Delayed Puberty by Ziram Is Associated with Down Regulation of Testicular Phosphorylated AKT1 and SIRT1/PGC-1α Signaling.
Lubin XieXiaoheng LiJiaying MoLinchao LiXianwu ChenLanlan ChenLeikai MaYong ChenFei GeJunzhao ZhaoRen-Shan GePublished in: Chemical research in toxicology (2018)
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-1α 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, Cyp17a1, and Hsd17b3), and their protein expression. However, ziram stimulated anti-Müllerian hormone production. Ziram lowered SIRT1/PGC-1α 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-1α and phosphorylated AKT1 signaling.
Keyphrases
- oxidative stress
- single cell
- cell cycle arrest
- signaling pathway
- cell therapy
- skeletal muscle
- induced apoptosis
- cell death
- cell proliferation
- stem cells
- dna damage
- endoplasmic reticulum stress
- risk assessment
- small molecule
- mass spectrometry
- bone marrow
- high resolution
- climate change
- dna methylation
- high glucose
- binding protein
- endothelial cells