Biology of Sex Differences最新文献

{"title":"Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments","authors":"María del Mar Fernández-Arjona, Juan Antonio Navarro, Antonio Jesús López-Gambero, Marialuisa de Ceglia, Miguel Rodríguez, Leticia Rubio, Fernando Rodríguez de Fonseca, Vicente Barrios, Julie A. Chowen, Jesús Argente, Patricia Rivera, Juan Suárez","doi":"10.1186/s13293-024-00603-5","DOIUrl":"https://doi.org/10.1186/s13293-024-00603-5","url":null,"abstract":"Children with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways. Plasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed. Reduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females. Sex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner. Understanding the physiological role of pregnancy-associated plasma protein-A2 (PAPP-A2), a proteinase involved in the insulin-like growth factor-1 (IGF1) availability to regulate growth, could provide insight into new treatments for patients with short stature and skeletal abnormalities. Although progressive postnatal growth retardation in patients with PAPP-A2 mutations can differ between males and females, we do not know the underlying differences in IGF1 system and signaling, and their response to treatment that contribute to growth improvement. The present study examines whether Pappa2 deficiency and pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 are associated with sex-specific differences in IGF1 ternary complexes and IGF1 signaling pathways. Reduced body and femur length of Pappa2-deficient mice was associated with sex- and tissue-specific alteration of IGF ternary/binary complexes and IGF1 signaling pathways. rhPAPP-A2 treatment induced female-specific increase in body and femur length and reduction in IGF ternary/binary complexes through STAT5-AKT-ERK2-AMPK signaling pathways in liver. The involvement of PAPP-A2 in sex-based growth physiology sup","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"6 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences and sex-specific regulation of motivated behavior by Melanin-concentrating hormone: a short review","authors":"Isabel R. K. Kuebler, Mauricio Suárez, Ken T. Wakabayashi","doi":"10.1186/s13293-024-00608-0","DOIUrl":"https://doi.org/10.1186/s13293-024-00608-0","url":null,"abstract":"Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH’s role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"32 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats","authors":"Ryan T. McCallum, Rachel-Karson Thériault, Joshua D. Manduca, Isaac S. B. Russell, Angel M. Culmer, Janan Shoja Doost, Tami A. Martino, Melissa L. Perreault","doi":"10.1186/s13293-024-00605-3","DOIUrl":"https://doi.org/10.1186/s13293-024-00605-3","url":null,"abstract":"<p><b>Correction: Biol Sex Differ 15, 16 (2024)</b></p><p>https://doi.org/10.1186/s13293-024-00589-0</p><p> Following publication of the original article [1], the authors reported an error in the methodology for calculating the discrimination ratio in the novel object recognition and object location tests.</p><p><b>Incorrect</b>: The discrimination ratio was calculated as the time of exploration of relocated object/total object exploration time*100.</p><p><b>Correct</b>: For the novel object recognition test the discrimination ratio was calculated as the time exploring the novel object – the time exploring the familiar object/total exploration time.</p><p>For the object location test the discrimination ratio was calculated as the time exploring the novel location – the time exploring the familiar location/total exploration time.</p><p> The authors also report an error in sampling for original Figs. 4 and 5. Therefore, all of the original microglia data in the results and figures have been removed and Fig. 6 renumbered as Fig. 4. The associated immunohistochemistry methodologies were removed, and any associated discussion of the microglia findings deleted. References were renumbered and the Abstract and Highlights also revised to remove the microglia findings.</p><ol data-track-component=\"outbound reference\"><li data-counter=\"1.\"><p>McCallum RT, Thériault RK, Manduca JD, et al. Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats. Biol Sex Differ. 2024;15:16. https://doi.org/10.1186/s13293-024-00589-0.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Department of Biomedical Sciences, University of Guelph, 50 Stone Rd. E, Guelph, ON, N1G 2W1, Canada</p><p>Ryan T. McCallum, Rachel-Karson Thériault, Joshua D. Manduca, Isaac S. B. Russell, Angel M. Culmer, Janan Shoja Doost, Tami A. Martino & Melissa L. Perreault</p></li></ol><span>Authors</span><ol><li><span>Ryan T. McCallum</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rachel-Karson Thériault</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Joshua D. Manduca</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Isaac S. B. Russell</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Angel M. Culmer</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"207 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Training in the implementation of sex and gender research policies: an evaluation of publicly available online courses","authors":"Annika Gompers, Madeline T. Olivier, Donna L. Maney","doi":"10.1186/s13293-024-00610-6","DOIUrl":"https://doi.org/10.1186/s13293-024-00610-6","url":null,"abstract":"Recently implemented research policies requiring the inclusion of females and males have created an urgent need for effective training in how to account for sex, and in some cases gender, in biomedical studies. Here, we evaluated three sets of publicly available online training materials on this topic: (1) Integrating Sex & Gender in Health Research from the Canadian Institutes of Health Research (CIHR); (2) Sex as a Biological Variable: A Primer from the United States National Institutes of Health (NIH); and (3) The Sex and Gender Dimension in Biomedical Research, developed as part of “Leading Innovative measures to reach gender Balance in Research Activities” (LIBRA) from the European Commission. We reviewed each course with respect to their coverage of (1) What is required by the policy; (2) Rationale for the policy; (3) Handling of the concepts “sex” and “gender;” (4) Research design and analysis; and (5) Interpreting and reporting data. All three courses discussed the importance of including males and females to better generalize results, discover potential sex differences, and tailor treatments to men and women. The entangled nature of sex and gender, operationalization of sex, and potential downsides of focusing on sex more than other sources of variation were minimally discussed. Notably, all three courses explicitly endorsed invalid analytical approaches that produce bias toward false positive discoveries of difference. Our analysis suggests a need for revised or new training materials that incorporate four major topics: precise operationalization of sex, potential risks of over-emphasis on sex as a category, recognition of gender and sex as complex and entangled, and rigorous study design and data analysis. Recently implemented research policies requiring the inclusion of females and males have created an urgent need for effective training in how to account for sex, and in some cases gender, in biomedical studies. We evaluated three publicly available online trainings on this topic: (1) Integrating Sex & Gender in Health Research from the Canadian Institutes of Health Research; (2) Sex as a Biological Variable: A Primer from the United States National Institutes of Health; and (3) The Sex and Gender Dimension in Biomedical Research, developed as part of “Leading Innovative Measures to Reach Gender Balance in Research Activities (LIBRA)” from the European Commission. We reviewed each course with respect to their coverage of (1) What is required by the policy; (2) Rationale for the policy; (3) Handling of the concepts “sex” and “gender;” (4) Research design and analysis; and (5) Interpreting and reporting data. All three discussed the importance of including males and females to better generalize results, discover potential sex differences, and tailor treatments to men and women. The interconnectedness of sex and gender, how to operationalize sex, and potential downsides of focusing on sex more than other sources of variation were minimal","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"102 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140594460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury","authors":"Vishal Chanana, Dila Zafer, Douglas B Kintner, Jayadevi H Chandrashekhar, Jens Eickhoff, Peter A Ferrazzano, Jon E Levine, Pelin Cengiz","doi":"10.1186/s13293-024-00596-1","DOIUrl":"https://doi.org/10.1186/s13293-024-00596-1","url":null,"abstract":" Following in vitro ischemia, the nerve growth factor receptor TrkB is activated in the presence of the TrkB agonist 7,8-DHF only in female and not in male cultured hippocampal neurons, leading to increased neuronal survival. Expression of ERα is increased following in vitro ischemia in female but not male hippocampal neurons. The female hippocampal neuronal specific responses to in vitro ischemia are blocked by pre-treatment with testosterone. The data support a model for a female-specific a neuroprotective pathway in hippocampal neurons. The pathway is activated by a TrkB agonist, dependent on ERα and blocked by testosterone. Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of learning disabilities and memory deficits in children. In both human and animal studies, female neonate brains are less susceptible to HI than male brains. Phosphorylation of the nerve growth factor receptor TrkB has been shown to provide sex-specific neuroprotection following in vivo HI in female mice in an estrogen receptor alpha (ERα)-dependent manner. However, the molecular and cellular mechanisms conferring sex-specific neonatal neuroprotection remain incompletely understood. Here, we test whether female neonatal hippocampal neurons express autonomous neuroprotective properties and assess the ability of testosterone (T) to alter this phenotype. We cultured sexed hippocampal neurons from ERα+/+ and ERα−/− mice and subjected them to 4 h oxygen glucose deprivation and 24 h reoxygenation (4-OGD/24-REOX). Sexed hippocampal neurons were treated either with vehicle control (VC) or the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following in vitro ischemia. End points at 24 h REOX were TrkB phosphorylation (p-TrkB) and neuronal survival assessed by immunohistochemistry. In addition, in vitro ischemia-mediated ERα gene expression in hippocampal neurons were investigated following testosterone (T) pre-treatment and TrkB antagonist therapy via q-RTPCR. Multifactorial analysis of variance was conducted to test for significant differences between experimental conditions. Under normoxic conditions, administration of 3 µM 7,8-DHF resulted an ERα-dependent increase in p-TrkB immunoexpression that was higher in female, as compared to male neurons. Following 4-OGD/24-REOX, p-TrkB expression increased 20% in both male and female ERα+/+ neurons. However, with 3 µM 7,8-DHF treatment p-TrkB expression increased further in female neurons by 2.81 ± 0.79-fold and was ERα dependent. 4-OGD/24-REOX resulted in a 56% increase in cell death, but only female cells were rescued with 3 µM 7,8-DHF, again in an ERα dependent manner. Following 4-OGD/3-REOX, ERα mRNA increased ~ 3 fold in female neurons. This increase was blocked with either the TrkB antagonist ANA-12 or pre-treatment with T. Pre-treatment with T also blocked the 7,8-DHF- dependent sex-specific neuronal survival in female neurons following 4-OGD/24-REOX. OGD/REOX results in sex-dependent TrkB phosphorylatio","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"2 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140594038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexual differences in neuronal and synaptic properties across subregions of the mouse insular cortex.","authors":"Daniela Iezzi, Alba Cáceres-Rodríguez, Benjamin Strauss, Pascale Chavis, Olivier J Manzoni","doi":"10.1186/s13293-024-00593-4","DOIUrl":"10.1186/s13293-024-00593-4","url":null,"abstract":"<p><strong>Background: </strong>The insular cortex (IC) plays a pivotal role in processing interoceptive and emotional information, offering insights into sex differences in behavior and cognition. The IC comprises two distinct subregions: the anterior insular cortex (aIC), that processes emotional and social signals, and the posterior insular cortex (pIC), specialized in interoception and perception of pain. Pyramidal projection neurons within the IC integrate multimodal sensory inputs, influencing behavior and cognition. Despite previous research focusing on neuronal connectivity and transcriptomics, there has been a gap in understanding pyramidal neurons characteristics across subregions and between sexes.</p><p><strong>Methods: </strong>Adult male and female C57Bl/6J mice were sacrificed and tissue containing the IC was collected for ex vivo slice electrophysiology recordings that examined baseline sex differences in synaptic plasticity and transmission within aIC and pIC subregions.</p><p><strong>Results: </strong>Clear differences emerged between aIC and pIC neurons in both males and females: aIC neurons exhibited distinctive features such as larger size, increased hyperpolarization, and a higher rheobase compared to their pIC counterparts. Furthermore, we observed variations in neuronal excitability linked to sex, with male pIC neurons displaying a greater level of excitability than their female counterparts. We also identified region-specific differences in excitatory and inhibitory synaptic activity and the balance between excitation and inhibition in both male and female mice. Adult females demonstrated greater synaptic strength and maximum response in the aIC compared to the pIC. Lastly, synaptic long-term potentiation occurred in both subregions in males but was specific to the aIC in females.</p><p><strong>Conclusions: </strong>We conclude that there are sex differences in synaptic plasticity and excitatory transmission in IC subregions, and that distinct properties of IC pyramidal neurons between sexes could contribute to differences in behavior and cognition between males and females.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"29"},"PeriodicalIF":7.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10983634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334613","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":"Resting heart rate associations with violence exposure and posttraumatic stress symptoms: sex differences in children","authors":"Charis N. Wiltshire, Nicole Kouri, Cassandra P. Wanna, Sean T. Minton, John M. France, Mariam H. Reda, William Davie, Sattvik Basarkod, Sterling Winters, Rebecca Hinrichs, Anais F. Stenson, Tanja Jovanovic","doi":"10.1186/s13293-024-00606-2","DOIUrl":"https://doi.org/10.1186/s13293-024-00606-2","url":null,"abstract":"Traumatic events experienced in childhood can lead to increased risk of cardiovascular disorders in adulthood. Black Americans are disproportionately affected, as they are at increased risk for experiencing childhood trauma and cardiovascular diseases in adulthood. One of the hypothesized mechanisms of this association is through long-lasting dysregulation of the autonomic nervous system, a hallmark physiological biomarker of posttraumatic stress disorder (PTSD), which is twice as prevalent in women compared to men. Ninety-one, majority Black American children, aged 9 were recruited to be a part of our longitudinal study of child development at research centers in Atlanta, GA and Detroit, MI. Resting HR was measured through a electrocardiogram (ECG) recording using the Biopac MP150. Self-report measures of violence exposure and PTSD symptoms were administered by research staff. Children with more violence exposure reported increased PTSS as well as lower resting HR. Regression analysis showed evidence of sex modifying this relationship, (B = -0.64, p &lt; 0.05), such that the association between resting HR and PTSS was stronger in girls than in boys. In our exploratory analysis with standard clinical cutoffs of resting HR, the normative HR group was found to significantly moderate the relationship between violence exposure and PTSS in boys, (B = -2.14, p &lt; 0.01), but not girls (B = -0.94, p = 0.27). In our sample of primarily Black urban children, we found that violence exposure was associated with slower, more adult-like HR, that girls showed greater PTSS associated with slower HR while boys did not, and that girls with lower than normative HR showed significantly higher PTSS compared to girls with normative HR. Our sample’s demonstration of psychological consequences in addition to the physiological implications could provide new information about a psychobiological sequelae of violence exposure. Experiencing traumatic events in childhood can lead to increased risk of heart disease in adulthood. One of the ways this might happen is through long-lasting changes of the autonomic nervous system. This system is dysregulated in posttraumatic stress disorder (PTSD), which is twice as common in women compared to men. We explored whether resting heart rate (HR), a measure of autonomic functioning was associated with violence exposure in children, and whether this relationship was different in boys and girls. We also explored whether categorizing our sample into resting HR groups based off standardized norms for HR predicted differing relationships between violence exposure and posttraumatic stress symptoms (PTSS). Because childhood trauma and heart disease impact Black Americans at greater rates, we recruited our sample of 92 nine-year-old children from research centers in Atlanta, GA and Detroit, MI. We measured their resting HR, exposure to violence, and PTSS. We found that violence exposure was associated with lower HR overall, that girls showed greate","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"2011 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140316784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menarche, pubertal timing and the brain: female-specific patterns of brain maturation beyond age-related development.","authors":"Nina Gottschewsky, Dominik Kraft, Tobias Kaufmann","doi":"10.1186/s13293-024-00604-4","DOIUrl":"10.1186/s13293-024-00604-4","url":null,"abstract":"<p><strong>Background: </strong>Puberty depicts a period of profound and multifactorial changes ranging from social to biological factors. While brain development in youths has been studied mostly from an age perspective, recent evidence suggests that pubertal measures may be more sensitive to study adolescent neurodevelopment, however, studies on pubertal timing in relation to brain development are still scarce.</p><p><strong>Methods: </strong>We investigated if pre- vs. post-menarche status can be classified using machine learning on cortical and subcortical structural magnetic resonance imaging (MRI) data from strictly age-matched adolescent females from the Adolescent Brain Cognitive Development (ABCD) cohort. For comparison of the identified menarche-related patterns to age-related patterns of neurodevelopment, we trained a brain age prediction model on data from the Philadelphia Neurodevelopmental Cohort and applied it to the same ABCD data, yielding differences between predicted and chronological age referred to as brain age gaps. We tested the sensitivity of both these frameworks to measures of pubertal maturation, specifically age at menarche and puberty status.</p><p><strong>Results: </strong>The machine learning model achieved moderate but statistically significant accuracy in the menarche classification task, yielding for each subject a class probability ranging from 0 (pre-) to 1 (post- menarche). Comparison to brain age predictions revealed shared and distinct patterns of neurodevelopment captured by both approaches. Continuous menarche class probabilities were positively associated with brain age gaps, but only the menarche class probabilities-not the brain age gaps-were associated with age at menarche.</p><p><strong>Conclusions: </strong>This study demonstrates the use of a machine learning model to classify menarche status from structural MRI data while accounting for age-related neurodevelopment. Given its sensitivity towards measures of puberty timing, our work suggests that menarche class probabilities may be developed toward an objective brain-based marker of pubertal development.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"25"},"PeriodicalIF":4.9,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10964568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292580","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":"Maternal immune suppression during pregnancy does not prevent abnormal behavior in offspring.","authors":"Ashley Griffin, Teylor Bowles, Lucia Solis, Teryn Railey, Samer Beauti, Reanna Robinson, Shauna-Kay Spencer, James P Shaffery, Kedra Wallace","doi":"10.1186/s13293-024-00600-8","DOIUrl":"10.1186/s13293-024-00600-8","url":null,"abstract":"<p><strong>Background: </strong>Offspring of hypertensive disorders of pregnancy are at an increased risk of developing neurodevelopmental and neurobehavioral disorders compared to offspring from non-affected pregnancies. Using rodent models of Preeclampsia (PreE; new onset of hypertension after 20 weeks gestation) and HELLP (hemolysis, elevated liver enzymes, and low platelets), we studied the behavioral outcome of their offspring in adolescence.</p><p><strong>Methods: </strong>A subset of dams received Orencia, a T-cell activation inhibitor, as T cells have been associated with the induction of hypertension and inflammation during pregnancy. We hypothesized that offspring from hypertensive dams would experience adverse behavioral outcomes in social, cognitive, locomotor, and anxiety tests, and offspring from dams treated with Orencia would demonstrate less adverse behaviors.</p><p><strong>Results: </strong>Male offspring of PreE + Orencia dams (p < 0.05) and female offspring from HELLP + Orencia dams (p < 0.05) spent more time playing compared to normal pregnant offspring. All offspring from hypertensive and Orencia-treated dams performed worse on the Barnes Maze test compared to normal pregnant. We also measured adult (postnatal day > 60) myelin basic protein (MBP) and NeuN expression in both the prefrontal cortex and hippocampus. In the hippocampus and prefrontal cortex, there was no difference in expression of either MBP or NeuN in all groups regardless of sex.</p><p><strong>Conclusion: </strong>The results from this study suggest that offspring of hypertensive disorders of pregnancy have behavioral changes, specifically cognitive differences. This study has shown that there is a sex dependent difference in offspring neurobehavioral development, influenced in part by the type of hypertensive disorder of pregnancy, and alterations in the maternal immune system.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"27"},"PeriodicalIF":7.9,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10967052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292579","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 and statin-related genetic associations at the PCSK9 gene locus: results of genome-wide association meta-analysis.","authors":"Janne Pott, Azin Kheirkhah, Jesper R Gadin, Marcus E Kleber, Graciela E Delgado, Holger Kirsten, Lukas Forer, Stefanie M Hauck, Ralph Burkhardt, Hubert Scharnagl, Markus Loeffler, Winfried März, Joachim Thiery, Christian Gieger, Annette Peters, Angela Silveira, Ferdinand Van't Hooft, Florian Kronenberg, Markus Scholz","doi":"10.1186/s13293-024-00602-6","DOIUrl":"10.1186/s13293-024-00602-6","url":null,"abstract":"<p><strong>Background: </strong>Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics.</p><p><strong>Methods: </strong>We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups.</p><p><strong>Results: </strong>We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10^-6), including the PCSK9 gene locus and five other lipid loci: APOB, TM6SF2, FADS1/FADS2, JMJD1C, and HP/HPR. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the PCSK9 gene locus, there were four independent signals, one with a significant sex-interaction showing stronger effects in men (rs693668). Regarding statin treatment, there were two significant interactions in PCSK9 missense mutations: rs11591147 had stronger effects in statin-free individuals, and rs11583680 had stronger effects in statin-treated individuals. Besides replicating known loci, we detected two novel genome-wide significant associations: one for statin-treated individuals at 6q11.1 (within KHDRBS2) and one for males at 12q24.22 (near KSR2/NOS1), both with significant interactions. In the MR of PCSK9 on LDL-C, we observed significant causal estimates within all subgroups, but significantly stronger causal effects in statin-free subjects compared to statin-treated individuals.</p><p><strong>Conclusions: </strong>We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"26"},"PeriodicalIF":4.9,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10964567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292581","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}