Cypermethrin induced liver oxidative DNA damage via the JNK/c-Jun pathway

Abstract

To clarify the adverse effect of cypermethrin(CYP) on the liver and explore the underlying role of the MAPK pathway. Twenty-four Sprague-Dawley(SD) rats were exposed to 0, 5, 10 and 20 mg/(kg·d) β-CYP by gavage for 31 days. Histomorphological and ultrastructural changes were evaluated by the hematoxylin & eosin(HE) staining and transmission electron microscope(TEM). Levels of MDA and 8-OHdG were detected by ELISA. Expressions of p-JNK and γ-H2A. X were assessed by IHC and IF respectively. RT-PCR was performed to examine mRNA levels of GPx1, GPx4, SOD1, and SOD2 in rat testes. Western blot was conducted to determine protein expressions of GPx1, SOD2, CAT, γ-H2A. X, and the MAPK pathway-associated proteins in rat testes. After β-CYP exposure, the histomorphology and ultrastructures of rat livers were abnormally altered, as evidenced by hepatic sinusoidal dilation, hepatic plate space formation, mitochondrial crest fracture, etc. Moreover, β-CYP induced mRNA levels of GPx1, GPx4, SOD1 and SOD2, as well as protein expressions of GPx1 and SOD2 in the liver. Compared to the control, GPx1 and SOD2 protein expressions were decreased by 57.9% and 50.0%(P<0.05), whereas the MDA level was increased by 56.2%(P<0.05) in the high-dose group. Additionally, the JNK/c-Jun pathway, one of MAPK pathways, in the liver was activated by β-CYP, as shown by the increase of JNK and c-Jun phosphorylation, and protein expressions of p-JNK and p-c-Jun in the high-dose group were elevated by 47.7% and 46.5%(P<0.05) in comparison to the control, but the ERK and p38 pathways were not affected after β-CYP exposure. Furthermore, β-CYP promoted 8-OHdG and γ-H2A. X expressions in the liver. Compared to the control, γ-H2A. X protein expression in the mid-and high-dose group was upregulated by 16.9% and 33.9%(P<0.05), respectively. Cypermethrin had detrimental effects on the liver. CYP not only directly altered liver histomorphology and ultrastructures, but also caused oxidative stress, which activated the JNK/c-Jun pathway, finally inducing the DNA damage.