Biology of Sex Differences最新文献

{"title":"Sex and gender differences in adverse events following influenza and COVID-19 vaccination.","authors":"Anna Yin, Nadia Wang, Patrick J Shea, Erica N Rosser, Helen Kuo, Janna R Shapiro, Katherine Z J Fenstermacher, Andrew Pekosz, Richard E Rothman, Sabra L Klein, Rosemary Morgan","doi":"10.1186/s13293-024-00625-z","DOIUrl":"10.1186/s13293-024-00625-z","url":null,"abstract":"<p><strong>Introduction: </strong>Active and passive surveillance studies have found that a greater proportion of females report adverse events (AE) following receipt of either the COVID-19 or seasonal influenza vaccine compared to males. In a predominately young adult female population of healthcare workers, we sought to determine the intersection of biological sex and sociocultural gender differences in prospective active reporting of vaccine outcomes, which remains poorly characterized.</p><p><strong>Methods: </strong>This cohort study enrolled Johns Hopkins Health System healthcare workers (HCWs) who were recruited from the mandatory annual fall 2019-2022 influenza vaccine and the fall 2022 COVID-19 bivalent vaccine campaigns. Vaccine recipients were enrolled the day of vaccination and AE surveys were administered two days post-vaccination for bivalent COVID-19 and influenza vaccine recipients. Data were collected regarding the presence of a series of solicited local and systemic AEs. Open-ended answers about participants' experiences with AEs also were collected for the COVID-19 vaccine recipients.</p><p><strong>Results: </strong>Females were more likely to report local AEs after either influenza (OR = 2.28, p = 0.001) or COVID-19 (OR = 2.57, p = 0.008) vaccination compared to males, regardless of age or race. Males and females had comparable probabilities of reporting systemic AEs after either influenza (OR = 1.18, p = 0.552) or COVID-19 (OR = 0.96, p = 0.907) vaccination. Hormonal birth control use did not impact the rates of reported AEs following influenza vaccination among reproductive-aged female HCWs. Women reported more interruptions in their daily routine following COVID-19 vaccination than men and were more likely to seek out self-treatment. More women than men scheduled their COVID-19 vaccination before their days off in anticipation of AEs.</p><p><strong>Conclusions: </strong>Our findings highlight the need for sex- and gender-inclusive policies to inform more effective mandatory occupational health vaccination strategies. Further research is needed to evaluate the potential disruption of AEs on occupational responsibilities following mandated vaccination for healthcare workers, a predominately female population, and to more fully characterize the post-vaccination behavioral differences between men and women.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"50"},"PeriodicalIF":4.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417546","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":"Differently different?: A commentary on the emerging social cognitive neuroscience of female autism.","authors":"Gina Rippon","doi":"10.1186/s13293-024-00621-3","DOIUrl":"10.1186/s13293-024-00621-3","url":null,"abstract":"<p><p>Autism is a neurodevelopmental condition, behaviourally identified, which is generally characterised by social communication differences, and restrictive and repetitive patterns of behaviour and interests. It has long been claimed that it is more common in males. This observed preponderance of males in autistic populations has served as a focussing framework in all spheres of autism-related issues, from recognition and diagnosis through to theoretical models and research agendas. One related issue is the near total absence of females in key research areas. For example, this paper reports a review of over 120 brain-imaging studies of social brain processes in autism that reveals that nearly 70% only included male participants or minimal numbers (just one or two) of females. Authors of such studies very rarely report that their cohorts are virtually female-free and discuss their findings as though applicable to all autistic individuals. The absence of females can be linked to exclusionary consequences of autism diagnostic procedures, which have mainly been developed on male-only cohorts. There is clear evidence that disproportionately large numbers of females do not meet diagnostic criteria and are then excluded from ongoing autism research. Another issue is a long-standing assumption that the female autism phenotype is broadly equivalent to that of the male autism phenotype. Thus, models derived from male-based studies could be applicable to females. However, it is now emerging that certain patterns of social behaviour may be very different in females. This includes a specific type of social behaviour called camouflaging or masking, linked to attempts to disguise autistic characteristics. With respect to research in the field of sex/gender cognitive neuroscience, there is emerging evidence of female differences in patterns of connectivity and/or activation in the social brain that are at odds with those reported in previous, male-only studies. Decades of research have excluded or overlooked females on the autistic spectrum, resulting in the construction of inaccurate and misleading cognitive neuroscience models, and missed opportunities to explore the brain bases of this highly complex condition. A note of warning needs to be sounded about inferences drawn from past research, but if future research addresses this problem of male bias, then a deeper understanding of autism as a whole, as well as in previously overlooked females, will start to emerge.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"49"},"PeriodicalIF":4.9,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316689","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 colorectal cancer: molecular mechanisms and treatment strategies.","authors":"Yair Rodríguez-Santiago, Claudia Angelica Garay-Canales, Karen Elizabeth Nava-Castro, Jorge Morales-Montor","doi":"10.1186/s13293-024-00623-1","DOIUrl":"10.1186/s13293-024-00623-1","url":null,"abstract":"<p><strong>Introduction: </strong>Sexual dimorphism significantly influences cancer incidence and prognosis. Notably, females exhibit a lower risk and favorable prognosis for non-reproductive cancers compared to males, a pattern observable beyond the scope of risk behaviors such as alcohol consumption and smoking. Colorectal cancer, ranking third in global prevalence and second in mortality, disproportionately affects men. Sex steroid hormones, particularly estrogens and androgens, play crucial roles in cancer progression, considering epidemiological in vivo and in vitro, in general estrogens imparting a protective effect in females and androgens correlating with an increasing risk of colorectal cancer development.</p><p><strong>Main body: </strong>The hormonal impact on immune response is mediated by receptor interactions, resulting in heightened inflammation, modulation of NF-kB, and fostering an environment conducive to cancer progression and metastasis. These molecules also influence the enteric nervous system, that is a pivotal in neuromodulator release and intestinal neuron stimulation, also contributes to cancer development, as evidenced by nerve infiltration into tumors. Microbiota diversity further intersects with immune, hormonal, and neural mechanisms, influencing colorectal cancer dynamics. A comprehensive understanding of hormonal influences on colorectal cancer progression, coupled with the complex interplay between immune responses, microbiota diversity and neurotransmitter imbalances, underpins the development of more targeted and effective therapies.</p><p><strong>Conclusions: </strong>Estrogens mitigate colorectal cancer risk by modulating anti-tumor immune responses, enhancing microbial diversity, and curbing the pro-tumor actions of the sympathetic and enteric nervous systems. Conversely, androgens escalate tumor growth by dampening anti-tumor immune activity, reducing microbial diversity, and facilitating the release of tumor-promoting factors by the nervous system. These findings hold significant potential for the strategic purposing of drugs to fine-tune the extensive impacts of sex hormones within the tumor microenvironment, promising advancements in colorectal cancer therapies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"48"},"PeriodicalIF":7.9,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11170921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309854","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":"Relationship between sex biases in gene expression and sex biases in autism and Alzheimer's disease.","authors":"Stuart B Fass, Bernard Mulvey, Rebecca Chase, Wei Yang, Din Selmanovic, Sneha M Chaturvedi, Eric Tycksen, Lauren A Weiss, Joseph D Dougherty","doi":"10.1186/s13293-024-00622-2","DOIUrl":"10.1186/s13293-024-00622-2","url":null,"abstract":"<p><strong>Background: </strong>Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions.</p><p><strong>Methods: </strong>In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks.</p><p><strong>Results: </strong>We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case-control gene expression studies suggests a female molecular predisposition towards Alzheimer's disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis.</p><p><strong>Conclusion: </strong>Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"47"},"PeriodicalIF":7.9,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11157820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282887","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":"Testosterone deficiency promotes arterial stiffening independent of sex chromosome complement.","authors":"Anil Sakamuri, Bruna Visniauskas, Isabella Kilanowski-Doroh, Alexandra B McNally, Ariane Imulinde, Anne Kamau, Divya Sengottaian, John McLachlan, Montserrat Anguera, Franck Mauvais-Jarvis, Sarah H Lindsey, Benard O Ogola","doi":"10.1186/s13293-024-00624-0","DOIUrl":"10.1186/s13293-024-00624-0","url":null,"abstract":"<p><strong>Background: </strong>Sex hormones and sex chromosomes play a vital role in cardiovascular disease. Testosterone plays a crucial role in men's health. Lower testosterone level is associated with cardiovascular and cardiometabolic diseases, including inflammation, atherosclerosis, and type 2 diabetes. Testosterone replacement is beneficial or neutral to men's cardiovascular health. Testosterone deficiency is associated with cardiovascular events. Testosterone supplementation to hypogonadal men improves libido, increases muscle strength, and enhances mood. We hypothesized that sex chromosomes (XX and XY) interaction with testosterone plays a role in arterial stiffening.</p><p><strong>Methods: </strong>We used four core genotype male mice to understand the inherent contribution of sex hormones and sex chromosome complement in arterial stiffening. Age-matched mice were either gonadal intact or castrated at eight weeks plus an additional eight weeks to clear endogenous sex hormones. This was followed by assessing blood pressure, pulse wave velocity, echocardiography, and ex vivo passive vascular mechanics.</p><p><strong>Results: </strong>Arterial stiffening but not blood pressure was more significant in castrated than testes-intact mice independent of sex chromosome complement. Castrated mice showed a leftward shift in stress-strain curves and carotid wall thinning. Sex chromosome complement (XX) in the absence of testosterone increased collagen deposition in the aorta and Kdm6a gene expression.</p><p><strong>Conclusion: </strong>Testosterone deprivation increases arterial stiffening and vascular wall remodeling. Castration increases Col1α1 in male mice with XX sex chromosome complement. Our study shows decreased aortic contractile genes in castrated mice with XX than XY sex chromosomes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"46"},"PeriodicalIF":4.9,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282888","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":"Low testosterone levels relate to poorer cognitive function in women in an APOE-ε4-dependant manner.","authors":"Melanie A Dratva, Sarah J Banks, Matthew S Panizzon, Douglas Galasko, Erin E Sundermann","doi":"10.1186/s13293-024-00620-4","DOIUrl":"10.1186/s13293-024-00620-4","url":null,"abstract":"<p><strong>Background: </strong>Past research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer's disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone's effects on brain health may be moderated by apolipoprotein E ε4 allele (APOE-ε4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE-ε4 genotype.</p><p><strong>Methods: </strong>Five hundred and sixty one participants aged 55-90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE-ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-ε4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language.</p><p><strong>Results: </strong>We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-ε4 carriers only. We did not find that testosterone, nor its interaction with APOE-ε4, related to cognitive outcomes in males.</p><p><strong>Conclusions: </strong>Findings suggest that low testosterone levels in older female APOE-ε4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE-ε4 carrier status when examining testosterone's role in cognitive health.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"45"},"PeriodicalIF":4.9,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11151480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247264","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":"CGRP as a potential mediator for the sexually dimorphic responses to traumatic brain injury.","authors":"Chunyan Li, Erum Ajmal, Khaled Alok, Keren Powell, Steven Wadolowski, Willians Tambo, Justin Turpin, Ernest Barthélemy, Yousef Al-Abed, David LeDoux","doi":"10.1186/s13293-024-00619-x","DOIUrl":"10.1186/s13293-024-00619-x","url":null,"abstract":"<p><strong>Background: </strong>The outcomes of traumatic brain injury (TBI) exhibit variance contingent upon biological sex. Although female sex hormones exert neuroprotective effects, the administration of estrogen and progesterone has not yielded conclusive results. Hence, it is conceivable that additional mediators, distinct from female sex hormones, merit consideration due to their potential differential impact on TBI outcomes. Calcitonin gene-related peptide (CGRP) exhibits sexually dimorphic expression and demonstrates neuroprotective effects in acute brain injuries. In this study, we aimed to examine sex-based variations in TBI structural and functional outcomes with respect to CGRP expression.</p><p><strong>Methods: </strong>Male and female Sprague Dawley rats were exposed to controlled cortical impact to induce severe TBI, followed by interventions with and without CGRP inhibition. In the acute phase of TBI, the study centered on elucidating the influence of CGRP on oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and endothelial nitric oxide synthase (eNOS) signaling in the peri-impact tissue. Subsequently, during the chronic phase of TBI, the investigation expanded to evaluate CGRP expression in relation to lesion volume, microvascular dysfunction, and white matter injury, as well as working and spatial memory, anxiety-like, and depression-like behaviors in subjects of both sexes.</p><p><strong>Results: </strong>Female rats exhibited elevated levels of CGRP in the peri-impact brain tissue during both baseline conditions and in the acute and chronic phases of TBI, in comparison to age-matched male counterparts. Enhanced CGRP levels in specific brain sub-regions among female rats correlated with superior structural and functional outcomes following TBI compared to their male counterparts. CGRP inhibition induced heightened oxidative stress and a reduction in the expression of Nrf2 and eNOS in both male and female rats, with the observed alteration being more pronounced in females than in males.</p><p><strong>Conclusions: </strong>This study marks the inaugural identification of CGRP as a downstream mediator contributing to the sexually dimorphic response observed in TBI outcomes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"44"},"PeriodicalIF":4.9,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11138127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178532","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":"Fatty Liver Index (FLI) is the best score to predict MASLD with 50% lower cut-off value in women than in men.","authors":"Lucilla Crudele, Carlo De Matteis, Fabio Novielli, Ersilia Di Buduo, Stefano Petruzzelli, Alessia De Giorgi, Gianfranco Antonica, Elsa Berardi, Antonio Moschetta","doi":"10.1186/s13293-024-00617-z","DOIUrl":"10.1186/s13293-024-00617-z","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the presence of hepatic steatosis, detected on ultrasonography (US) imaging or histology, and at least one of criteria for Metabolic Syndrome diagnosis. Simple non-invasive tests (NITs) have been proposed as an acceptable alternative when US and biopsy are not available or feasible but have not been validated for MASLD. In this observational study, we investigated the reliability of NITs for MASLD detection and whether sex-differences in screening methods should be considered.</p><p><strong>Methods: </strong>We included 1069 individuals (48% males and 52% females) who underwent their first clinical examination for Metabolic Syndrome in the period between January 2015 and December 2022. Liver steatosis was detected through US and anthropometric and clinical parameters were recorded.</p><p><strong>Results: </strong>Liver steatosis was detected in 648 patients and MASLD was diagnosed in 630 subjects (355 males; 275 females). Women with MASLD showed better metabolic profile and lower prevalence of Metabolic Syndrome criteria than men. Among NITs, Fatty Liver Index (FLI) showed the best ability for detection of MASLD, with a cut-off value of 44 (AUC = 0.82). When considering the two sexes for MASLD detection via FLI, despite no substantial differences regarding FLI correlations with metabolic biomarkers except for age, women showed marked lower FLI cut-off value (32; AUC = 0.80) than men (60; AUC = 0.80).</p><p><strong>Conclusions: </strong>In this study, we found that FLI is the best non-invasive predictor of both liver steatosis and MASLD. The finding that in women FLI cut-off value for MASLD detection is 50% lower than in men suggests the need of a sex-specific personalized program of screening and prevention of dysmetabolism-related liver diseases, despite outwardly healthy biomarkers profile.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"43"},"PeriodicalIF":4.9,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11100212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955638","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 impacts of prenatal bisphenol A exposure on genes associated with cortical development, social behaviors, and autism in the offspring's prefrontal cortex.","authors":"Songphon Kanlayaprasit, Thanit Saeliw, Surangrat Thongkorn, Pawinee Panjabud, Kasidit Kasitipradit, Pattanachat Lertpeerapan, Kwanjira Songsritaya, Wasana Yuwattana, Thanawin Jantheang, Depicha Jindatip, Valerie W Hu, Takako Kikkawa, Noriko Osumi, Tewarit Sarachana","doi":"10.1186/s13293-024-00614-2","DOIUrl":"10.1186/s13293-024-00614-2","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in the offspring's hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits in learning. However, the sex differences in the effects of prenatal BPA exposure on the developing prefrontal cortex, which is another brain region highly implicated in autism spectrum disorder (ASD), have not been investigated.</p><p><strong>Methods: </strong>We obtained transcriptome data from RNA sequencing analysis of the prefrontal cortex of male and female rat pups prenatally exposed to BPA or control and reanalyzed. BPA-responsive genes associated with cortical development and social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis of primary cells from the prefrontal cortex of pups prenatally exposed to BPA or control was examined. The social behaviors of the pups were assessed using the two-trial and three-chamber tests. The male-specific impact of the downregulation of a selected BPA-responsive gene (i.e., Sema5a) on cortical development in vivo was interrogated using siRNA-mediated knockdown by an in utero electroporation technique.</p><p><strong>Results: </strong>Genes disrupted by prenatal BPA exposure were associated with ASD and showed sex-specific dysregulation. Sema5a and Slc9a9, which were involved in neuritogenesis and social behaviors, were downregulated only in males, while Anxa2 and Junb, which were also linked to neuritogenesis and social behaviors, were suppressed only in females. Neuritogenesis was increased in males and showed a strong inverse correlation with Sema5a and Slc9a9 expression levels, whereas, in the females, neuritogenesis was decreased and correlated with Anxa2 and Junb levels. The siRNA-mediated knockdown of Sema5a in males also impaired cortical development in utero. Consistent with Anxa2 and Junb downregulations, deficits in social novelty were observed only in female offspring but not in males.</p><p><strong>Conclusion: </strong>This is the first study to show that prenatal BPA exposure dysregulated the expression of ASD-related genes and functions, including cortical neuritogenesis and development and social behaviors, in a sex-dependent manner. Our findings suggest that, besides the hippocampus, BPA could also exert its adverse effects through sex-specific molecular mechanisms in the offspring's prefrontal cortex, which in turn would lead to sex differences in ASD-related neuropathology and clinical manifestations, which deserves further investigation.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"40"},"PeriodicalIF":7.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11094985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943904","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":"Modeling brain sex in the limbic system as phenotype for female-prevalent mental disorders.","authors":"Gloria Matte Bon, Dominik Kraft, Erika Comasco, Birgit Derntl, Tobias Kaufmann","doi":"10.1186/s13293-024-00615-1","DOIUrl":"10.1186/s13293-024-00615-1","url":null,"abstract":"<p><strong>Background: </strong>Sex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics.</p><p><strong>Methods: </strong>We here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV).</p><p><strong>Results: </strong>Limbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male-female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction.</p><p><strong>Conclusions: </strong>Overall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"42"},"PeriodicalIF":7.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943902","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}