Arecoline Induces Testicular Injury and Impairs Spermatogenesis in Rats Through Notch Signaling-Mediated Oxidative Stress
- 1Department of Obstetrics and Gynecoloy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
- 2Department of Pathology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China
- 3Department of Neurosurgery, Xi’an Jiaotong University Medical College First Affiliated Hospital, Xi’an 710061, China
Abstract
Millions of people chew areca nut to boost work efficiency and relieve stress. Areca nut contains arecoline, which adversely affects reproductive function, although the underlying molecular mechanisms remain unclear. Herein, we evaluated arecoline-mediated reproductive toxicity using Sprague–Dawley (SD) rat models and an in vitro GC-1 cell model. Molecular docking, quantitative reverse transcription PCR (qRT-PCR), Western blot, cell-based assays, and functional rescue experiments were used to investigate the mechanisms involved. Dose-dependent spermatogenic damage was observed in male rats receiving 50, 100 and 200 mg/kg arecoline, with reduced sperm counts and quality, higher testicular MDA and lower activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Molecular docking predicted a possible interaction between arecoline and Notch1. qRT-PCR and Western blot analyses showed that the expression of Notch1 and its ligands, Jagged-1 and Dll-1, was downregulated in testicular tissues and GC-1 cells following arecoline exposure. Notch1 expression was strongly positively correlated with seminiferous tubule diameter and seminiferous epithelium height. In vitro, arecoline induced ROS accumulation, inhibited proliferation and promoted apoptosis in GC-1 cells. Rescue experiments showed that the Notch activator valproic acid, used to enhance Notch signaling, alleviated arecoline-induced toxicity, whereas Notch inhibitor FLI-06 worsened cell injury. These findings support a role for altered Notch signaling and oxidative stress in arecoline-induced spermatogenic injury and provide insight into the molecular mechanisms of its reproductive toxicity.
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BibTeX
@article{yang2026arecoline,
title = {{Arecoline Induces Testicular Injury and Impairs Spermatogenesis in Rats Through Notch Signaling-Mediated Oxidative Stress}},
author = {Yan-Qi Yang and Wen-Xing Li and Pan Ge and Mo-Qi Lv and Ying Sun and Qing Chen and Jian Zhang and Rui-Fang Sun and Dang-Xia Zhou and Ming Liu},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219728},
url = {https://www.mdpi.com/1422-0067/27/21/9728},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Arecoline Induces Testicular Injury and Impairs Spermatogenesis in Rats Through Notch Signaling-Mediated Oxidative Stress
AU - Yan-Qi Yang
AU - Wen-Xing Li
AU - Pan Ge
AU - Mo-Qi Lv
AU - Ying Sun
AU - Qing Chen
AU - Jian Zhang
AU - Rui-Fang Sun
AU - Dang-Xia Zhou
AU - Ming Liu
PY - 2026
DA - 2026/10/29
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219728
UR - https://www.mdpi.com/1422-0067/27/21/9728
AB - Millions of people chew areca nut to boost work efficiency and relieve stress. Areca nut contains arecoline, which adversely affects reproductive function, although the underlying molecular mechanisms remain unclear. Herein, we evaluated arecoline-mediated reproductive toxicity using Sprague–Dawley (SD) rat models and an in vitro GC-1 cell model. Molecular docking, quantitative reverse transcription PCR (qRT-PCR), Western blot, cell-based assays, and functional rescue experiments were used to investigate the mechanisms involved. Dose-dependent spermatogenic damage was observed in male rats receiving 50, 100 and 200 mg/kg arecoline, with reduced sperm counts and quality, higher testicular MDA and lower activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Molecular docking predicted a possible interaction between arecoline and Notch1. qRT-PCR and Western blot analyses showed that the expression of Notch1 and its ligands, Jagged-1 and Dll-1, was downregulated in testicular tissues and GC-1 cells following arecoline exposure. Notch1 expression was strongly positively correlated with seminiferous tubule diameter and seminiferous epithelium height. In vitro, arecoline induced ROS accumulation, inhibited proliferation and promoted apoptosis in GC-1 cells. Rescue experiments showed that the Notch activator valproic acid, used to enhance Notch signaling, alleviated arecoline-induced toxicity, whereas Notch inhibitor FLI-06 worsened cell injury. These findings support a role for altered Notch signaling and oxidative stress in arecoline-induced spermatogenic injury and provide insight into the molecular mechanisms of its reproductive toxicity.
SN - 1422-0067
ER -