Adrenomedullin gene delivery rescues estrogen production in Leydig cells via the inhibition of TGF-β1/Smads signaling pathway

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY Reproductive toxicology Pub Date : 2025-01-08 DOI:10.1016/j.reprotox.2025.108834

You-wen Luo , Xia-lian Zhu , Zhi-min Yang , Jian-hua Zhou , Tong Tao , Bing-hai Chen , Song-lin Qin , Bo-long Liu , Wei Hu

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Abstract

Our previous findings demonstrated that adrenomedullin (ADM) protects against the reduction in testosterone production and apoptosis of Leydig cells both in vitro and in vivo. In this study, we investigated whether ADM could preserve estrogen production in Leydig cells by suppressing the transforming growth factor-β1 (TGF-β1) / Smads signaling pathway. Leydig cells were treated with lipopolysaccharide (LPS) and recombinant adenovirus ADM (Ad-ADM), an adeno-associated viral vector expressing ADM. Cell viability and cytochrome P450 aromatase (P450arom) activity were assessed. Estrogen, testosterone, and TGF-β1 concentrations in the culture medium were measured. Additionally, the gene expression and protein levels of CYP19, TGF-β1, and Smads were evaluated. The results indicated that Ad-ADM mitigated the reductions in Leydig cell viability and testosterone production, counteracted the decreases in P450arom activity, and restored CYP19 gene expression and protein levels in LPS-treated cells. Moreover, Ad-ADM reduced the elevated gene expression and protein levels of Smads and TGF-β1 induced by LPS. Based on these findings, we propose that ADM safeguards estrogen production in Leydig cells by inhibiting the TGF-β1/Smads signaling pathway.

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肾上腺髓质素基因传递通过抑制TGF-β1/Smads信号通路恢复间质细胞雌激素的产生。

我们之前的研究结果表明，肾上腺髓质素（ADM）在体外和体内都能防止睾丸激素分泌减少和间质细胞凋亡。在本研究中，我们研究了ADM是否通过抑制转化生长因子-β1 (TGF-β1) / Smads信号通路来维持间质细胞雌激素的产生。用脂多糖（LPS）和重组腺病毒ADM (Ad-ADM)（一种表达ADM的腺相关病毒载体）处理间质细胞，测定细胞活力和细胞色素P450芳香化酶（P450arom）活性。测定培养基中雌激素、睾酮和TGF-β1的浓度。检测CYP19、TGF-β1、Smads的基因表达及蛋白水平。结果表明，Ad-ADM减轻了间质细胞活力和睾酮产生的下降，抵消了P450arom活性的下降，恢复了lps处理细胞中CYP19基因的表达和蛋白水平。此外，Ad-ADM降低了LPS诱导的Smads和TGF-β1基因表达和蛋白水平升高。基于这些发现，我们提出ADM通过抑制TGF-β1/Smads信号通路来保护间质细胞雌激素的产生。

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来源期刊

Reproductive toxicology 生物-毒理学

CiteScore

6.50

自引率

3.00%

发文量

131

审稿时长

45 days

期刊介绍： Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.