Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-κB pathway

FASEB J. 2019 Feb;33(2):2782-2795. doi: 10.1096/fj.201801289R. Epub 2018 Oct 11.


Fenvalerate (FEN), a mainstream pyrethroid pesticide, was initially recommended as a low-toxicity agent for controlling agricultural and domestic pests. Despite the widespread use of FEN worldwide, little data are available on FEN-induced hepatic lesions and molecular mechanisms. In the present study, we first performed an occupational cross-sectional study on FEN factory workers and found that the levels of serum alanine aminotransferase (ALT) and total antioxidant capacity increased, whereas malondialdehyde decreased in laborers in the working areas where the levels of airborne FEN were much higher compared with the office area. The results were then confirmed by animal experiments that abnormal hepatic histology, increased ALT level, and compromised hepatic oxidative capability were observed in rats exposed to a high concentration of FEN. Furthermore, the bioinformatics analysis of gene microarray in rat liver tissue showed that FEN significantly changed the expressions of genes related to the regulation of intracellular calcium ion homeostasis and the calcium signal pathway. Finally, the functional experiments in Buffalo rat liver (BRL) cells demonstrated that FEN first activated ERK MAPK, followed by IKK and NF-κB, which triggered the transcription of genes responsible for accelerating an overload of intracellular calcium ions, prompted reactive oxygen species generation in the mitochondria, and finally, induced hepatic cellular apoptosis. The calcium signaling pathway and in particular, an overload of intracellular calcium play a critical role in this pathophysiological process via the ERK/IKK/NF-κB pathway. Our study furthers the understanding of the mechanism of FEN-induced hepatic injuries and may have implications in the prevention and control of liver diseases induced by environmental pesticides.-Qiu, L.-L., Wang, C., Yao, S., Li, N., Hu, Y., Yu, Y., Xia, R., Zhu, J., Ji, M., Zhang, Z., Wang S.-L. Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-κB pathway.

Keywords: calcium signal pathway; liver injury; pyrethroid pesticides; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calcium / metabolism*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology*
  • Cross-Sectional Studies
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Insecticides / adverse effects
  • MAP Kinase Signaling System / drug effects*
  • Male
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nitriles / adverse effects*
  • Occupational Exposure / adverse effects*
  • Oxidative Stress
  • Pyrethrins / adverse effects*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*


  • Insecticides
  • NF-kappa B
  • Nitriles
  • Pyrethrins
  • I-kappa B Kinase
  • Calcium
  • fenvalerate