Molecular and Cellular Endocrinology最新文献

{"title":"Selective steroid receptor modulators, degraders and PROTACs: Therapeutic strategies in management of endocrine-related cancers","authors":"Anjali Tripathi,&nbsp;Ayushi Chhabra,&nbsp;Sheeba Rizvi,&nbsp;Rakesh K. Tyagi","doi":"10.1016/j.mce.2025.112569","DOIUrl":"10.1016/j.mce.2025.112569","url":null,"abstract":"<div><div>Endocrine-related disorders are highly prevalent globally, affecting millions of people. Such diseases are multifactorial in origin and are influenced by the complex interplay of genetics, lifestyle, and environmental factors. Recurring disruptions in the endocrine homeostasis can lead to a cascade of endocrine-related cancers. It is well known that nuclear receptors (NRs), particularly estrogen receptor and androgen receptor malfunctioning promote the oncogenesis of breast cancer and prostate cancer, respectively. However, existing therapeutics against these diseases, including aromatase inhibitors, (anti-) hormonal therapy, etc., often yield limited success, prompting to explore alternative methods of disease management. Additionally, drug resistance is prominent in cancer patients undergoing multidrug therapy. Currently, novel drug design strategies targeting NRs are being implemented for the discovery of a new generation of small molecule modulators, including selective NR modulators (SNuRMs) and degraders (SNuRDs). Moreover, proteolysis-targeting chimeras (PROTACs) as NR degraders, are also being developed primarily to overcome drug resistance, enhance protein selectivity, and mitigate off-target toxicity. This review highlights recent advancements in SNuRMs and SNuRDs for managing NRs-associated endocrine/metabolic disorders. Furthermore, we discuss the therapeutic potential of PROTAC degraders as a stand-alone strategy for receptor-mediated disease intervention, offering new avenues for precision medicine.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112569"},"PeriodicalIF":3.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937484","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":"Estrogen increases Setdb1 cytoplasmic localization to stabilize Serpinh1 and improve protein homeostasis in osteoblasts","authors":"Chunqing Han ,&nbsp;Peiwen Wang ,&nbsp;Junxing Ye ,&nbsp;Ruijian Wang ,&nbsp;Xian Shi ,&nbsp;Guoqin Hu ,&nbsp;Xiping Hu ,&nbsp;Jin Shen ,&nbsp;Mengqing Zhang ,&nbsp;Xian Zhang ,&nbsp;Yu Wu","doi":"10.1016/j.mce.2025.112568","DOIUrl":"10.1016/j.mce.2025.112568","url":null,"abstract":"<div><div>Estrogen regulates osteoblast activity at the epigenetic level. Setdb1 is an epigenetic regulator that functions in skeleton homeostasis maintenance. Setdb1 shows nuclear and cytoplasm localization in cells; however, the subcellular distribution of Setdb1 and the role of cytoplasmic Setdb1 in osteoblasts are largely unknown. Here, immunofluorescence staining and immunoblotting analysis showed that the distribution of Setdb1 in the cytoplasm increased upon β-estradiol treatment by increasing nuclear Setdb1 stability in osteoblasts. In β-estradiol-treated MC3T3-E1 cells, knocking-down Atf7ip expression enhanced Setdb1 cytoplasmic localization, but the cytoplasmic distribution of Setdb1 decreased in cells treated with the Setdb1 inhibitor (R,R)-59. Moreover, ovariectomized (OVX) mice lacking Atf7ip in mature osteoblasts showed better bone microstructure than the OVX controls. The proteomic analysis of the cytoplasmic binding of Setdb1 showed that cytoplasmic Setdb1 in osteoblasts mainly functioned to regulate protein homeostasis. Setdb1 binds to Serpinh1, a regulator of pro-collagen folding and maturation, and enhances Serpinh1 stability. Interrupting Setdb1 cytoplasmic localization by treating the cells with Leptomycin B (LMB) or (R,R)-59 led to an accumulation of unfolded protein and the elicitation of endoplasmic reticulum (ER) stress. The findings revealed a previously unrecognized role of cytoplasmic Setdb1 in the regulation of β-estradiol-mediated osteoblast homeostasis, which could enhance the understanding of estrogen's mechanism of action in regulating osteoblasts.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112568"},"PeriodicalIF":3.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928512","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":"Interactive effects of light at night and high fructose intake on the central circadian clock and endocrine outputs in rats","authors":"Michal Zeman ,&nbsp;Peter Stefanik ,&nbsp;Valentina Sophia Rumanova ,&nbsp;Monika Okuliarova","doi":"10.1016/j.mce.2025.112559","DOIUrl":"10.1016/j.mce.2025.112559","url":null,"abstract":"<div><div>Light pollution is an increasing global environmental risk factor that contributes to the recent burden of metabolic diseases. The underlying mechanisms are not understood, but disruption of circadian control of physiological and behavioural processes may be involved. The negative consequences of chronodisruption can be augmented by co-exposure to high energy intake. Therefore, we investigated the individual and combined effects of artificial light at night (ALAN) and 10 % fructose in drinking water on the central clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and circadian hormonal outputs in male rats. After 10 weeks of ALAN exposure and high fructose intake, the clockwork in the SCN was attenuated as indicated by eliminated day/night differences in the core clock gene <em>Per1</em>. Additionally, ALAN suppressed the daily variability and fructose induced upregulation of a gamma-aminobutyric acid–synthesising enzyme (GAD65), potentially affecting inhibitory neurotransmission in the SCN. ALAN and fructose additively inhibited plasma melatonin levels revealing excessive fructose intake as a chronodisruptive factor that can be potentiated by ALAN. In contrast to melatonin, daytime plasma testosterone concentrations were increased by high fructose and supressed by ALAN. Furthermore, high fructose intake elevated the plasma levels of two adipokines, leptin and adiponectin, but this response was absent specifically during the daytime in rats exposed to ALAN, indicating that ALAN reduced adipose tissue responsiveness. Our results document the complex consequences of ALAN and high fructose intake on endocrine control mechanisms that can have a long-term negative impact on metabolic health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112559"},"PeriodicalIF":3.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898846","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 environmental contaminants, tributyltin and bisphenol S, alone or in combination, harm the hypothalamus-pituitary-gonadal axis and uterus","authors":"Denilson de Sousa Anselmo ,&nbsp;Damáris Barcelos Cunha Azeredo ,&nbsp;Reinaldo Röpke Junior ,&nbsp;Luana Lopes de Souza ,&nbsp;Patrícia Cristina Lisboa ,&nbsp;Jones Bernardes Graceli ,&nbsp;Lycia de Brito Gitirana ,&nbsp;Andrea Claudia Freitas Ferreira ,&nbsp;Francisca Diana Paiva-Melo ,&nbsp;Leandro Miranda-Alves","doi":"10.1016/j.mce.2025.112558","DOIUrl":"10.1016/j.mce.2025.112558","url":null,"abstract":"<div><div>Endocrine disrupting-chemicals (EDCs) are chemical compounds found in the environment that can have adverse impacts on human health. Among these agents are tributyltin (TBT) and bisphenol S (BPS). TBT is used in anti-fouling paints, and its indiscriminate use has health repercussions. BPS is found in plastic products and marketed as a safe alternative to bisphenol A (BPA). Little is known about the effects resulting from interactions between different EDCs on the organisms. The aim of this study was to analyze changes induced by exposure to these compounds in hypothalamic-pituitary-gonadal (HPG) axis and uterus. We divided four groups: Control, TBT 100 ng kg⁻¹.day⁻¹, BPS 50 μg kg⁻¹.day⁻¹, and the group simultaneously exposed to TBT and BPS. Rats were gavaged for 15 days and euthanized in the estrus phase. All EDCs groups showed uterus with cellular hyperplasia, glandular degeneration, increased epithelial thickness, and vacuolization. In the ovaries, there was an increase in atretic follicles in all EDCs groups. In the hypothalamus, the group exposed to the mixture showed an increase in the <em>GnRH</em> gene. In the blood, all EDCs groups had reduced levels of FSH and LH. Additionally, the BPS and mixture groups exhibited reduced levels of prolactin. Therefore, we suggest that exposure to these agents may contribute to damage to the female reproductive system, and that doses considered safe by regulatory agencies need to be reassessed.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112558"},"PeriodicalIF":3.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916551","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":"Pleiotropic signaling of single-chain thyrostimulin (GPB5-GPA2) on homologous glycoprotein hormone receptors (ScFSHR, ScLHR, ScTSHR) in the elasmobranch Scyliorhinus canicula reproduction","authors":"Fabian Jeanne ,&nbsp;Stanislas Pilet ,&nbsp;Yves Combarnous ,&nbsp;Benoît Bernay ,&nbsp;Sylvie Dufour ,&nbsp;Pascal Favrel ,&nbsp;Pascal Sourdaine","doi":"10.1016/j.mce.2025.112553","DOIUrl":"10.1016/j.mce.2025.112553","url":null,"abstract":"<div><div>The pituitary glycoprotein hormones (GPHs) control several physiological processes in vertebrates such as reproduction and metabolism. They include the luteinizing hormone (LH), the follicle-stimulating hormone (FSH), and the thyroid-stimulating hormone (TSH), which activate their cognate leucine-rich repeat G protein-coupled receptors (LGRs), LHR, FSHR, and TSHR. Each GPH consists of a common α subunit and a specific βFSH, βLH or βTSH subunit. More recently, two supplementary GPH proteins, GPA and GPB, were identified in nearly all bilaterians and are the ancestors of the pituitary GPH α- and β-subunits, respectively. Chondrichthyans (holocephalans and elasmobranchs), the sister group of bony vertebrates, are the most ancient clade to possess diversified GPH subunits. In the present study, GPA2, GPB5, TSHβ2, but not TSHβ1, and TSHR sequences have been identified in several elasmobranch genomes, and their 3D models were analyzed. Functional hormone-receptor interactions were studied in the small-spotted catshark (<em>Scyliorhinus canicula</em>) and showed that conditioned media from cells expressing the recombinant single-chain <em>Sc</em>GPB5-<em>Sc</em>GPA2 were more effective than independent subunits in activating <em>Sc</em>TSHR, <em>Sc</em>FSHR, and <em>Sc</em>LHR. Expression profiles were analyzed by real-time PCR, <em>in situ</em> hybridization, and immunohistochemistry along the male genital tract, other male and female tissues, and female tissues. A broader tissue distribution expression was observed for <em>tshr</em> and <em>gpa2</em> than for <em>gpb5,</em> which was mainly observed in the testes. In testis, expression of <em>tshr</em> and <em>gpb5</em> by Sertoli cells and of <em>gpa2</em> by germ cells suggested paracrine/autocrine functions of GPA2/GPB5/GPHR signaling during spermatogenesis. This study complements the data on GPA2 and GPB5 by studying a chondrichthyan of phylogenetic interest for understanding the evolution of endocrine regulation in vertebrates.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"604 ","pages":"Article 112553"},"PeriodicalIF":3.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864064","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":"Impact of BPA and its analogs on sperm hyperactivity, acrosome reaction, epigenetic profiles and in vitro embryo development","authors":"Ola S. Davis ,&nbsp;Olivia L.M. Scandlan ,&nbsp;Erica A. Potestio ,&nbsp;Catherine Robinson ,&nbsp;Katie D. Hickey ,&nbsp;Mikayla Ross ,&nbsp;Laura A. Favetta","doi":"10.1016/j.mce.2025.112555","DOIUrl":"10.1016/j.mce.2025.112555","url":null,"abstract":"<div><div>Bisphenols, particularly BPA, are ubiquitous environmental contaminants known to affect male reproductive health. However, their specific impacts on sperm function and subsequent embryo development remain understudied especially for BPA's commonly used replacements, BPS and BPF. This study investigated the effects of direct sperm exposure to BPA, BPS, and BPF on fertilization capacity and embryo development using a bovine model, as translational for humans. Sperm samples were exposed to 0.05 mg/mL of each bisphenol <em>in vitro</em>. Parameters, including hyperactivity and acrosome reaction, as well as fertilization outcomes, such as developmental rates and blastocyst quality, were further evaluated following IVF. miRNA profiles were also analyzed in sperm and embryos to detect potential biomarkers of bisphenol exposure. We found that BPF significantly increased sperm hyperactivity, and BPA decreased acrosome reaction levels (p &lt; 0.05). Cleavage and blastocyst rates were also notably decreased in embryos derived from BPA-exposed sperm (p &lt; 0.05). Furthermore, blastocysts produced from BPA, BPS and BPF treated sperm all had significantly lower cell counts and increased DNA fragmentation (p &lt; 0.05). Although no statistically significant changes in miRNA levels were observed, this study highlights some of the detrimental effects of bisphenols on bovine sperm and subsequent embryo development, with potential implications for human reproductive health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"604 ","pages":"Article 112555"},"PeriodicalIF":3.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873279","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":"5,7,3′,4′,5′-pentamethoxyflavone (PMF) exhibits anti-obesity and neuroprotective effects in an obese zebrafish model","authors":"Muhammad Sufyan Vohra ,&nbsp;Bilal Ahmad ,&nbsp;Emerald R. Taylor ,&nbsp;Khaled Benchoula ,&nbsp;Isabel Lim Fong ,&nbsp;Ishwar S. Parhar ,&nbsp;Satoshi Ogawa ,&nbsp;Christopher J. Serpell ,&nbsp;Eng Hwa Wong","doi":"10.1016/j.mce.2025.112554","DOIUrl":"10.1016/j.mce.2025.112554","url":null,"abstract":"<div><div>Obesity is a multi-chronic illness characterized by superfluous fat accumulation, contributing to significant metabolic and neurological complications. Current therapeutic approaches have limited efficacy and notable side effects, underscoring an urgent demand for novel, safer alternatives. This study is the first to investigate the anti-obesity potential of 5,7,3′,4′,5′-pentamethoxyflavone (PMF) <em>in vivo</em> using a zebrafish model. Our findings demonstrate that PMF administration exerts pronounced anti-obesogenic effects, evidenced by reductions in blood glucose, plasma triglycerides, total cholesterol, hepatic low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Mechanistically, PMF suppressed hepatic adipogenic and lipogenic gene expression while promoting lipid catabolism through activation of peroxisome proliferator-activated receptor-alpha (PPAR-α) and its downstream enzymes, including acyl-CoA oxidase 1 (ACOX1), medium-chain acyl-CoA dehydrogenase (ACADM), and carnitine palmitoyl transferase 1B (CPT-1β). Additionally, PMF markedly mitigated oxidative stress by lowering malondialdehyde (MDA) and nitric oxide (NO) levels, accompanied by increased antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione S-transferase (GST). Notably, PMF effectively prevented obesity by suppressing food intake, downregulating orexigenic genes, and enhancing anorexigenic signals. Furthermore, PMF exhibited neuroprotective properties by elevating brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B2 (TrkB2), revealing a novel link between metabolic and neurological regulation. This study provides pioneering, comprehensive <em>in vivo</em> evidence supporting PMF as a promising therapeutic candidate with dual beneficial roles in metabolic health and neuroprotection.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"604 ","pages":"Article 112554"},"PeriodicalIF":3.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852047","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":"Exploratory analysis of differences at the transcriptional interface between the maternal and fetal compartments of the sheep placenta and potential influence of fetal sex","authors":"Katherine M. Halloran ,&nbsp;Nadia Saadat ,&nbsp;Brooke Pallas ,&nbsp;Arpita K. Vyas ,&nbsp;Vasantha Padmanabhan","doi":"10.1016/j.mce.2025.112546","DOIUrl":"10.1016/j.mce.2025.112546","url":null,"abstract":"<div><div>An understanding of the inner workings of the placenta is imperative to elucidate how the maternal and fetal compartments coordinate to mediate fetal development. The two compartments can be separated and studied before term in sheep, a feat not possible in humans, thus providing a valuable translational model. This study investigated differential expression of gene signaling networks in the maternal and fetal compartments of the placenta and explored the potential influence of fetal sex. On approximately gestational day 120 (term: 147 days), ewes were euthanized and fetuses removed and sexed. Placentomes [n = 5 male, n = 3 female] were collected, and caruncles (maternal) and cotyledons (fetal) were separated and sequenced to assess RNA expression. Analysis revealed 2627 differentially expressed genes (FDR&lt;0.01, abslog2FC ≥ 2) contributing to key transcriptional differences between maternal and fetal compartments, which suggested that the maternal compartment drives extracellular signaling at the interface whereas the fetal compartment controls internal mechanisms crucial for fetal-placental development. X-chromosome inactivation equalized expression of a vast majority of X-linked genes in the fetal compartment. Additionally, the female placenta had more fine-tuned regulation of key pathways for fetal-placental development, such as DNA replication, mRNA surveillance, and RNA transport, compared to males, which had enrichment of metabolic pathways including TCA cycle and galactose metabolism. These findings, in addition to supporting differences in expression in the maternal and fetal placental compartments and the possible influence of fetal sex, offer a transcriptional platform to compare placental perturbations that occur at the maternal-fetal interface that contribute to adverse pregnancy outcomes.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"603 ","pages":"Article 112546"},"PeriodicalIF":3.8,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826134","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":"N-acetylcysteine influence on PI3K/Akt/mTOR and sphingolipid pathways in rats with MASLD induced by HFD: a promising new therapeutic purpose","authors":"Klaudia Sztolsztener,&nbsp;Daniel Michalak,&nbsp;Adrian Chabowski","doi":"10.1016/j.mce.2025.112545","DOIUrl":"10.1016/j.mce.2025.112545","url":null,"abstract":"<div><div>Sphingolipid and glucose metabolism play important roles in the induction and progression of severe liver disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). The perturbation in sphingolipid formation may improve the liver structure and functioning and may constitute the potential therapeutic options for the development of simple steatosis and its progression to steatohepatitis. This study aims to assess the influence of N-acetylcysteine (NAC) on the sphingolipid and insulin signaling pathways in rats subjected to standard or high-fat diets. Sphingolipid level was measured using high-performance liquid chromatography (HPLC). A multiplex assay kit determined the level of phosphorylated form of proteins included in the PI3K/Akt/mTOR pathway. The immunoblotting estimated the expression of proteins from sphingolipid and insulin transduction pathways. A histological Oil red O staining was used to assess the hepatic accumulation of lipid droplets. Molecular docking was applied to showcase NAC interaction with PI3K/Akt/mTOR pathway proteins. NAC decreased dihydroceramide and ceramide levels and increased phosphorylation of sphingosine and sphinganine. This antioxidant also enhanced phosphorylated Akt, GSK3α/β, and P70 S6 kinase and decreased phosphorylated S6RP. In silico docking analysis of insulin signaling molecules evidenced the higher binding affinity of NAC with all tested proteins, i.e., IRS1, PTEN, Akt, GSK3α/β, P70 S6 kinase, and S6RP, suggesting a potential protective influence on insulin resistance development, which is one of the criteria for MASLD diagnosing. Based on these data, NAC improved the hepatic insulin sensitivity and sphingolipid synthesis and storage, improving and restoring glucose homeostasis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"603 ","pages":"Article 112545"},"PeriodicalIF":3.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826135","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":"Maternal dopamine agonist treatment before pregnancy reverses infertility and hyperprolactinemia in hCG-overexpressing mice through lactation: Evidence of generational effects","authors":"Laura D. Ratner ,&nbsp;Agustina Marcial Lopez ,&nbsp;Noelia P. Di Giorgio ,&nbsp;Matti Poutanen ,&nbsp;Ilpo Huhtaniemi ,&nbsp;Susana B. Rulli","doi":"10.1016/j.mce.2025.112538","DOIUrl":"10.1016/j.mce.2025.112538","url":null,"abstract":"<div><div>Dopamine agonists, such as cabergoline (Cab), have demonstrated efficacy in restoring reproductive function in cases of hyperprolactinemia and hormonal dysregulation. This study investigates the long-term consequences of maternal Cab treatment on the reproductive phenotype of the progeny in a female transgenic (TG) mouse model with hyperprolactinemia and infertility due to human chorionic gonadotropin (hCG) β-subunit overexpression. The TG females that received Cab between weeks 3–4 of life exhibited a reversion of hyperprolactinemia and infertility, whereas WT females retained their fertility. When TG-cab- or WT-Cab-treated females were crossed with WT or TG males, respectively, their female TG offspring showed a reversal of precocious puberty, regularization of estrous cycles, fertility, and prevention of hyperprolactinemia and prolactinomas. Despite the persistent high LH/hCG bioactivity, the normalization of prolactin levels led to a reduction in ovarian luteinization markers and progesterone levels. The TG female pups born to either WT-cab- or TG-cab-treated females exhibited a normalized phenotype, thus suggesting that the effects were indeed due to maternal Cab administration, and not to the transgene. Cross-fostering experiments showed that the long-lasting programming effect of maternal Cab on offspring occurred during lactation because the TG female pups from non-treated WT female/TG male pregnancies, but nursed by Cab-treated females, were free from the altered TG phenotype. These results suggest that Cab treatment before pregnancy may have a multigenerational effect on the hypothalamic-pituitary-gonadal axis of the offspring, mediated during lactation. This highlights potential implications for generational health and clinical practices regarding the use of dopamine agonists during lactation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"602 ","pages":"Article 112538"},"PeriodicalIF":3.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786203","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}