Neurotoxicology · 2026
Pyrethrin II impairs mitochondrial potential through ROS and MAPK pathways in HT‑22 cells.
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Gao Jiaojiao, Zhang Xinbi, Mu Qie, Liu Yurong, Yang Hong, Cao Rui, Wang Xiuwei, Yu Baofeng, Zhang Li, Guo Yaoyao
Аннотация
OBJECTIVE: Pyrethrin II, a key active monomer of natural pyrethrins, is widely used in household insecticides. This study investigated whether Pyrethrin II induces hippocampal neuronal injury through ROS overproduction and MAPK pathway dysregulation.
METHODS: HT-22 cells were treated with Pyrethrin II at concentrations of 10 and 40 μg/mL for 24 h. Subsequently, cell viability was evaluated using the CCK-8 assay, transcriptomic sequencing was performed to identify global transcriptional changes, intracellular ROS levels were measured by flow cytometry, MAPK pathway protein expression was analyzed via Western blotting, mitochondrial membrane potential was assessed with JC-1 staining, apoptosis was determined by TUNEL staining and cleaved caspase-3 levels, and cell proliferation was examined using EdU incorporation and PCNA expression.
RESULTS: Transcriptomic analysis revealed dose-dependent transcriptional alterations, with the MAPK pathway identified as the core toxic mechanism. Pyrethrin II induced excessive ROS production, which activated JNK and p38 but suppressed ERK1/2. The ROS inhibitor NAC partially reversed these effects. JNK activation decreased mitochondrial membrane potential and triggered compensatory mitochondrial biogenesis (upregulated TOMM20). ERK suppression reduced cell proliferation, which was partially restored by the ERK activator TPA. JNK activation promoted apoptosis (increased cleaved caspase-3 and TUNEL‑positive cells), an effect attenuated by the JNK inhibitor SP600126.
CONCLUSION: Pyrethrin II disrupts the proliferation-apoptosis balance by inducing ROS overproduction, suppressing ERK, and activating JNK/p38, leading to mitochondrial dysfunction and neuronal injury. Our findings identify the ROS‑mediated JNK/ERK axis as a key mechanism of its in vitro neurotoxicity. However, given the essential physiological functions of JNK and ERK, direct targeting may cause systemic side effects. Future studies should explore upstream or more selective modulators to avoid disrupting normal cellular functions.
METHODS: HT-22 cells were treated with Pyrethrin II at concentrations of 10 and 40 μg/mL for 24 h. Subsequently, cell viability was evaluated using the CCK-8 assay, transcriptomic sequencing was performed to identify global transcriptional changes, intracellular ROS levels were measured by flow cytometry, MAPK pathway protein expression was analyzed via Western blotting, mitochondrial membrane potential was assessed with JC-1 staining, apoptosis was determined by TUNEL staining and cleaved caspase-3 levels, and cell proliferation was examined using EdU incorporation and PCNA expression.
RESULTS: Transcriptomic analysis revealed dose-dependent transcriptional alterations, with the MAPK pathway identified as the core toxic mechanism. Pyrethrin II induced excessive ROS production, which activated JNK and p38 but suppressed ERK1/2. The ROS inhibitor NAC partially reversed these effects. JNK activation decreased mitochondrial membrane potential and triggered compensatory mitochondrial biogenesis (upregulated TOMM20). ERK suppression reduced cell proliferation, which was partially restored by the ERK activator TPA. JNK activation promoted apoptosis (increased cleaved caspase-3 and TUNEL‑positive cells), an effect attenuated by the JNK inhibitor SP600126.
CONCLUSION: Pyrethrin II disrupts the proliferation-apoptosis balance by inducing ROS overproduction, suppressing ERK, and activating JNK/p38, leading to mitochondrial dysfunction and neuronal injury. Our findings identify the ROS‑mediated JNK/ERK axis as a key mechanism of its in vitro neurotoxicity. However, given the essential physiological functions of JNK and ERK, direct targeting may cause systemic side effects. Future studies should explore upstream or more selective modulators to avoid disrupting normal cellular functions.