Biology of Sex Differences最新文献

Introduction: Dopamine is involved in reward processing and plays a critical role in the development and progression of alcohol use disorder (AUD). However, little is known about the effect of sex on the relationship between dopamine and alcohol use/AUD. There is a critical need to identify the neurobiological mechanisms that contribute to sex differences in AUD to inform treatment approaches. This study aimed to review existing literature on sex differences in the effects of alcohol on brain dopamine measures in animals and individuals with heavy drinking/AUD.

Methods: A systematic review was conducted using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PubMed was searched from inception to July 23rd, 2024.

Results: Of the 1,412 articles identified, 10 met study criteria (1 human, 9 animal), including in vivo (two positron emission tomography, four microdialysis) and ex vivo (two liquid chromatography, two fast-scan cyclic voltammetry) studies. Six studies included an alcohol challenge; three showed that females had greater alcohol-induced dopamine release than males in the ventral striatum and frontal cortex, while three showed no sex-related differences. Notably, the latter three studies examined sex in a combined AUD/control group or measured dopamine levels days after alcohol exposure. Two studies that examined the effects of prenatal alcohol exposure showed that prenatal-alcohol-exposed male offspring versus sex-matched air-exposed controls had greater prefrontal cortical dopamine D₁ receptor availability, and prenatal-alcohol-exposed female offspring versus sex-matched air-exposed controls had greater striatal dopamine concentration. Two studies investigating the mu-opioid receptor (MOR) regulation of alcohol-induced dopamine release showed a faster decline in females relative to males while the other study found females may be less dependent on MOR activity at lower doses of alcohol relative to higher doses.

Conclusions: This systematic review showed mixed results regarding sex differences in brain dopamine measures in alcohol-exposed animals and individuals with AUD, which may arise from differences in the timing, quantity, and duration of alcohol exposure, species, conditions, models, and techniques. More research examining the effect of sex on the relationship between alcohol use and brain dopamine measures is needed to enhance our understanding of AUD development, progression, and treatment in both females and males.

Background: Sexual maturation in Atlantic salmon entails a transition in energy utilization, regulated by genes and environmental stimuli in sex-specific manner. Males require less energy, in the form of adiposity, to mature and typically mature younger than females. Maturation age is also influenced in a sex-dependent fashion by the vgll3 genotype (vestigial-like 3), a co-factor in the Hippo pathway. The underlying molecular processes of sex-dependent maturation age, and their interplay with adiposity and vgll3 genotypes, remain unclear.

Methods: To elucidate the mechanisms underlying sex- and genotype-specific maturation differences, we investigated the association of early (E) and late (L) maturation vgll3 alleles with the transcription of > 330 genes involved in the regulation of the Hippo pathway and sexual maturation, and related molecular signals in brain, adipose, and gonads.

Results: The strongest effect of vgll3 genotype was observed in adipose for females and in brain for males, highlighting sex-specific expression differences in association with vgll3 genotype. Genes related to ovarian development showed increased expression in vgll3*EE compared to vgll3*LL females. Moreover, vgll3*EE females compared to vgll3*EE males exhibited reduced markers of pre-adipocyte differentiation and lipolysis yet enhanced expression of genes related to adipocyte maturation and lipid storage. Brain gene expression further showed sex-specific expression signals for genes related to hormones and lipids, as well as tight junction assembly.

Conclusions: Overall, these sex-specific patterns point towards a greater lipid storage and slower energy utilization in females compared to males. These results suggest Hippo-dependent mechanisms may be important mediators of sex differences in maturation age in salmon.

Background: Disruptions in brain development can impact behavioral traits and increase the risk of neurodevelopmental conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder, often in sex-specific ways. Dysregulation of the kynurenine pathway (KP) of tryptophan metabolism has been implicated in cognitive and neurodevelopmental disorders. Increased brain kynurenic acid (KYNA), a neuroactive metabolite implicated in cognition and sleep homeostasis, and variations in the Kmo gene, which encodes kynurenine 3-monooxygenase (KMO), have been identified in these patients. We hypothesize that parental Kmo genetics influence KP biochemistry, sleep behavior and brain energy demands, contributing to impairments in cognition and sleep in offspring through the influence of parental genotype and genetic nurture mechanisms.

Methods: A mouse model of partial Kmo deficiency, Kmo heterozygous (HET-Kmo^+/-), was used to examine brain KMO activity, KYNA levels, and sleep behavior in HET-Kmo^+/- compared to wild-type control (WT-Control) mice. Brain mitochondrial respiration was assessed, and KP metabolites and corticosterone levels were measured in breast milk. Behavioral assessments were conducted on wild-type offspring from two parental groups: (i) WT-Control from WT-Control parents, (ii) wild-type Kmo (WT-Kmo^+/+) from Kmo heterozygous parents (HET-Kmo^+/-). All mice were C57Bl/6J background strain. Adult female and male offspring underwent behavioral testing for learning, memory, anxiety-like behavior and sleep-wake patterns.

Results: HET-Kmo^+/- mice exhibited reduced brain KMO activity, increased KYNA levels, and disrupted sleep architecture and electroencephalogram (EEG) power spectra. Mitochondrial respiration (Complex I and Complex II activity) and electron transport chain protein levels were impaired in the hippocampus of HET-Kmo^+/- females. Breast milk from HET-Kmo^+/- mothers increased kynurenine exposure during lactation but corticosterone levels were unchanged. Compared to WT-Control offspring, WT-Kmo^+/+ females showed impaired spatial learning, heightened anxiety, reduced sleep and abnormal EEG spectral power. WT-Kmo^+/+ males had deficits in reversal learning but no sleep disturbances or anxiety-like behaviors.

Conclusions: These findings suggest that Kmo deficiency impacts KP biochemistry, sleep behavior, and brain mitochondrial function. Even though WT-Kmo^+/+ inherit identical genetic material as WT-Control, their development might be shaped by the parent's physiology, behavior, or metabolic state influenced by their Kmo genotype, leading to phenotypic sex-specific differences in offspring.

Background: Childhood maltreatment and HIV are both associated with a greater risk for adverse mental health, including posttraumatic stress disorder (PTSD), depression, and increased systemic inflammation. However, it remains unknown whether childhood maltreatment and HIV interact to exacerbate PTSD, depression, and inflammation in a manner that may further increase the risk of adverse health outcomes in people living with HIV. This study investigated the interaction between childhood maltreatment and HIV status on PTSD and depression symptom severity, and on peripheral concentrations of lipopolysaccharide (LPS) and high sensitivity C-reactive protein (hsCRP) in women. We hypothesized that women living with HIV (WLWH) who report high levels of childhood maltreatment exposure would show the greatest PTSD and depressive symptoms, as well as the highest concentrations of LPS and hsCRP.

Methods: We conducted a cross-sectional study of 116 women (73 WLWH and 43 women without HIV). Participants completed interviews to measure trauma exposure, including childhood maltreatment, and PTSD and depression symptoms. They also provided blood samples that were analyzed for LPS and hsCRP concentrations.

Results: Both women living with and without HIV reported high rates of trauma exposure and showed no statistically significant differences in overall rates of childhood maltreatment. Moderate to severe childhood maltreatment was associated with higher PTSD symptom severity (p =.005), greater depression severity (p =.005), and elevated plasma LPS concentrations (p =.045), regardless of HIV status. There were no effects of childhood maltreatment on hsCRP concentrations. There were no detectable significant effects of HIV status, or interactions between HIV status and childhood maltreatment, on PTSD and depression symptoms, or LPS and hsCRP concentrations (all p's > 0.05).

Conclusions: Our findings highlight the impact of childhood maltreatment on depression and PTSD symptoms and LPS concentrations in women. These results underscore the importance of trauma-informed health care in addressing childhood maltreatment to potentially improve both mental and physical health outcomes of adult women.

Background: The human placenta is distinct from most organs due to its uniquely low-methylated genome. DNA methylation (DNAme) is particularly depleted in the placenta at partially methylated domains and on the inactive X chromosome (Xi) in XX samples. While Xi DNAme is known to be critical for X-chromosome inactivation (XCI) in other tissues, its role in the placenta remains unclear. Understanding X-linked DNAme variation in the placenta may provide insights into XCI and have implications for prenatal development and phenotypic sex differences.

Methods: DNAme data were analyzed from over 350 human placental (chorionic villus) samples, along with samples from cord blood, amnion and chorion placental membranes, and fetal somatic tissues. We characterized X chromosome DNAme variation in the placenta relative to sample variables including cell composition, ancestry, maternal age, placental weight, and fetal birth weight, and compared these patterns to other tissues. We also evaluated the relationship between X-linked DNAme and previously reported XCI gene expression status in placenta.

Results: Our findings confirm that the placenta exhibits significant depletion of DNAme on the Xi compared to other tissues. Additionally, we observe that X chromosome DNAme profiles in the placenta are influenced by cell composition, particularly trophoblast proportion, with minimal DNAme variation across gestation. Notably, low promoter DNAme is observed at most genes on the Xi regardless of XCI status, challenging known associations in somatic tissues between low promoter DNAme and escape from XCI.

Conclusions: This study provides evidence that the human placenta has a distinct Xi DNAme landscape, which may inform our understanding of sex differences during prenatal development. Future research should explore the mechanisms underlying the placenta's unique X-linked DNAme profile, and the factors involved in placental XCI maintenance.

Background: Women are more susceptible to stress-induced alcohol drinking, and preclinical data suggest that stress can increase alcohol intake in female rodents; however, a comprehensive understanding of the neurobiological processes underlying this sex difference is still emerging. Neuroimmune signaling, particularly by microglia, the brain's macrophages, is known to contribute to dysregulation of limbic circuits following stress and alcohol exposure. Females exhibit heightened immune reactivity, so we set out to characterize sex differences in the microglial response to stress and alcohol exposure.

Methods: Male and female C57BL/6J mice were administered alcohol over 15 or 22 trials of a modified Drinking in the Dark paradigm, with repeated exposure to inescapable footshock stress and the stress-paired context. Mice were perfused immediately after drinking and we performed immunohistochemical analyses of microglial density, morphology, and protein expression in subregions of the amygdala and hippocampus.

Results: We observed dynamic sex differences in microglial phenotypes at baseline and in response to stress and alcohol. Microglia in the hippocampus displayed more prominent sex differences and heightened reactivity to stress and alcohol. Chronic alcohol exposure decreased density of amygdala microglia and lysosomal expression.

Conclusion: We analyzed multiple measures of microglial activation, resulting in a comprehensive assessment of microglial changes mediated by sex, stress, and alcohol. These findings highlight the complexity of microglial contributions to the development of AUD and comorbid mood and stress disorders in men and women.

Sex differences in rodent models of diet-induced obesity are still poorly documented, particularly regarding how central mechanisms vary between sexes in response to an obesogenic diet. Here, we wanted to determine whether obese phenotype and hypothalamic response to a high-fat diet (HFD) differed between male and female C57Bl/6J mice. Mice were exposed to either a 60% HFD or a standard diet first for both a long- (14 weeks) and shorter-periods of time (3, 7, 14 and 28 days). Analysis of the expression profile of key neuronal, glial and inflammatory hypothalamic markers was performed using RT-qPCR. In addition, astrocytic and microglial morphology was examined in the arcuate nucleus. Monitoring of body weight and composition revealed that body weight and fat mass gain appeared earlier and was more pronounced in male mice. After 14 weeks of HFD exposure, normalized increase of body weight reached similar levels between male and female mice. Overall, both sexes under HFD displayed a decrease of orexigenic neuropeptides expression while an increase in Pomc gene expression was observed only in female mice. In addition, changes in the expression of hypothalamic inflammatory markers were relatively modest. We also reported that the glial cell markers expression and morphology were affected by HFD in a sex- and time dependent manner, suggesting a more pronounced glial cell activation in female mice. Taken together, these data show that male and female mice responded differently to HFD exposure, both on short- and long-term and suggest that a strong inflammatory hypothalamic profile is not systematically present in diet-induced obesity models. Nevertheless, in addition to these present data, the underlying mechanisms should be deciphered in further investigations.

Background: Evolutionary selection pressures, most notably sexual selection, have created (and continue to sustain) many psychobehavioral differences between females and males. One such domain where psychobehavioral sex differences may be prominent is romantic love. The ways in which females and males may experience and express romantic love differently has been studied in psychology as well as in the arts down the ages; however, no studies have focused specifically on romantic love (i.e., passionate love) using validated measures of romantic love solely in people who are currently experiencing this form of love.

Methods: This study investigated sex differences in features and aspects of romantic love among 808 young adults experiencing romantic love. Univariate and multivariate analyses were conducted to measure sex differences in the number of times participants had fallen in love, when they fell in love relative to when they started their romantic relationship (love progression), intensity of romantic love, obsessive thinking about a loved one, and commitment. Additional univariate comparisons were made for sex differences in Passionate Love Scale scores.

Results: Univariate analyses showed that males had fallen in love a greater number of times than females. Males had also fallen in love more quickly than females. Females had higher intensity of romantic love, higher commitment, and higher obsessive thinking about a loved one than males. These findings remained robust in multivariate analyses, controlling for several variables believed to influence romantic love, with the exception of commitment, which was no longer significant when other variables were controlled for.

Conclusions: The findings are considered with reference to the evolutionary theory of sexual selection. We suggest that the specific adaptive challenges faced by females and males in the evolutionary history of romantic love may contribute to sex differences in romantic love. The findings shed light on contemporary sex differences in romantic love, as well as the possible evolutionary history and evolutionary functions of romantic love.

Background: Accumulating evidence indicates that the dysbiosis of gastrointestinal microbiota is associated with the development of gastric carcinogenesis. However, the sex-specific traits of gastrointestinal microbiota and their correlation with the sexually dimorphic response to gastric cancer remain poorly understood.

Methods: Male and female transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer were randomly administered Brucella Broth or Helicobacter pylori (H. pylori). Stomachs were evaluated by histopathology. The gastric inflammation was examined by immunohistochemical and immunofluorescence staining. Gastric mucosal and fecal samples were collected for microbiota analysis using 16S rRNA gene sequencing.

Results: Following H. pylori infection, male mice showed heightened inflammatory infiltration and notably greater intestinal metaplasia compared to female mice. The structure of gastrointestinal microbiota was different between male and female mice, with relative higher diversity in females than males. Notably, we found gender disparities in the alterations of gastric and intestinal microbiota in mice post H. pylori infection. While the enrichment of Bifidobacterium and Lachnospiraceae was observed in female mice, Escherichia_Shigella and Akkermansia were more abundant in males. Furthermore, the microbial profile was distinct in estrogen-deficient ovariectomized (OVX) mice, including the overgrowth of Akkermansia and the loss of Butyricicoccus. Infected OVX females developed significantly more severe gastric lesions, which was normalized through co-housing with intact females.

Conclusions: We have identified a novel microbiome-based mechanism that provides insight into the sexual dimorphism in the development of H. pylori-associated gastric cancer.