaction in human plasma, with binding requiring Domain V of β2GPI.

Conclusions: Our findings identify β2GPI as a sex-specific regulator of HDL metabolism. In females, β2GPI modulates Apo E-containing HDL particles, influencing cholesterol distribution and lipoprotein composition. These results reveal a novel mechanism linking β2GPI to lipid homeostasis, with potential implications for cardiovascular risk in women with autoimmune disease. Targeting β2GPI-Apo E interactions may represent a therapeutic avenue for correcting dysregulated HDL metabolism in female-specific cardiometabolic and autoimmune contexts.

Background: Genotypic (GSD) and environmental (ESD) sex determination coexist in many species of reptiles, fish, and amphibians. Inherited genotypic signals and environmental factors conceivably interact as pro-testis or pro-ovary signals during sex determination, but how such interactions affect gonadal sex differentiation in these species remains largely unexplained. This study uses a model gonochoristic fish with coexisting GSD and ESD, the pejerrey Odontesthes bonariensis, to examine how synergism and antagonism between sex genotype (XX/XY) and thermal (feminizing/masculinizing) regimes interactively affect environmental sensitiveness and the critical time of environmental sex determination as well as how genotype-by-environment conflicts are resolved.

Methods: We performed a series of controlled rearing experiments involving shift-once and shift-twice transfers of fish of known sex genotype (XX/XY) between feminizing and masculinizing temperatures at different stages of gonadal sex differentiation. Match/mismatch analysis of phenotypic (ovary/testis) and genotypic (absence/presence of the master sex determining gene amhy) sex was performed in juveniles to estimate sex reversal rates and the critical period of sex determination for each combination of sex genotype and thermal conditions.

Results: The results show that convergence/divergence between genotypic and environmental signals advances/delays the critical time of sex determination and lowers/raises the degree of environmental sensitiveness, respectively, even when genotypic control is ultimately overridden. This study also provides evidence that ovarian formation is the default state regardless of genotypic sex but commitment to femaleness is a lengthy, passive process requiring absolute seclusion from environmental pro-male stimuli in the span of weeks. Testis formation, in turn, is the alternative state that can be imposed on this default, regardless of genotype, by an extremely short (range of hours) environmental stimulus of sufficient strength at any time before ovarian commitment. We argue that this combination of developmental features increases the likelihood of male development and at the same time may be crucial to avoid ambiguous differentiation under conflicting genotypic/environmental signals in GSD + ESD species.

Conclusions: Overall, the results reveal genotypic sex-dimorphic critical periods of sex determination, show that it is "easier" to make males in pejerrey, and provide clues to understand how GSD + ESD species may prevent discrepant sex determination/differentiation when genotype and environment diverge.

Background: The phrase "Throwing like a girl" persists in popular culture and in scientific research as a trope about biological differences between males and females. In this review/theoretical paper I critically examine the support for the idea that sex differences in throwing style and force result from innate biological difference.

Methods: This article contains (1) a limited critical review of selected literature, (2) the application of a systems approach to the development of ball play that starts the study of throwing capacity as it develops in infancy and considers its emergence going forward and (3) a demonstration of this approach using qualitative descriptions of events (at ages 9-15 months) involving toddlers' first engagements in ball play.

Results: The literature cited to support the claim that sex differences in throwing are a ubiquitous/universal feature of human children is weak. When I compared two toddlers over several months, starting at the time of their first ball throwing game, I learned that the boy and his mother played frequently even before he could walk. In contrast, the girl began ball play at an older age that coincided with her learning to walk. For 8 additional children, the boys started playing ball almost 2.5 months earlier than the girls, and all before they could walk.

Conclusions: The boy could raise the ball higher and throw it further at 13-14 months because he had practiced more from the more stable sitting and kneeling positions which allowed him to master double-handed overhead ball throwing before he could walk. The girl tried throwing the ball while walking unsteadily. Thus, when trying to raise the ball above her head, she often fell, and could not throw it very far. I conclude that to understand sex differences in embodied motor skills in children requires that we study the processes of motor learning beginning at birth.

Background: Females have been underrepresented in preclinical and clinical research. Research on females is important for conditions that directly affect women, disproportionately impact women, and manifest differently in women. Sex and gender mandates were introduced, in part, to increase women's health research. This study aimed to understand how much of women's health research is being funded in open grant competitions in Canada that fall under the top burden and/or death of disease for women globally.

Methods: Publicly available funded Canadian Institute of Health Research (CIHR) project grant abstracts from 2009 to 2023 were coded for the mention of female-specific research to assess what percentage of grant abstracts focused on the top 11 areas of global disease burden and/or death that disproportionately affect females. We also examined changes from 2020 to 2023 in the representation of grant abstracts that mentioned sex, gender, or two-spirit, lesbian, gay, bisexual, trans, queer, intersex (2S/LGBTQI).

Results: The percentage of abstracts mentioning sex or gender doubled whereas the percentage of abstracts mentioning 2S/LGBTQI quadrupled from 2020 to 2023, but remained at under 10% of overall funded abstracts. In contrast, female-specific research representation remained at ~ 7% of all research. Under 5% of the total funded grant abstracts mentioned studying one of the top 11 global burdens of disease and/or death for women over 15 years. Of the 681 female-specific grants, cancer research accounted for 35% of funding (or 2.25% of overall grants), whereas the other top 10 collectively accounted for 37% of female-specific funding (or 2.35% overall) across 15 years. The percentage of overall funding towards understanding female-specific contributions to cardiovascular disease was 0.70% followed by diabetes (0.34%), HIV/AIDS (0.54%), depression (0.32%), anxiety (0.17%), musculoskeletal disorders (0.13%), dementia (0.09%), respiratory disorders (0.06%), headache disorders (0.002%) and low back pain (0.01%).

Conclusions: Research acknowledging the sex and gender population in CIHR abstracts is increasing but remains at under 10% while the percentage of funding for women's health remains unchanged at 7% of funded grants across 15 years.