Molecular and Cellular Endocrinology最新文献

{"title":"Inhibiting the fructose transporter GLUT5 boosts testosterone production in a murine mLTC-1 leydig cell line","authors":"Aikaterini Kallianioti , Guillaume Bourdon , Claire Chevaleyre , Christine Péchoux , Christelle Ramé , Jérôme Bourgeais , Olivier Hérault , Nancy Geoffre , Thomas Darde , Ingrid Plotton , Véronique Douard , Joëlle Dupont , Pascal Froment","doi":"10.1016/j.mce.2025.112658","DOIUrl":"10.1016/j.mce.2025.112658","url":null,"abstract":"<div><div>Over the past few decades, a significant change globally in sugar intake has coincided with a rising incidence of male infertility, which is now a major public health concern. Diets rich in fructose have been implicated in both male infertility and increased susceptibility to metabolic disorders, such as obesity, diabetes, and related heart problems. While fructose is known to be present in seminal fluid and crucial for sperm motility, the precise role of fructose in testicular function remains largely unknown.</div><div>GLUT5 is an exclusive fructose transporter essential for dietary fructose uptake in the intestine. It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the <em>Glut5</em> gene in male mice impairs spermatogenesis and steroidogenesis. However, its specific role within Leydig cells remains unexplored. Therefore, we investigated its role by inhibiting GLUT5 in a murine Leydig cell line (mLTC-1) using a specific inhibitor of GLUT5, MSNBA, combined with a multi-omics approach.</div><div>Exposing mLTC-1 cells to MSNBA reduced the intracellular fructose content, limited cell proliferation, and enhanced progesterone and androgens production (Δ4-androstenedione and testosterone). The latter was associated with the upregulation of two genes and proteins involved in steroidogenesis, such as <em>Hsd3b</em> and steroidogenic acute regulatory protein (<em>StAR</em>). GLUT5 inhibition in mLTC-1 cells also modified lipid and carbohydrate metabolism. Lipidomic analysis showed decreased cholesterol esters and a shift in the ratio of polyunsaturated fatty acids (PUFAs) to monounsaturated fatty acids (MUFAs). These lipid changes correlated with alterations in the expression of mRNA-encoding enzymes involved in lipogenesis, such as ELOVL6. Metabolomics analysis showed a reduction in most glycolysis metabolites, except for pyruvate and lactate. However, pyruvate could conserve its level by a production through an amino acid pathway using the higher branched-chain amino acid content. Nevertheless, the activity of mitochondria measured by seahorse was not altered. The transcriptomic analysis performed by BRB-seq approach revealed an upregulation of several androgen-sensitive genes, such as <em>Akap5, Slc39a9,</em> an androgen receptor or lactate dehydrogenase A (<em>Ldha</em>), which produces lactate, and downregulation of several genes associated with the insulin pathway such as <em>Tsc2 or</em> the hexokinase <em>Hkdc1</em>.</div><div>In conclusion, GLUT5 supported fructose intake in the murine Leydig cell line mLTC-1, leading to a reduction in cell proliferation. The consequences of inhibition of GLUT5 led to an increase in fatty acids cell content, a perturbation in glycolysis and amino-acid metabolism but an enhanced androgen production. Since androgens regulate spermatogenesis, hyperandrogenism induced by a lower fructose content in Leydig cells may be a primary cause leading to the disruption of spe","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112658"},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oocyte-specific Ahr deletion disrupts folliculogenesis and female fertility in mice","authors":"Pengtao Chen ,&nbsp;Jinpeng Ruan ,&nbsp;Fanzheng Xue ,&nbsp;Xuejuan Dai ,&nbsp;Chen Tang ,&nbsp;Mingyue Chen ,&nbsp;Nengming Xiao ,&nbsp;Zhijian Cai ,&nbsp;Chunyan Yang ,&nbsp;Chengyong He ,&nbsp;Wei Wang ,&nbsp;Zhenghong Zuo","doi":"10.1016/j.mce.2025.112656","DOIUrl":"10.1016/j.mce.2025.112656","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates various biological processes, including xenobiotic metabolism, immune response, and reproduction. Although previous studies have shown that AHR plays a role in ovarian follicle development, the precise role of oocyte-expressed AHR in female reproduction remains unclear. In this study, oocyte-specific <em>Ahr</em> knockout (cKO) mice generated by crossing the <em>Ahr</em> ^{<em>flox/flox</em>} (<em>Ahr</em> ^{<em>fl/fl</em>}) and <em>Gdf9-cre</em> transgenic mouse strains were used to answer this open question. The cKO female mice exhibited a disrupted estrous cyclicity and subfertility. Histological analyses demonstrated that oocyte AHR loss reduces the number of primary follicles while increasing the number of secondary follicles and corpus lutea in mouse ovary. Hormonal analysis revealed decreased serum estradiol and follicle-stimulating hormone, indicating a disruption of the hypothalamic-pituitary-gonadal axis in cKO mice. TUNEL and Western blotting results demonstrate that deletion of oocyte AHR also results in increased apoptosis in ovarian granulosa cells (GCs), downregulated expression of <em>Gdf9</em> and <em>Bmp15</em> in oocytes<em>,</em> and disrupted bidirectional oocyte-GC communication. In conclusion, our findings reveal that the aryl hydrocarbon receptor plays a role beyond sensing environmental chemicals and endogenous compounds and underscore a critical role of oocyte-expressed Ahr in maintain follicle development, ovarian function, and female reproductive health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112656"},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental programming: Differing impact of prenatal testosterone and prenatal bisphenol-A -treatment on hepatic methylome in female sheep","authors":"John Dou ,&nbsp;Soundara Viveka Thangaraj ,&nbsp;Yiran Zhou ,&nbsp;Vasantha Padmanabhan ,&nbsp;Kelly Bakulski","doi":"10.1016/j.mce.2025.112655","DOIUrl":"10.1016/j.mce.2025.112655","url":null,"abstract":"<div><div>Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environmental chemicals, can lead to metabolic dysfunctions in offspring. The research focuses on how exposure to testosterone (T) and bisphenol A (BPA) affects the liver's DNA methylome, a key component of the epigenome influencing long-term health. Using Suffolk sheep, the study involved two cohorts: one exposed to prenatal-T and the other to prenatal-BPA. Whole genome bisulfite sequencing was employed to map DNA methylation across over 22 million CpG sites. Regions with p-value&lt;10⁻⁴ and a magnitude of difference of at least 5 % methylation between groups were considered differentially methylated. Results demonstrated substantial differential methylation in the liver tissues due to both treatments, with prenatal-T causing unique epigenetic modifications distinct from those induced by prenatal-BPA. Specifically, prenatal-T treatment resulted in 53 differentially methylated regions (DMRs), of which 31 were located in gene regions, including exons. Prenatal-BPA exposure led to 32 DMRs, with 22 associated with gene regions. These modifications were associated with genes governing lipid and glucose metabolism, potentially underlying the observed metabolic disruptions such as insulin resistance and dyslipidemia. Pathway analysis revealed that genes differentially methylated due to prenatal-T were involved in cellular organization, while those affected by prenatal-BPA were enriched in signal regulation pathways. The findings underscore how prenatal exposure to steroid excess and steroid-mimics influence epigenetic landscapes, contributing to metabolic disease programming.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112655"},"PeriodicalIF":3.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA binding protein SERBP1 is indispensable for oocyte development and maturation in mice.","authors":"Lingjuan Wang, Sijin OuYang, Bin Li, Na Kong","doi":"10.1016/j.mce.2025.112644","DOIUrl":"https://doi.org/10.1016/j.mce.2025.112644","url":null,"abstract":"<p><p>RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression and RNA processing during mammalian oocyte development. SERPINE1 mRNA-binding protein 1 (SERBP1), a conserved RNA-binding protein (RBP), exhibits prominent expression in the female reproductive system and throughout oogenesis. Conditional deletion of Serbp1 using oocyte-specific Zp3⁠/⁠Gdf9⁠-Cre drivers resulted in arrested oocyte growth, female infertility, and failure of blastocyst formation from two-cell embryos. Phenotypic analysis revealed spindle assembly defects, impaired asymmetric division, and compromised meiotic competence in oocytes. Notably, Serbp1 ablation also induced granulosa cell apoptosis and elevated Erk1/2 phosphorylation levels, indicating dysregulation of somatic microenvironment. Furthermore, conditional knockout mice exhibited prolonged diestrus cycles. Collectively, these findings demonstrate that SERBP1 coordinates essential RNA-regulatory functions for oocyte developmental competence through both cell-autonomous mechanisms and somatic-germline crosstalk.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112644"},"PeriodicalIF":3.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The N-terminal region of HASPIN regulates phosphorylation of AURKA and meiotic progression in spermatocytes","authors":"Haojie Li ,&nbsp;Yaoting Xu ,&nbsp;Xinyi Jiang ,&nbsp;Jie Ren ,&nbsp;Yulian Wang ,&nbsp;Xiangzheng Zhang ,&nbsp;Mengmeng Gao ,&nbsp;Longsheng Zhang ,&nbsp;Yue Wang ,&nbsp;Zongze Li ,&nbsp;Suwei Wang ,&nbsp;Tianye Wang ,&nbsp;Mengyi Wang ,&nbsp;Chenghao Situ ,&nbsp;Xuejiang Guo ,&nbsp;Hui Zhu","doi":"10.1016/j.mce.2025.112645","DOIUrl":"10.1016/j.mce.2025.112645","url":null,"abstract":"<div><div>Protein phosphorylation is an important post-translational modification that plays a critical regulatory role in meiosis. HASPIN, a kinase highly conserved from yeast to mammals, is required for male fertility. In this study, we found that the intrinsically disordered N-terminal domain of HASPIN is also required for this function. Mice with deletion of N-terminal amino acids (aa) 1-243 of HASPIN exhibited reduced testicular size, sperm count, and fertility. Using immunoprecipitation-mass spectrometry and phosphoproteomics analysis, we found that HASPIN could interact with AURKA and regulate its phosphorylation at T279 via its N-terminus. Taken together, our results suggest that the N-terminus of HASPIN regulates AURKA kinase activity to affect male fertility.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112645"},"PeriodicalIF":3.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Linolenic acid rich-chia seed improves glucose tolerance, modulates gluconeogenic pathway and hepatic insulin signaling in an experimental model of metabolic syndrome","authors":"Michelle Berenice Vega Joubert ,&nbsp;María Eugenia Oliva ,&nbsp;Paola Ingaramo ,&nbsp;María Eugenia D'Alessandro","doi":"10.1016/j.mce.2025.112643","DOIUrl":"10.1016/j.mce.2025.112643","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as the hepatic manifestation of Metabolic Syndrome. The aim of this work was to evaluate the effects of chia seed, rich in α-linolenic acid, on glucose tolerance, enzyme activities and transcription factors involved in gluconeogenesis, and key molecules in insulin signaling in sucrose-rich diet (SRD) fed rats. Male Wistar rats were fed a reference diet (RD) for 6 months or a SRD for 3 months. Then, the latter group was randomly divided into two subgroups. One subgroup continued receiving SRD for up to 6 months and the other was fed with a SRD where chia seed was incorporated as a source of dietary fat for the next 3 months (SRD + CHIA). The results showed that chia seed improved glucose tolerance, reversed the increase in PEPCK, FBPase, and Glucose-6-Pase, and reduced the Glucose-6-Pase/GK ratio. Additionally, chia seed improved tAMPK and pAMPK protein levels, while maintaining GLUT-2 protein levels similar to those in the RD group. Under insulin stimulation, p-AKT protein levels were higher in the SRD + CHIA group than in the unstimulated group. IRS-1 and PGC-1α protein expression levels were similar among the three experimental groups. Liver FOXO-1 mRNA expression was decreased in the SRD + CHIA group. Finally, chia seed increased the n-3/n-6 ratio in hepatic membrane phospholipids. The present study demonstrated that chia seed modulate multiple mechanisms that enhance glucose metabolism and insulin signaling in SRD fed rats. These effects are mediated, at least in part, by the enrichment of n-3 PUFAs in liver tissue.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112643"},"PeriodicalIF":3.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic modifications in maternal pancreatic islets during the period around weaning in mice","authors":"Xadeni Burgos-Gamez ,&nbsp;Paulina Morales-Castillo ,&nbsp;Alain Hernández-Vázquez ,&nbsp;Karina Pastén-Hidalgo ,&nbsp;Francisco García-Vázquez ,&nbsp;Cristina Fernandez-Mejia","doi":"10.1016/j.mce.2025.112642","DOIUrl":"10.1016/j.mce.2025.112642","url":null,"abstract":"<div><div>Identifying the mechanisms and molecular factors that enhance beta-cell mass is crucial for developing strategies to combat diabetes, as beta-cell mass declines with disease progression. Recent research has indicated an increase in beta-cell proliferation and a significant islet expansion around the weaning period in mice. This study aims to identify transcripts associated with changes in the islets around weaning—a physiological stage previously unexplored in islets. A ribonucleic acid (RNA) sequencing analysis of the transcriptome was performed at four key time points: the end of lactation, when beta-cell proliferation increases; the day of weaning, when the hormonal and metabolic environment transitions from lactation to the non-lactating stage; the third day post-weaning, when islet area peaks, as observed in our prior studies; and in age-matched female control mice. The results revealed dynamic transcriptomic changes. The messenger ribonucleic acid (mRNA) expression levels of genes regulated by prolactin, including its receptor, signaling inhibitor <em>Cish</em>, tryptophan hydroxylase, and osteoprotegerin, increased during lactation and subsequently declined. Plasma prolactin concentrations rose during lactation, but plasma osteoprotegerin levels remained stable across groups. Notably, no changes were observed in known prolactin-regulated cyclins that positively influence the cell cycle, such as <em>Ccna2</em>, <em>Ccnb1</em>, and <em>Ccnb2</em>. However, a decrease in the expression of <em>Cdkn1a</em>, a negative regulator of the cell cycle, was noted. Surprisingly, microscopy analysis indicated increased apoptosis markers in islet peripheral cells that were negative for insulin immunostaining. This study is the first to identify transcriptomic and cellular changes around weaning, offering new insights into islet mass plasticity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112642"},"PeriodicalIF":3.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MeCP2 attenuates inflammation and regulates T cell phenotype via SFRP4 suppression in preeclampsia","authors":"Mei Peng ,&nbsp;Yanting Nie ,&nbsp;Ying Luo,&nbsp;Grace Divine Milebe Nkoua,&nbsp;Shaohan Zhang,&nbsp;Hongyu Liu,&nbsp;Wen Zhang,&nbsp;Songyuan Xiao,&nbsp;Yang Zhou,&nbsp;Weisi Lai,&nbsp;Yali Deng,&nbsp;Ling Yu,&nbsp;Jinyu Liu,&nbsp;Xihong Zhou,&nbsp;Yiling Ding","doi":"10.1016/j.mce.2025.112637","DOIUrl":"10.1016/j.mce.2025.112637","url":null,"abstract":"<div><div>Preeclampsia (PE) is a major pregnancy complication characterized by an aberrant immune response. Methyl CpG binding protein 2 (MeCP2) is a potential regulator of secreted frizzled-related protein 4 (SFRP4), and both MeCP2 and SFRP4 are implicated in immune homeostasis. This study investigated the regulatory role of MeCP2/SFRP4 in immune cells in PE. A rat model of PE induced by reduced uterine perfusion pressure (RUPP) and an <em>in vitro</em> model using lipopolysaccharide (LPS)-stimulated HTR-8/SVneo cells were established. A co-culture system of LPS-challenged HTR-8/SVneo cells and T cells was also employed. MeCP2 expression was reduced and inversely correlated with SFRP4 levels in PE. MeCP2 overexpression suppressed Th1/Th17 differentiation while promoting Th2/Treg phenotypes, along with modulation of associated immune cytokines. It also enhanced colony formation, proliferation, migration, and invasion, while reducing apoptosis following co-culture. SFRP4 supplementation reversed the effects of MeCP2 overexpression on T cell proliferation and cytokine release. Collectively, these findings suggest that MeCP2 regulates T cell phenotype and inflammatory responses by inhibiting SFRP4, providing potential avenues for immunotherapeutic intervention in PE.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112637"},"PeriodicalIF":3.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose tissue-specific Yap knockout exacerbates diet-induced obesity through suppression of lipolysis","authors":"Huabing Xiao ,&nbsp;Ping Jiang ,&nbsp;Fan Xia ,&nbsp;Dayu Wu ,&nbsp;Hui Huang ,&nbsp;Sihui Tu ,&nbsp;Huilan Luo ,&nbsp;Yiling Wu ,&nbsp;Qiong Duan ,&nbsp;Lingyan Zhu","doi":"10.1016/j.mce.2025.112631","DOIUrl":"10.1016/j.mce.2025.112631","url":null,"abstract":"<div><h3>Background and aims</h3><div>YAP regulates various cellular processes, including cell contact inhibition, mechanotransduction, cell differentiation and proliferation, apoptosis, and cancer progression. Although YAP suppresses adipogenesis <em>in vitro</em>, its role in obesity has not yet been completely elucidated.</div></div><div><h3>Methods and results</h3><div>In this study, we generated an adipose tissue-specific <em>Yap</em> knockout mouse model (<em>Yap</em>aKO), and found that male, but not female, <em>Yap</em>aKO mice showed an enhanced high-fat diet-induced obesity phenotype compared to control mice. Mechanistically, this effect is potentially due to suppressed lipolytic activity, which results from the decreased expression of triglyceride lipolytic enzymes, including ATGL and HSL. The inhibition of lipolytic activity led to reduced levels of circulating free fatty acids during fasting, making male mice unable to maintain core body temperature after cold exposure and showing impaired exercise capability in the fasted state. This study reveals a novel role of YAP in controlling lipolysis.</div></div><div><h3>Conclusion</h3><div>YAP is a physiological regulator of lipolysis in the adipose tissue. YAP activation in adipose tissue may facilitate lipolysis and reduce obesity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112631"},"PeriodicalIF":3.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of sex: the role of DNA methylation and zbtb38 in zebrafish sex differentiation and heat-induced masculinization","authors":"Fabien Pierron,&nbsp;Débora Heroin,&nbsp;Flore Daramy","doi":"10.1016/j.mce.2025.112636","DOIUrl":"10.1016/j.mce.2025.112636","url":null,"abstract":"<div><div>There is increasing evidence that global change can threaten biodiversity by inducing skewed sex ratios. Accumulating evidences support a role of epigenetics, mainly DNA methylation, in sex differentiation. The aim of the present work was to investigate the potential role of <em>zbtb38,</em> a transcriptional factor that binds to methylated promoters, in sex differentiation and/or maintenance in zebrafish. We analyzed the methylation and transcription level of <em>zbtb38</em> in males, females and undifferentiated individuals raised at standard or high temperature, a masculinizing factor. Results were compared to those obtained for genes already known to be involved in sex differentiation/maintenance (<em>cyp19a1a</em>, <em>foxl2a</em>, <em>dmrt1</em>). All genes presented a sex-specific pattern of DNA methylation and transcription but the most significant differences between sexes were observed for <em>zbtb38</em>. Moreover, a highly significant positive correlation was observed between the methylation level of <em>zbtb38</em> and <em>cyp19a1a</em>, which encodes an enzyme that converts androgens into estradiol. However, while the hypermethylation of <em>cyp19a1a</em> was associated with its down-regulation, an inverse relationship was observed for <em>zbtb38</em>, providing a basis for mutual antagonism. Furthermore, <em>zbtb38</em> was the only gene for which its transcription level was affected by temperature, being up-regulated in females that escaped to masculinization. Finally, despite embryos presented a paternal methylome, <em>zbtb38</em> was the only gene for which its methylation level rapidly changed during early development to reach intermediate values between males and females at the larval stage, ie a bi-potential state. Our results strongly support a strategic role of DNA methylation and <em>zbtb38</em> in sex differentiation and maintenance.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112636"},"PeriodicalIF":3.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}