1. Chlorocholine chloride exposure induced spermatogenic dysfunction via iron overload caused by AhR/PERK axis-dependent ferritinophagy activation.
- Author
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Guo, Wanqian, Kang, Chenping, Wang, Xiaoxia, Zhang, Haoran, Yuan, Lilan, Wei, Xuetao, Xiao, Qianqian, and Hao, Weidong
- Subjects
IRON overload ,ARYL hydrocarbon receptors ,SPERMATOGENESIS ,CHOLINE chloride ,PLANT regulators ,WESTERN immunoblotting ,ENDOPLASMIC reticulum ,DEFEROXAMINE - Abstract
Chlorocholine chloride (CCC) is a plant growth regulator used worldwide that is detectable in cereals, fruits and animal products. The health effects of CCC exposure have raised public concern. Our previous research showed that CCC exposure decreased testosterone synthesis in pubertal rats. However, little is known about whether and how pubertal CCC exposure impacts spermatogenesis. In this study, we used BALB/c mice and spermatogonia-derived GC-1 cells to examine CCC-induced spermatogenic dysfunction. In vivo , pubertal CCC exposure led to decreased testicular weight, decreased testicular germ cells and poor sperm quality. This effect worsened after cessation of CCC exposure for the next 30 days. RNA-seq and western blot analysis revealed that CCC induced aryl hydrocarbon receptor (AhR) signaling, endoplasmic reticulum stress (ERS) and ferritinophagy. Increased iron content and lipid peroxidation levels were also observed in CCC-treated testes. In vitro , it was identified that iron overload mediated by enhanced ferritinophagy occurred in CCC-treated GC-1 cells, which might be attributed to the PERK pathway in ERS. Further, for the first time, our study elucidated the involvement of AhR in CCC-induced iron overload, which aggravated testicular oxidative damage via lipid peroxidation. Considering the adverse impact of CCC exposure on rodents, supportive evidence from GC-1 cells, and the critical importance of spermatogenesis on male development, the effects of CCC on the male reproduction warrant increased attention. [Display omitted] • CCC pubertal exposure led to spermatogenesis disorders which remained after cessation of CCC exposure for the next 30 days. • CCC-induced iron overload by ferritinophagy activation contributed to lipid peroxidation in GC-1 cells. • PERK pathway in endoplasmic reticulum stress triggered ferritinophagy activation in CCC-treated cells. • AhR was involved in CCC-induced ROS production and PERK-dependent iron overload, which caused testicular oxidative damage. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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