Melatonin promotes male reproductive performance and increases testosterone synthesis in mammalian Leydig cells

Author:

Yang Minghui1,Guan Shengyu1,Tao Jingli12,Zhu Kuanfeng1,Lv Dongying1,Wang Jing1,Li Guangdong1,Gao Yuefeng1,Wu Hao1,Liu Jinghao3,Cao Lin4,Fu Yao1,Ji Pengyun1,Lian Zhengxing1,Zhang Lu1,Liu Guoshi1

Affiliation:

1. National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China

2. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

3. Laboratory Animal Centre, Peking University, Beijing, China

4. Beijing Institute of Feed Control, Beijing Municipal Bureau of Agriculture and Rural Affairs, Beijing, China

Abstract

Abstract Leydig cells play a critical role in male reproductive physiology, and their dysfunction is usually associated with male infertility. Melatonin has an important protective and regulatory role in these cells. However, the lack of suitable animal models impedes us from addressing the impact of endogenous melatonin on these cells. In the current study, by using arylalkylamine N-acetyltransferase (AANAT) overexpression transgenic sheep and AANAT knockout mice, we confirmed the regulatory effects of endogenously occurring melatonin on Leydig cells as well as its beneficial effects on male reproductive performance. The results showed that the endogenously elevated melatonin level was correlated with decreased Leydig cell apoptosis, increased testosterone production, and improved quality of sperm in melatonin-enriched transgenic mammals. Signal transduction analysis indicated that melatonin targeted the mitochondrial apoptotic Bax/Bcl2 pathway and thus suppressed Leydig cell apoptosis. In addition, melatonin upregulated the expression of testosterone synthesis-related genes of Steroidogenic Acute Regulatory Protein (StAR), Steroidogenic factor 1 (SF1), and Transcription factor GATA-4 (Gata4) in Leydig cells. This action was primarily mediated by the melatonin nuclear receptor RAR-related orphan receptor alpha (RORα) since blockade of this receptor suppressed the effect of melatonin on testosterone synthesis. All of these actions of melatonin cause Leydig cells to generate more testosterone, which is necessary for spermatogenesis in mammals. In contrast, AANAT knockout animals have dysfunctional Leydig cells and reduced reproductive performance.

Funder

Major Project of Breeding New Varieties of Transgenic Organisms

National Creature Breeding Grand Project

National Natural Science Foundation of China

Beijing Dairy Industry Innovation Team

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,General Medicine,Reproductive Medicine

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