Molecular and Cellular Endocrinology最新文献_第2页

Estrogen therapies enhance mammary carcinogenesis in aging gerbil females under endocrine disruption 雌激素治疗在内分泌紊乱的老年沙鼠雌性中促进乳腺癌的发生

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-17 DOI: 10.1016/j.mce.2025.112720

Thalles Fernando Rocha Ruiz , Stella Bicalho Silva , Vitor Grigio , Paula Rahal , Marília de Freitas Calmon , Patrícia Simone Leite Vilamaior , Ellen Cristina Rivas Leonel , Sebastião Roberto Taboga

Breast cancer is closely associated with the hormonal sensitization that the mammary gland (MG) undergoes. We evaluated the effects of endogenous (E2) and synthetic (EE2) estrogens, commonly used as hormonal therapies during menopause, in a context of a pro-carcinogenic environment of endocrine disruption. This scenario was modeled to mimic the menopausal involution of the MG during aging in the Mongolian gerbil experimental model under previous bisphenol A exposure, during pregnancy and lactation. Our findings revealed significant remodeling of the epithelial compartment, characterized by increased branching density and loss of normal features, including decreased CD117+ luminal cells and loss of E-cadherin expression. Hormonal therapy with E2 or EE2 led to the development of epithelial lesions, characterized by an increase in invasive microcarcinomas and a decrease in basal (p63+α-SMA-) and myoepithelial (p63+α-SMA+) progenitor cells, contributing to increased neoplastic invasiveness. These changes were orchestrated by overexpression of EZH2 and a decrease in BRCA1, indicating a poor prognosis, especially for EE2. Furthermore, an imbalance between proliferation (PH-H3⁺ cells) and apoptosis (cleaved caspase 3) was observed in the MG of females treated with E2 and EE2. Additionally, distinct hormone receptor profiles were identified, with consistent upregulation of ERα and concomitant downregulation of ERβ and PR, particularly in EE2-treated MG. These alterations may contribute to the observed dysregulation of proliferation and apoptosis. Our results demonstrate that estrogenic hormonal therapies promote neoplastic progression of the aging MG previously subjected to endocrine disruption.

乳腺癌与乳腺（MG）经历的激素致敏密切相关。我们评估了内源性（E2）和合成（EE2）雌激素在内分泌干扰的促致癌环境中的作用，这两种雌激素通常用于绝经期间的激素治疗。这一情景模拟了蒙古沙鼠实验模型在怀孕和哺乳期间暴露于双酚A下衰老过程中MG的更年期退化。我们的研究结果揭示了上皮室的显著重塑，其特征是分支密度增加和正常特征的丧失，包括CD117+腔细胞的减少和E-cadherin表达的丧失。E2或EE2激素治疗可导致上皮病变的发展，其特征是浸润性微癌增加，基底（p63+α-SMA-）和肌上皮（p63+α-SMA+）祖细胞减少，导致肿瘤侵袭性增加。这些变化是由EZH2的过表达和BRCA1的减少引起的，表明预后较差，特别是对于EE2。此外，E2和EE2在雌性MG细胞中观察到增殖（PH-H3+细胞）和凋亡（裂解caspase 3）之间的不平衡。此外，还发现了不同的激素受体谱，ERα持续上调，ERβ和PR同时下调，特别是在ee2处理的MG中。这些改变可能导致观察到的增殖和凋亡的失调。我们的研究结果表明，雌激素激素治疗促进了先前受到内分泌干扰的衰老MG的肿瘤进展。

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引用次数: 0

Endocrine programming of the pituitary–thyroid–adrenal axis: Sex-Specific effects of maternal malnutrition in rats 垂体-甲状腺-肾上腺轴的内分泌编程：大鼠母体营养不良的性别特异性影响。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-15 DOI: 10.1016/j.mce.2025.112715

Ana Lívia Silvério Vieira, Gustavo Monezzi Cordeiro, Vinicius Alexandre de Andrade Felipe, Matheus Naia Fioretto, Luísa Annibal Barata, Marina Pereira Pires, Pedro Menchini Vitali, Renato Mattos, Isabelle Tenori Ribeiro, Flávia Alessandra Maciel, Hecttor Sebastian Baptista, Luis Antonio Justulin

The Developmental Origins of Health and Disease (DOHaD) concept highlights that early-life development can be influenced by environmental factors, leading to long-term metabolic programming in the offspring. Maternal Protein Restriction (MPR) is a well-established model within this framework, inducing cellular stress and hormonal imbalances that disrupt basal metabolic regulation in descendants. We aim to investigate the consequences of MPR (6 %) on the metabolism and the pituitary-thyroid-adrenal axis of male and female postweaning rats. Systemically, there was a decrease in hormones T3 and T4 in the males and a decrease in T4 in the females. In the pituitary, we observed an increase in the Ppar a, Ppar g, and Neurod1 gene expression and a decrease in the Prl gene in the males of the GLLP group, while females exhibited a decrease in the Pomc and Ir gene expression. In the thyroid, male rats showed an increase in the Tshr and Ar gene expression. In gene expression of adrenal glands, we observed an increase in the expression of the Sts gene in males and a decrease in Cyp21a2 and Mao in females. In silico analyses demonstrated the potential sex-specific disturbance of MPR, mainly on developmental biology, endocrine response, endoplasmic reticulum, and endocytic pathways, indicating a risk scenario for endocrine diseases. Therefore, we conclude that MPR directly affects the early functioning of the pituitary–thyroid–adrenal axis in a sex-specific manner, highlighting its role in metabolic programming and the developmental origins of endocrine disorders.

健康和疾病的发育起源（DOHaD）概念强调，生命早期的发育可以受到环境因素的影响，从而导致后代的长期代谢程序。母体蛋白限制（MPR）在这一框架内是一个成熟的模型，诱导细胞应激和激素失衡，破坏后代的基础代谢调节。我们的目的是研究MPR（6%）对雄性和雌性断奶后大鼠的代谢和垂体-甲状腺-肾上腺轴的影响。全身范围内，男性的T3和T4激素水平下降，女性的T4水平下降。在垂体中，我们观察到GLLP组男性的Ppar a、Ppar g和Neurod1基因表达增加，Prl基因表达减少，而女性的Pomc和Ir基因表达减少。在甲状腺中，雄性大鼠Tshr和Ar基因表达增加。在肾上腺的基因表达中，我们观察到雄性中Sts基因的表达增加，而雌性中Cyp21a2和Mao基因的表达减少。计算机分析显示MPR的潜在性别特异性干扰，主要在发育生物学、内分泌反应、内质网和内吞途径上，表明内分泌疾病的风险情景。因此，我们得出结论，MPR以性别特异性的方式直接影响垂体-甲状腺-肾上腺轴的早期功能，突出其在代谢编程和内分泌疾病的发育起源中的作用。

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引用次数: 0

Role of FKBP5 in adipose tissue function: Implications for obesity and insulin sensitivity FKBP5在脂肪组织功能中的作用：对肥胖和胰岛素敏感性的影响。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-13 DOI: 10.1016/j.mce.2025.112718

Rutger Laterveer , Susanne Hetty , Argyri Mathioudaki , Martin H. Lundqvist , Maria K. Svensson , Magnus Sundbom , Petros Katsogiannos , Jan W. Eriksson , Maria J. Pereira

FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue remains unclear. This study investigated the role of FKBP51 in human adipose tissue and its impact on glucose metabolism and insulin signaling. FKBP5 was measured in paired subcutaneous (SAT) and omental (OAT) adipose tissue samples from 56 subjects with and without obesity, and in SAT from individuals with obesity during weight loss up to 104 weeks post-bariatric surgery. Furthermore, FKBP51 knockdown adipocytes were used to study its effects on insulin signaling and glucose uptake. FKBP5 gene expression, but not protein expression, was significantly lower in obese individuals in both SAT and OAT compared to lean and overweight subjects, and it inversely correlated with insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR). After bariatric surgery, FKBP5 expression in SAT increased to levels similar to those in non-obese controls. Knockdown of FKBP5 in human adipocytes reduced GLUT1 gene expression and insulin-stimulated AKT Ser473 phosphorylation, however, maximal insulin-stimulated glucose uptake rate remained unchanged. Our findings suggest that FKBP5 levels in adipose tissue are reduced in obesity, and this decrease impairs insulin signaling in adipocytes without altering maximal glucose capacity, indicating a limited effect on glucose uptake under the tested conditions.

fk506结合蛋白51 （FKBP51，由FKBP5基因编码）是糖皮质激素信号传导的关键调节因子，与代谢和胰岛素敏感性有关，但其在人类脂肪组织中的具体作用尚不清楚。本研究探讨了FKBP51在人脂肪组织中的作用及其对葡萄糖代谢和胰岛素信号传导的影响。FKBP5在56名肥胖和非肥胖受试者的配对皮下（SAT）和网膜（OAT）脂肪组织样本中进行了测量，并在减肥手术后104周的减肥期间测量了肥胖个体的SAT。此外，FKBP51敲低脂肪细胞被用来研究其对胰岛素信号传导和葡萄糖摄取的影响。FKBP5基因表达在SAT和OAT的肥胖个体中显著低于瘦和超重个体，而蛋白表达不显著低于瘦和超重个体，并且与胰岛素抵抗的稳态模型评估（HOMA-IR）测量的胰岛素抵抗呈负相关。减肥手术后，FKBP5在SAT中的表达增加到与非肥胖对照组相似的水平。在人脂肪细胞中，FKBP5的下调降低了GLUT1基因的表达和胰岛素刺激的AKT S473磷酸化，但胰岛素刺激的最大葡萄糖摄取率保持不变。我们的研究结果表明，肥胖患者脂肪组织中的FKBP5水平降低，这种降低会损害脂肪细胞中的胰岛素信号，但不会改变最大葡萄糖容量，这表明在测试条件下，FKBP5对葡萄糖摄取的影响有限。

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引用次数: 0

The in vivo metabolism of 11-oxyandrogens and 11-oxyprogesterones: novel pathways in the steroid metabolome 11-氧雄激素和11-氧孕酮的体内代谢：类固醇代谢组的新途径。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-12 DOI: 10.1016/j.mce.2025.112719

Amanda Cecilia Swart , Bianca Heyns , Martin Kidd , Rialet Pieters , Stephen Lawrence Atkin

The steroid metabolome remains incomplete as the metabolic pathways of the 11-oxyprogestogens and 11-oxyandrogens, biosynthesized in the adrenal and converted in the periphery, have never been characterized in vivo.

This study aims to identify these 11-oxy steroids in the human hair follicle. Hair segments provide a matrix representing one month of steroid production, unaffected by the circadian rhythm. Steroids were extracted from 37 segments using a novel automated method, and 52 steroids were analyzed using ultra-performance convergence chromatography-tandem mass spectrometry.

Quantification of intermediates and end-products of 11-hydroxyprogesterone, 21-deoxycortisol, 11-hydroxyandrostenedione and 11-hydroxytestosterone identified nine novel 11-oxy steroids and showed: 11-hydroxyprogesterone metabolites >21-deoxycortisol metabolites: 170–1400 v. 190–540 pg/mg; 11-oxyandrogens > classical androgens: 600–1500 v. 110–350 pg/mg; active 11-oxyandrogens > active classical androgens: in females, 36.5 v. 1.3 pg/mg, and in males, 60.75 v. 11.7 pg/mg. The most abundant active androgen in both genders was 11-hydroxydihydrotestosterone; 11-ketodihydrotestosterone was detected in males only; 11-hydroxytestosterone levels were comparable, and 11-ketotestosterone levels were higher in males. The most abundant 11-oxyprogestogens in both genders were 11-ketoprogesterone (55.7–2173.8 pg/mg) and two metabolites, 11-oxo-17-hydroxyallopregnanolone (11KPdione) and 11,17-dihydroxyallopregnanolone (11OHPdiol). Metabolites included the neurosteroid, alfaxalone (11-ketoallopregnanolone), and another potential neurosteroid 11-hydroxyallopregnanolone.

This is the first targeted study profiling the 11-oxyandrogens and the 11-oxyprogestogens and their respective metabolites in humans. Novel in vivo steroidogenic pathways have been confirmed, not necessarily linked to clinical conditions, having utility in clinical diagnostics reliant on the steroid metabolome.

类固醇代谢组仍然不完整，因为11-羟孕激素和11-羟雄激素的代谢途径，在肾上腺中生物合成并在外周转化，从未在体内被表征。本研究旨在鉴定人类毛囊中这些11-氧基类固醇。毛发片段提供了一个矩阵，代表一个月的类固醇生产，不受昼夜节律的影响。使用新型自动化方法从37个片段中提取类固醇，并使用超高性能收敛色谱-串联质谱法分析52种类固醇。11-羟孕酮、21-去氧皮质醇、11-羟基雄烯二酮和11-羟睾酮的中间体和终产物定量鉴定了9种新的11-羟类固醇，并显示：11-羟孕酮代谢物> 21-去氧皮质醇代谢物：170-1400 vs . 190-540 pg/mg；11-氧雄激素>经典雄激素：600-1500 v 110-350 pg/mg；活性11-氧雄激素>活性经典雄激素：女性为36.5 v. 1.3 pg/mg，男性为60.75 v. 11.7 pg/mg。两性中活性雄激素含量最高的是11-羟基二氢睾酮；11-酮二氢睾酮仅在男性中检测到；11-羟睾酮水平比较，男性11-酮睾酮水平较高。11-羟孕酮在两性中含量最高的是11-酮孕酮（557 -2173.8 pg/mg）和两种代谢物11-氧-17-羟基异孕酮（11KPdione）和11,17-二羟基异孕酮（11OHPdiol）。代谢物包括神经类固醇，alfaxone（11-酮异孕酮）和另一种潜在的神经类固醇11-羟基异孕酮。这是第一次有针对性地研究11-氧雄激素和11-氧孕激素及其在人体内的代谢产物。新的体内类固醇生成途径已被证实，不一定与临床条件相关，在依赖类固醇代谢组的临床诊断中具有实用性。

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引用次数: 0

CD36 may regulate glycolytic and steroidogenic processes but not the fatty acid uptake in bovine granulosa cells CD36调节牛颗粒细胞的糖酵解和类固醇生成过程，但不调节脂肪酸摄取。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-11 DOI: 10.1016/j.mce.2025.112717

Xuelian Tao, Marten Michaelis, Julia Brenmoehl, Jens Vanselow, Vijay Simha Baddela

Postpartum metabolic stress increases non-esterified fatty acid (NEFA) concentration in follicular fluid, thereby impairing oocyte and granulosa cell (GC) function. CD36, a multifunctional scavenger receptor, is involved in the uptake of NEFAs in various cell types. This study examines lipid droplet (LD) accumulation and CD36 expression in GCs treated with oleate (OA), palmitate (PA), stearate (SA), and their combination. We also explored the role of CD36 in lipid uptake, glucose metabolism, and steroidogenesis in GCs. Flow cytometry analysis revealed that SA, OA, and the combined NEFA treatments resulted in significant LD accumulation, while PA had a minimal effect. Interestingly, CD36 expression mirrored the levels of LD accumulation in all treatments. However, SLC27A1, another highly expressed NEFA transporter, was upregulated by SA but was unchanged by PA and OA treatments. Combination of OA, PA, and SA has increased both CD36 and SLC27A1 expression. OA treatment induced a dose-dependent increase in LD accumulation and CD36 expression. However, CD36 knockdown did not affect either LD accumulation or triglyceride levels, indicating that CD36 is not essential for NEFA uptake, despite its increased expression. Previously, we showed that OA enhances glycolysis in GCs; here, we found that CD36 is involved in glucose metabolism as its silencing significantly reduced the extracellular acidification rate and mitochondrial membrane potential in GCs. Furthermore, CD36 knockdown significantly reduced progesterone production. These findings suggest that while CD36 is dispensable for NEFA uptake, it may play a regulatory role in maintaining glycolytic activity, mitochondrial function, and steroidogenesis in GCs under elevated NEFA levels.

产后代谢应激增加卵泡液中非酯化脂肪酸（NEFA）浓度，从而损害卵母细胞和颗粒细胞（GC）功能。CD36是一种多功能清道夫受体，参与多种细胞对nefa的摄取。本研究检测了油酸酯（OA）、棕榈酸酯（PA）、硬脂酸酯（SA）及其组合处理的gc中脂滴（LD）的积累和CD36的表达。我们还探讨了CD36在GCs中脂质摄取、葡萄糖代谢和类固醇生成中的作用。流式细胞术分析显示，SA、OA和NEFA联合治疗导致LD显著积累，而PA的影响很小。有趣的是，CD36的表达反映了所有处理中LD积累的水平。然而，另一种高表达的NEFA转运蛋白SLC27A1被SA上调，但在PA和OA处理下没有变化。OA、PA和SA联合使用可增加CD36和SLC27A1的表达。OA处理诱导LD积累和CD36表达的剂量依赖性增加。然而，CD36敲低并不影响LD积累或甘油三酯水平，这表明尽管CD36的表达增加，但它并不是NEFA摄取所必需的。之前，我们发现OA增强了GCs的糖酵解；在这里，我们发现CD36参与葡萄糖代谢，因为它的沉默显著降低了GCs的细胞外酸化速率和线粒体膜电位。此外，CD36敲除显著减少黄体酮的产生。这些发现表明，虽然CD36对于NEFA的摄取是不可缺少的，但在NEFA水平升高的情况下，它在维持糖酵解活性、线粒体功能和GCs的类固醇生成方面发挥着调节作用。

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引用次数: 0

Bone marrow transplantation attenuates inflammation and improves glycemic control in type 2 non-obese diabetic Goto-Kakizaki rats 骨髓移植减轻2型非肥胖糖尿病Goto-Kakizaki大鼠的炎症并改善血糖控制

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-11 DOI: 10.1016/j.mce.2025.112716

João Carlos de Oliveira Borges , Ilana Souza Correa , Gabriela Mandú Gimenes , Liliane de Araújo Ferreira , Maria Andréa Rodrigues de Moura Silva , Janaina Ribeiro Barbosa Pauferro , Tiago Bertola Lobato , Amara Cassandra dos Anjos Alves , Ana Carolina Gomes Pereira , Karolayne Oliveira Souza , Camila Soares dos Santos , Adriana Cristina Levada- Pires , Tania Cristina Pithon-Curi , Gabriel Nasri Marzuca-Nassr , Sandro Massao Hirabara , Rui Curi , Renata Gorjão , Laureane Nunes Masi

Chronic hyperglycemia induces changes in the bone marrow (BM) microenvironment, favoring the expansion and differentiation of stem cells toward a pro-inflammatory profile. Since leukocyte recruitment plays a key role in chronic inflammation during the onset of type 2 diabetes mellitus (T2DM), the aim of this study was to evaluate the influence of bone marrow transplantation (BMT) on glycemic control and inflammatory markers in Goto-Kakizaki (GK) rats transplanted after weaning. GK rats are spontaneously non-obese, T2DM animals. We performed BMT from normoglycemic Wistar (WT) rats to GK animals (aged 28 days), previously immunosuppressed with busulfan (20 mg/kg) and cyclophosphamide (150 mg/kg). The mRNA expression of pro-inflammatory cytokines IL-1β and IL-7 was increased in the BM of weaned GK rats, and it was reduced in the BM mononuclear cells (BMMCs) 100 days after BMT. Hepatic cytokine levels were also evaluated by flow cytometry to calculate the Inflammatory Marker Index (based on IFN-γ, TNF-α, IL-6, and IL-10), which was decreased in transplanted GK rats. Moreover, transplanted GK rats also showed reduced fasting glucose evaluated at 30, 60, and 90 days after transplantation. BMT also induced a significant decrease in plasma insulin and attenuated insulin resistance (HOMA-IR). Overall, BMT in just-weaned GK rats, characterized by an elevated inflammatory profile in the BM and liver, culminated in improvement of glycemic control compared with non-transplanted GK animals. In conclusion, modulation of the BM microenvironment emerges as a novel therapeutic avenue for managing non-obese T2DM and preventing its complications.

慢性高血糖诱导骨髓（BM）微环境的变化，有利于干细胞向促炎方向的扩张和分化。由于白细胞募集在2型糖尿病（T2DM）发病期间的慢性炎症中起着关键作用，本研究的目的是评估断奶后移植的Goto-Kakizaki （GK）大鼠骨髓移植（BMT）对血糖控制和炎症标志物的影响。GK大鼠是自发非肥胖的2型糖尿病动物。我们将血糖正常的Wistar （WT）大鼠移植到GK动物（28日龄），之前用丁硫丹（20 mg/kg）和环磷酰胺（150 mg/kg）进行免疫抑制。促炎因子IL-1β和IL-7 mRNA在断奶GK大鼠骨髓中表达升高，在骨髓单核细胞（BMMCs）中表达降低。通过流式细胞术评估肝脏细胞因子水平，计算炎症标志物指数（基于IFN-γ， TNF-α， IL-6和IL-10），移植GK大鼠的炎症标志物指数降低。此外，移植的GK大鼠在移植后30,60和90天也显示空腹血糖降低。BMT还导致血浆胰岛素显著下降和胰岛素抵抗（HOMA-IR）减弱。总体而言，与未移植的GK动物相比，刚断奶的GK大鼠的BMT以BM和肝脏炎症升高为特征，最终改善了血糖控制。总之，调节脑基微环境是治疗非肥胖型2型糖尿病和预防其并发症的一种新的治疗途径。

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引用次数: 0

Prenatal perfluorooctanoic sulfonate exposure is associated with polycystic ovary syndrome-like and related traits in female offspring mice 产前全氟辛烷磺酸暴露与雌性后代小鼠多囊卵巢综合征样及相关性状相关

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-10 DOI: 10.1016/j.mce.2025.112707

C. Urrutia-Lopez , L. González-Carranza , A. Barajas-Salinas , E. Bonilla , J.J. Rodriguez-Mercado , A. Aviles , E. Langley , J.P. Reyes-Grajeda , F. Casillas , A. Lopez , E. Casas , M. Betancourt , M.C. González-Torres , I. Bahena-Ocampo

Polycystic Ovary Syndrome (PCOS), is the most common female endocrine disorder affecting women of reproductive age. Its prevalence is estimated to be up to 13 % worldwide. This heterogeneous clinical condition is characterized by marked clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and frequent development of polycystic ovaries. Several studies have focused on the relationship between endocrine-disrupting pollutants and PCOS development. Perfluorooctanesulfonate (PFOS) is ubiquitously detected in the environment. Exposure to endocrine-disrupting chemicals, including PFOS, during early fetal development may lead to alterations similar to the PCOS phenotype. Using mice as a model, we compared the effects of prenatal exposure to PFOS or dihydrotestosterone (a model of PCOS induction). After analyzing steroid status, we detected delayed pubertal onset accompanied by increased testosterone concentrations in adulthood, as well as altered estrous cycles with a longer metestrus phase. At this point, two of three Rotterdam criteria have been confirmed as PCOS features. Finally, we identified endocrine disruption in the ovaries from adult females prenatally exposed to PFOS, as evidenced by altered expression of genes involved in steroidogenesis pathways, as well as altered expression of gonadotropin hormone receptors, and Amh signaling. These data support a role of PFOS in endocrine disruption and in promoting development of PCOS symptom development.

多囊卵巢综合征（PCOS）是影响育龄妇女最常见的女性内分泌疾病。据估计，其全球患病率高达13%。这种异质性临床状况的特点是临床和/或生化上明显的高雄激素、排卵功能障碍和多囊卵巢的频繁发展。一些研究集中在内分泌干扰污染物与多囊卵巢综合征发展之间的关系。全氟辛烷磺酸（PFOS）在环境中无处不在。胎儿早期发育期间暴露于干扰内分泌的化学物质，包括全氟辛烷磺酸，可能导致与多囊卵巢综合征表型相似的改变。以小鼠为模型，我们比较了产前暴露于全氟辛烷磺酸或二氢睾酮（PCOS诱导模型）的影响。在分析类固醇状态后，我们检测到青春期开始延迟伴随着成年期睾酮浓度的增加，以及月经周期的改变和更长的月经期。在这一点上，三个鹿特丹标准中的两个已被确认为PCOS特征。最后，我们发现成年女性在产前暴露于全氟辛烷磺酸后，卵巢内分泌受到干扰，这可以通过类固醇生成途径相关基因的表达改变，以及促性腺激素受体和Amh信号的表达改变来证明。这些数据支持全氟辛烷磺酸在内分泌干扰和促进多囊卵巢综合征症状发展中的作用。

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引用次数: 0

Developmental programming: gestational exposure to excess testosterone disrupts maternal steroid homeostasis and perturbs the steroid-lipid relationship in sheep 发育规划：妊娠期暴露于过量的睾酮会破坏母体类固醇体内平衡，并扰乱绵羊体内类固醇-脂质关系。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-24 DOI: 10.1016/j.mce.2025.112706

Nadia Saadat , Rehma Saeed , Brooke Pallas , Arpita K. Vyas , Richard J. Auchus , Vasantha Padmanabhan

Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal steroid profile and the steroid-lipid relationship. Using sheep, we investigated maternal delta-4 (Δ4) and delta-5 (Δ5) steroids and the steroid-lipidome relationship in gestational testosterone excess (n = 12, 100 mg T-propionate days 30–90 of gestation twice-weekly intramuscularly) and control (n = 5, vehicle) Suffolk sheep. Steroids were measured using liquid chromatography-tandem mass spectrometry and lipids by shotgun lipidomics. Principal component analysis showed clear separation of control and the gestational testosterone excess groups. The main impact of testosterone excess was on the Δ5 pathway, with reductions in 17-OH pregnenolone, androstenediol, allopregnanolone, and androsterone. In the Δ4 pathway only a trend for reduced androstenedione and a large magnitude increase in corticosterone and decrease in 11-deoxycorticosterone was observed. Dimensionality reduction partial least squares regression models revealed disruptive impact of testosterone-excess on the steroid-lipid relationship prevailing in controls namely with lipid biosynthesis and metabolism and enrichment in cholesterol biosynthetic, circadian clock and transcriptional regulatory, and liver steatosis pathways. Disrupted steroid-lipid associations in the gestational testosterone excess group showed linkage to complex disease-profiles centering on lipid metabolism and transport, cholesterol, and of relevance to hyperlipidemia, gestational diabetes, and hypertension in the enrichment analysis. Fewer lipid species were associated with individual steroids in gestational testosterone excess group, indicative of loss of the majority of the homeostatic steroid-lipid associations. This study provides a novel screening insight into the steroid-lipid relationship that prevails during normal pregnancy and the disruptive impact of hyperandrogenism in perturbing this homeostasis.

妊娠期高雄激素症可能会破坏类固醇和脂质代谢的稳态平衡，这对妊娠进展很重要。我们假设，过量的妊娠期睾酮会破坏母体类固醇谱和类固醇脂质关系。以羊为研究对象，研究了母羊δ -4（Δ4）和δ -5（Δ5）类固醇以及妊娠睾酮过量（n=12，妊娠30-90天每周两次肌注100mg t -丙酸）和对照（n=5，载体）萨福克羊的类固醇-脂质组关系。类固醇采用液相色谱-串联质谱法测定，脂质采用散弹枪脂质组学测定。主成分分析显示对照组与妊娠期睾酮过量组明显分离。睾酮过量主要影响Δ5通路，17-OH孕烯醇酮、雄烯二醇、异孕烯醇酮和雄酮减少。在Δ4通路中，只观察到雄烯二酮的减少和皮质酮的大量增加和11-脱氧皮质酮的减少。降维偏最小二乘回归模型揭示了睾酮过量对对照组中普遍存在的类固醇-脂质关系的破坏性影响，即脂质生物合成、代谢和胆固醇生物合成、生物钟和转录调节以及肝脏脂肪变性途径中的富集。在浓缩分析中，妊娠期睾酮过量组的类固醇-脂质关联中断显示出与以脂质代谢和转运、胆固醇为中心的复杂疾病谱相关，并与高脂血症、妊娠期糖尿病和高血压相关。在妊娠期睾酮过量组中，与单个类固醇相关的脂质种类较少，表明大多数体内平衡类固醇-脂质关联丢失。这项研究为正常妊娠期间普遍存在的类固醇-脂质关系以及高雄激素症扰乱这种体内平衡的破坏性影响提供了一种新的筛选见解。

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引用次数: 0

In vitro activation of brown adipocyte thermogenesis by fermented hypholomine B-enriched Sanghuangporus sanghuang mycelia through FNDC5/Irisin pathway 通过FNDC5/鸢尾素途径发酵富含菌丝碱b的桑黄孢子菌丝体外激活棕色脂肪细胞产热

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-22 DOI: 10.1016/j.mce.2025.112705

I-Chen Li , Yu-En Chan , Yu-Li Lin , Tzong-Yuan Wu , Liang-Yi Wu , Ching-Yi Tsai , Hsin-Tang Lin , Chin-Chu Chen

In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented Sanghuangporus sanghuang mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in brown adipose tissue activation. Using HEK293 cells with FNDC5 promoter-EGFP constructs and differentiated 3T3-L1 adipocytes, we demonstrate that both compounds significantly enhance FNDC5 expression and irisin secretion. We reveal distinct mechanistic profiles: SS-IM1 showed superior efficacy in irisin induction and thermogenesis activation, while isolated hypholomine B demonstrated unprecedented potency in reducing lipid accumulation. Seahorse analysis revealed enhanced mitochondrial respiration and UCP1-mediated proton leak, confirming their thermogenic effects. Furthermore, we discovered that SS-IM1 uniquely enhanced glucose uptake through GLUT4 upregulation. These findings not only elucidate novel molecular mechanisms underlying the anti-obesity effects of S. sanghuang but also establish hypholomine B as a promising first-in-class therapeutic candidate for addressing the worldwide challenges of obesity and metabolic disorders.

面对全球肥胖流行（globesity），我们首次全面研究了发酵桑黄孢子桑黄菌丝体提取物（SS-IM1）及其新型生物活性化合物-丝孢胺B在棕色脂肪组织激活中的作用。通过构建FNDC5启动子egfp的HEK293细胞和分化的3T3-L1脂肪细胞，我们发现这两种化合物都能显著提高FNDC5的表达和鸢尾素的分泌。我们揭示了不同的机制：SS-IM1在鸢尾素诱导和生热活化方面表现出卓越的功效，而分离的丝光胺B在减少脂质积累方面表现出前所未有的效力。海马分析显示，线粒体呼吸和ucp1介导的质子泄漏增强，证实了它们的产热作用。此外，我们发现SS-IM1通过上调GLUT4独特地增强葡萄糖摄取。这些发现不仅阐明了桑黄抗肥胖作用的新分子机制，而且确立了连色胺B作为解决全球肥胖和代谢紊乱挑战的有前景的一流治疗候选者。

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引用次数: 0

Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism 雄激素剥夺可诱导调节葡萄糖、脂质和氨基酸代谢的基因发生明显的肌肉特异性转录变化

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-20 DOI: 10.1016/j.mce.2025.112704

Wayne A. Ayers-Creech , Jennifer L. Steiner , Grant R. Laskin , Bradley S. Gordon

Background

Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear.

Methods and results

Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration.

Conclusion

These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.

背景：雄激素如睾酮调节全身代谢稳态。低雄激素水平导致代谢的不良变化，包括葡萄糖氧化降低，脂质依赖增加，氨基酸代谢改变。骨骼肌是调节燃料底物代谢的主要部位，但是否所有肌肉都参与了低雄激素水平下的不良代谢变化尚不清楚。方法和结果小鼠分别在术后7、14、21、28、49天进行假手术或去势手术。测定胫骨前肌（TA）和腓肠肌中葡萄糖、脂质和氨基酸代谢相关基因的含量。与葡萄糖代谢相关的基因含量发生了改变，这与阉割后TA和腓肠肌的氧化率降低一致，尽管TA的变化幅度通常更明显。与脂质氧化相关的基因以一种与阉割后TA较高的氧化率一致的方式改变。与氨基酸分解代谢相关的基因在阉割后没有改变，甚至更低。结论与腓肠肌相比，TA在糖脂代谢方面发生了更明显的转录变化，可能在雄激素剥夺过程中对全身代谢变化的贡献更大。

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引用次数: 0