Biology of Sex Differences最新文献

{"title":"Sex-specific DNA methylation signatures of autism spectrum disorder from whole genome bisulfite sequencing of newborn blood.","authors":"Julia S Mouat, Nickilou Y Krigbaum, Sophia Hakam, Emily Thrall, George E Kuodza, Julia Mellis, Dag H Yasui, Piera M Cirillo, Yunin J Ludena, Rebecca J Schmidt, Michele A La Merrill, Irva Hertz-Picciotto, Barbara A Cohn, Janine M LaSalle","doi":"10.1186/s13293-025-00712-9","DOIUrl":"https://doi.org/10.1186/s13293-025-00712-9","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions currently diagnosed through behavioral assessments in childhood, though neuropathological changes begin in utero. ASD is more commonly diagnosed in males, a disparity attributed to both biological sex differences and diagnostic biases. Identifying molecular biomarkers, such as DNA methylation signatures, could provide more objective screening for ASD-risk in newborns, allowing for early intervention. Epigenetic dysregulation has been reported in multiple tissues from newborns who are later diagnosed with ASD, but this is the first study to investigate sex-specific DNA methylation signatures for ASD in newborn blood, an accessible and widely banked tissue.</p><p><strong>Methods: </strong>We assayed DNA methylation from newborn blood of ASD and typically developing (TD) individuals (discovery set n = 196, replication set n = 90) using whole genome bisulfite sequencing (WGBS). Sex-stratified differentially methylated regions (DMRs) were assessed for replication, comparisons by sex, overlaps with DMRs from other tissues, and enrichment for biological processes and SFARI ASD-risk genes.</p><p><strong>Results: </strong>We found that newborn blood ASD DMRs from both sexes significantly replicated in an independent cohort and were enriched for hypomethylation in ASD compared to TD samples, as well as location in promoters, CpG islands, and CpG island shores. By comparing female to male samples, we found that most sex-associated DMRs in TD individuals were also found in ASD individuals, alongside additional ASD-specific sex differences. Female-specific DMRs were enriched for X chromosomal location. Across both sexes, newborn blood DMRs overlapped significantly with DMRs from umbilical cord blood and placenta but not post-mortem cerebral cortex. DMRs from all tissues were enriched for neurodevelopmental processes (females) and known ASD genes (both sexes).</p><p><strong>Conclusions: </strong>Overall, we identified and replicated a sex-specific DNA methylation signature of ASD in newborn blood that supported the female protective effect and highlighted convergence of epigenetic and genetic signatures of ASD in newborns. Despite the study's limitations, particularly in female sample sizes, our results demonstrate the potential of newborn blood in ASD screening and emphasize the importance of sex-stratification in future studies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"30"},"PeriodicalIF":4.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease.","authors":"Aphrodite Demetriou, Birgitta Lindqvist, Heba G Ali, Mohamed M Shamekh, Mukesh Varshney, Jose Inzunza, Silvia Maioli, Per Nilsson, Ivan Nalvarte","doi":"10.1186/s13293-025-00711-w","DOIUrl":"https://doi.org/10.1186/s13293-025-00711-w","url":null,"abstract":"<p><strong>Background: </strong>Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimer's disease (AD). Activation of estrogen receptor beta (ERβ) can be clinically relevant since it avoids the adverse systemic effects of ERα activation. However, very few studies have explored ERβ-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study, we specifically explored the role of ERβ in mediating sex-specific protection against AD pathology in the App^NL-G-F knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model.</p><p><strong>Methods: </strong>We treated male and female App^NL-G-F knock-in mice with the clinically relevant and selective ERβ agonist LY500307. A subset of the females was ovariectomized prior to treatment. Y-maze and contextual fear conditioning tests were used to assess memory performance, and biochemical assays such as qPCR, immunohistochemistry, Western blot, and multiplex immunoassays, were used to evaluate amyloid pathology.</p><p><strong>Results: </strong>We found that Female App^NL-G-F mice had higher soluble Aβ levels in cortex and hippocampus than males and more activated microglia. ERβ activation protected against amyloid pathology and cognitive decline in both male and female App^NL-G-F mice. Although ovariectomy increased soluble amyloid beta (Aβ) in cortex and insoluble Aβ in hippocampus, as well as sustained neuroinflammation after ERβ activation, it had otherwise limited effects on pathology. We further identified that ERβ did not alter APP processing, but rather exerted its protection at least partly via microglia activation in a sex-specific manner.</p><p><strong>Conclusion: </strong>Combined, we provide new understanding to the sex differences in AD by demonstrating that ERβ protects against AD pathology differently in males and females, warranting reassessment of ERβ in combating AD.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"29"},"PeriodicalIF":4.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific response to A1BG loss results in female dilated cardiomyopathy.","authors":"James I Emerson, Wei Shi, Frank L Conlon","doi":"10.1186/s13293-025-00713-8","DOIUrl":"https://doi.org/10.1186/s13293-025-00713-8","url":null,"abstract":"<p><strong>Background: </strong>Cardiac disease often manifests with sex-specific differences in frequency, pathology, and progression. However, the molecular mechanisms underlying these differences remain incompletely understood. The glycoprotein A1BG has emerged as a female-specific regulator of cardiac structure and integrity, yet its precise role in the female heart is not well characterized.</p><p><strong>Methods: </strong>To investigate the sex-specific role of A1BG in the heart, we generated both a conditional A1bg knockout allele and an A1bg Rosa26 knockin allele. We employed histological analysis, electrocardiography, RNA sequencing (RNA-seq), transmission electron microscopy (TEM), western blotting, mass spectrometry, and immunohistochemistry to assess structural, functional, and molecular phenotypes.</p><p><strong>Results: </strong>Loss of A1BG in cardiomyocytes leads to persistent structural remodeling in female, but not male, hearts. Despite preserved systolic function in female A1bg^CM/CM mice left ventricular dilation and wall thinning are evident and sustained over time, consistent with early-stage dilated cardiomyopathy (DCM). Transcriptomic analyses reveal that A1BG regulates key metabolic pathways in females, including glucose-6-phosphate and acetyl-CoA metabolism. TEM imaging highlights sex-specific disruption of intercalated disc architecture in female cardiomyocytes. These findings suggest that the absence of A1BG initiates chronic pathological remodeling in female hearts, potentially predisposing them to DCM under stress or aging.</p><p><strong>Conclusion: </strong>A1BG is essential for maintaining ventricular structural integrity in female, but not male, hearts, leading to a chronic remodeling consistent with early-stage DCM.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"27"},"PeriodicalIF":4.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of androgens and global and tissue-specific androgen receptor expression on body composition, exercise adaptation, and performance.","authors":"Sabrina Tzivia Barsky, Douglas Ashley Monks","doi":"10.1186/s13293-025-00707-6","DOIUrl":"https://doi.org/10.1186/s13293-025-00707-6","url":null,"abstract":"<p><p>Gonadal testosterone stimulates skeletal muscle anabolism and contributes to sexually differentiated adipose distribution through incompletely understood mechanisms. Observations in humans and animal models have indicated a major role for androgen receptor (AR) in mediating sex differences in body composition throughout the lifespan. Traditional surgical, genetic and pharmacological studies have tested systemic actions of circulating androgens, and more recent transgenic approaches have allowed for tests of AR gene function in specific androgen responsive niches contributing to body composition, including: skeletal muscle and surrounding interstitial cells, white and brown adipose, as well as trabecular and cortical bone. Less well understood is how these functions of gonadal androgens interact with exercise. Here, we summarize the understood mechanisms of action of AR and its interactions with exercise, specifically on outcomes of body composition and muscle function, and the global- and tissue-specific role of AR in regulating skeletal muscle, adipose, and bone morphology. Additionally, we describe the known effects of androgen and AR manipulation on female body composition, muscle morphology, and sport performance, while highlighting a need for greater inclusion of female subjects in human and animal muscle physiology and endocrinology research.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"28"},"PeriodicalIF":4.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexual dimorphism in metabolomic and phenotypic spectra of UGT deficiency: findings from the Canadian Longitudinal Study on Aging.","authors":"Ana Lucia Rivera-Herrera, Michèle Rouleau, Mahukpe Narcisse Ulrich Singbo, Tania Cuppens, Julien Prunier, Arnaud Droit, David Simonyan, Chantal Guillemette","doi":"10.1186/s13293-025-00708-5","DOIUrl":"https://doi.org/10.1186/s13293-025-00708-5","url":null,"abstract":"<p><strong>Background: </strong>Two of the most frequently deleted genes in the human genome are the UDP-glycosyltransferases UGT2B17 and UGT2B28. They encode metabolic enzymes of the glucuronidation pathway that plays a pivotal role in the maintenance of cellular homeostasis for a variety of small molecule metabolites. These deletions may impact health, yet their effects remain poorly understood. We evaluated the impact of UGT deficiency on the plasma metabolome and examined the association between altered metabolites and health outcomes.</p><p><strong>Methods: </strong>The metabolomic profiles of 4262 proficient gene carriers were compared with those of 352 UGT2B17-deficient, 97 UGT2B28-deficient, and 20 double-gene-deficient individuals from the Canadian Longitudinal Study on Aging. Significant metabolites found in these comparisons were analyzed for their associations with common diseases.</p><p><strong>Results: </strong>The unexpectedly broad molecular divergence found in UGT-deficient metabolomes, which affected > 10% of metabolites, implies their significant influence across various metabolite classes-particularly lipids and amino acids - extending beyond their known substrates. The metabolic profiles of UGT2B17-deficient men and UGT2B28-deficient women were most impacted, with UGT2B17 deficiency affecting various metabolites linked to metabolic diseases, arthritis, and osteoporosis. Metabolites impacted by a UGT2B28 deficiency such as amino acids, were linked to metabolic disorders in women.</p><p><strong>Conclusion: </strong>The findings significantly advance our understanding of the metabolic landscape associated with these frequently deleted genes in the human genome, which may influence susceptibility to various diseases in a sex-specific manner, laying the groundwork for determining their pathological mechanisms and impact on human health.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"26"},"PeriodicalIF":4.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential brainstem connectivity according to sex and menopausal status in healthy male and female individuals.","authors":"Lisa A Kilpatrick, Arpana Church, David Meriwether, Swapna Mahurkar-Joshi, Vince W Li, Jessica Sohn, Juliana Reist, Jennifer S Labus, Tien Dong, Jonathan P Jacobs, Bruce D Naliboff, Lin Chang, Emeran A Mayer","doi":"10.1186/s13293-025-00709-4","DOIUrl":"https://doi.org/10.1186/s13293-025-00709-4","url":null,"abstract":"<p><strong>Background: </strong>Brainstem nuclei play a critical role in both ascending monoaminergic modulation of cortical function and arousal, and in descending bulbospinal pain modulation. Even though sex-related differences in the function of both systems have been reported in animal models, a complete understanding of sex differences, as well as menopausal effects, in brainstem connectivity in humans is lacking. This study evaluated resting-state connectivity of the dorsal raphe nucleus, right and left locus coeruleus complex (LCC), and periaqueductal gray (PAG) according to sex and menopausal status in healthy individuals. In addition, relationships between systemic estrogen levels and brainstem-network connectivity were examined in a subset of participants.</p><p><strong>Methods: </strong>Resting-state fMRI was performed in 47 healthy male (age, 31.2 ± 8.0 years), 53 healthy premenopausal female (age, 24.7 ± 7.3 years; 22 in the follicular phase, 31 in the luteal phase), and 20 postmenopausal female participants (age, 54.6 ± 7.2 years). Permutation Analysis of Linear Models (5000 permutations) was used to evaluate differences in brainstem-network connectivity according to sex and menopausal status, controlling for age. In 10 males and 17 females (9 premenopausal; 8 postmenopausal), estrogen and estrogen metabolite levels in plasma and stool were determined by liquid chromatography-mass spectrometry/mass spectrometry. Relationships between estrogen levels and brainstem-network connectivity were evaluated by partial least squares analysis.</p><p><strong>Results: </strong>Left LCC-executive control network connectivity showed an overall sex difference (p = 0.02), with higher connectivity in females than in males; however, this was mainly due to differences between males and premenopausal females (p = 0.008). Additional sex differences were dependent on menopausal status: PAG-default mode network (DMN) connectivity was higher in postmenopausal females than in males (p = 0.04), and PAG-sensorimotor network (SMN) connectivity was higher in premenopausal females than in males (p = 0.03) and postmenopausal females (p = 0.007). Notably, higher free 2-hydroxyestrone levels in stool were reliably associated with higher PAG-SMN and PAG-DMN connectivity in premenopausal females (p < 0.01).</p><p><strong>Conclusions: </strong>Healthy females show higher brainstem-network connectivity involved in cognitive control, sensorimotor function, and self-relevant processes than males, dependent on their menopausal status. Further, 2-hydroxyestrone, implicated in pain, may modulate PAG connectivity in premenopausal females. These findings may relate to differential vulnerabilities to chronic stress-sensitive disorders at different life stages.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"25"},"PeriodicalIF":4.9,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and clinical sex differences in the effects of alcohol on measures of brain dopamine: a systematic review.","authors":"Nathalie Barrios, Will Riordan, Vernon Garcia-Rivas, MacKenzie R Peltier, Walter Roberts, Terril L Verplaetse, Robert Kohler, Hang Zhou, Bubu A Banini, Sherry A McKee, Kelly P Cosgrove, Yasmin Zakiniaeiz","doi":"10.1186/s13293-025-00706-7","DOIUrl":"10.1186/s13293-025-00706-7","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"24"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippo-vgll3 signaling may contribute to sex differences in Atlantic salmon maturation age via contrasting adipose dynamics.","authors":"Ehsan Pashay Ahi, Jukka-Pekka Verta, Johanna Kurko, Annukka Ruokolainen, Paul Vincent Debes, Craig R Primmer","doi":"10.1186/s13293-025-00705-8","DOIUrl":"10.1186/s13293-025-00705-8","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"23"},"PeriodicalIF":4.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parental kynurenine 3-monooxygenase genotype in mice directs sex-specific behavioral outcomes in offspring.","authors":"Snezana Milosavljevic, Maria V Piroli, Emma J Sandago, Gerardo G Piroli, Holland H Smith, Sarah Beggiato, Norma Frizzell, Ana Pocivavsek","doi":"10.1186/s13293-025-00703-w","DOIUrl":"10.1186/s13293-025-00703-w","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"22"},"PeriodicalIF":4.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of childhood maltreatment, HIV status, and their interaction on mental health outcomes and markers of systemic inflammation in women.","authors":"Amanda Arnold, Heqiong Wang, C Christina Mehta, Paula-Dene C Nesbeth, Brahmchetna Bedi, Caitlin Kirkpatrick, Caitlin A Moran, Abigial Powers, Alicia K Smith, Kimbi Hagen, M Neale Weitzmann, Ighovwerha Ofotokun, Cecile D Lahiri, Jessica A Alvarez, Arshed A Quyyumi, Gretchen N Neigh, Vasiliki Michopoulos","doi":"10.1186/s13293-025-00704-9","DOIUrl":"10.1186/s13293-025-00704-9","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"21"},"PeriodicalIF":4.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}