Chlorpyrifos exposure induced cytotoxic death in pancreatic islet β-cells via the functional co-activation of JNK and AMPKα signaling downstream-mediated mitochondria-dependent apoptosis pathway.
Journal
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
Journal Volume
214
Start Page
116111
ISSN
1873-6351
Date Issued
2026-08
Author(s)
Yang, Ching-Yao
Lee, Kuan-I
Chen, Ya-Wen
Fang, Kai-Min
Kuo, Chun-Ying
Lia, Wei-Cheng
Chang, Kai-Chih
Ke, Jun-An
Wu, Cheng-Tien
Huang, Chun-Fa
Su, Chin-Chuan
Abstract
Chlorpyrifos (CPF), a typical pesticide used worldwide, is known to induce diabetic symptoms such as hyperglycaemia/decreased insulin levels in mammals, which may be a risk factor for the development of diabetes mellitus. Nevertheless, the exact mechanisms underlying CPF-mediated pancreatic islet β-cell cytotoxicity remain unclear. This study aimed to investigate the mechanism of CPF-induced toxic responses in β-cells. CPF exposure with the environmentally relevant concentrations significantly inhibited in cell viability and insulin secretion, accompanied with mitochondrial dysfunction, and apoptotic events. Additionally, CPF exposure markedly induced the phosphorylated expressions of Akt, AMPKα, JNK, and ERK1/2, but did not affect p38-MAPK protein expression. Cells pretreated with pharmacological inhibitors of JNK (SP600125) and AMPK (compound C) effectively attenuated the CPF-induced cytotoxicity, and apoptotic events. However, the inhibitors of ERK1/2 (PD98059) or Akt (LY294002) did not prevent the CPF-induced viability reduction and caspase-3 activity increase. Interestingly, both the inhibitors could prevent the CPF-induced JNK and AMPKα protein activation, mutually affecting each other. Collectively, these findings imply that CPF exposure exerts cytotoxicity via a signaling pathway of mitochondria-dependent apoptosis, ultimately contributing to β-cell death. The functional co-activation of JNK and AMPKα signaling-regulated apoptotic pathway may provide a beneficial evidence into the mechanism understanding CPF-elicited β-cell cytotoxicity.
Subjects
AMPKα
Apoptosis
Chlorpyrifos
JNK
Mitochondria
Pancreatic islet β-cells
Publisher
Elsevier B.V
Type
journal article