Delayed Puberty by Ziram Is Associated with Down Regulation of Testicular Phosphorylated AKT1 and SIRT1/PGC-1α Signaling

作者：Xie, Lubin; Li, Xiaoheng; Mo, Jiaying; Li, Linchao; Chen, Xianwu; Chen, Lanlan; Ma, Leikai; Chen, Yong; Ge, Fei; Zhao, Junzhao^*; Ge, Ren-Shan^*

来源：Chemical Research in Toxicology, 2018, 31(12): 1315-1322.

DOI：10.1021/acs.chemrestox.8b00201

• RAT LEYDIG-CELLS
• ANTI-MULLERIAN HORMONE
• DITHIOCARBAMATE FUNGICIDE
• FACTOR-I
• RECEPTOR
• ACTIVATION
• DIFFERENTIATION
• PROLIFERATION
• APOPTOSIS
• MUTATION

Ziram is a dimethyldithiocarbamate fungicide, which may influence the male reproductive system as a potential endocrine disruptor. We interrogated the disruption of ziram on rat progenitor Leydig cell development. Prepubertal male Sprague-Dawley rats were orally treated with 0, 2, 4, or 8 mg/kg ziram for 2 weeks. We investigated the effects of ziram on serum testosterone levels, Leydig cell number, and Leydig and Sertoli cell gene and protein expression, SIRT1/PGC-1 alpha levels, and phosphorylation of AKT1, ERK1/2, and AMPK in vivo. We also interrogated the effects of ziram on reactive oxidative species (ROS) level, apoptosis rate, and mitochondrial membrane potential of progenitor Leydig cells in vitro. Ziram decreased serum testosterone and follicle-stimulating hormone levels, the down-regulated Leydig cell-specific gene (Lhcgr, Scarb1, Star, Cyp 17a1, and Hsd17b3), and their protein expression. However, ziram stimulated anti-Miillerian hormone production. Ziram lowered SIRT1/PGC-1 alpha and phosphorylated protein levels of AKT1. Ziram induced ROS and apoptosis and lowered the mitochondrial membrane potential of progenitor Leydig cells in vitro. In conclusion, ziram disrupts Leydig cell development during the prepubertal period potentially through the SIRT1/PGC-1 alpha and phosphorylated AKT1 signaling.

• 出版日期2018-12
• 单位温州医科大学