2. Academic Validation
  3. Icariin promotes mouse Leydig cell testosterone synthesis via the Esr1/Src/Akt/Creb/Sf-1 pathway

Icariin promotes mouse Leydig cell testosterone synthesis via the Esr1/Src/Akt/Creb/Sf-1 pathway

  • Toxicol Appl Pharmacol. 2022 Apr 15;441:115969. doi: 10.1016/j.taap.2022.115969.
Jiandong Sun 1,  Weiwei Xu 1,  Shuyuan Zheng 2,  Chengyu Lv 3,  Jianmin Lin 1,  Siqi Chen 1,  Yonghong Qiu 2,  Xia Jiang 2,  Eman Draz 4,  Shie Wang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China.
  • 2 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China; Undergraduate Class, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China.
  • 3 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China; Department of Obstetrics and Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, PR China.
  • 4 Department of Histology, and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China; Human Anatomy and Embryology department, Suez Canal University, 12411, Egypt.
  • 5 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China; Department of Histology, and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China. Electronic address: shiewang@fjmu.edu.cn.
PMID: 35259346 DOI: 10.1016/j.taap.2022.115969
Abstract

Icariin (ICA), extracted from Epimedium, is a flavonoid used in traditional Chinese medicine. Di(2-ethylhexyl) phthalate (DEHP) is a phthalate used in commercial products as a plasticizer that can influence the human endocrine and reproduction system. We previously found that ICA reversed DEHP-induced damage through the prevention of Reactive Oxygen Species accumulation and promotion of testosterone secretion. Here we investigated the mechanisms of ICA in promoting testosterone secretion from murine Leydig cells. We used ICA, DEHP, the Akt Agonist SC-79, the Akt Inhibitor MK2206, and the Creb inhibitor KG501 to determine the effect of these treatments on the expression levels of the steroidogenic Enzymes, Cyp11a1 and Hsd3b, which play critical roles in androgen production, in Leydig cells. Bioinformatic analysis was used to search for ICA-targeted proteins and their associated pathways. We found that icariin interacted with Estrogen Receptor on the cell membrane, leading to increased phosphorylation levels of Akt and Creb proteins and enhanced transcription of genes encoding steroidogenic Enzymes and testosterone synthesis. We further investigated ICA activity in vivo using male mice pretreated with 100 mg/kg ICA and then treated with 750 mg/kg DEHP. ICA pretreatment reversed the reduced protein expression levels of Cyp11a1 and Hsd3b induced by DEHP in Leydig cells in vivo. Furthermore, while the phosphorylation levels of Akt and Creb were decreased in testes of mice exposed to DEHP alone, these effects were reversed by ICA pretreatment. These findings indicate that ICA promotes testosterone synthesis via the Esr1/Src/Akt/Creb/Sf-1 signaling pathway.

Keywords

Akt; Icariin; Leydig cells; Mouse; Steroidogenic enzymes.

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