β-Cypermethrin and its metabolite 3-phenoxybenzoic acid induce cytotoxicity and block granulocytic cell differentiation in HL-60 cells

The most widely used type II pyrethroid is beta-cypermethrin (beta-CYP), and 3-phenoxybenzoic acid (3-PBA) is one of its primary metabolites. Although CYP has been shown to pose toxic effects in some immune cells, as of now the immunotoxicity of CYP on immune progenitor cells has not been well studied. In this study, we evaluated the immunotoxicity of beta-CYP and 3-PBA on the human promyelocytic leukemia cell line, HL-60. Both beta-CYP and 3-PBA reduced cell viability. In addition, both beta-CYP and 3-PBA stimulated the intrinsic apoptotic pathway in a dose- and time-dependent manner, while only beta-CYP induced cell cycle arrest in G1 stage. Moreover, exposure to beta-CYP and 3-PBA at 100 mu M inhibited all-trans retinoic acid (ATRA)-induced mRNA expressions of the granulocytic differentiation-related genes, CD11b and CSF-3R. Furthermore, exposure to beta-CYP and 3-PBA resulted in a downregulation of the granulocytic differentiation promoting transcriptional factors, PU. 1 and C/EBP epsilon. Furthermore, we found that beta-CYP and 3-PBA exposure led to elevated levels of cellular reactive oxygen species (ROS), and that pretreatment with N-acetylcysteine (NAC) blocked the toxic effects caused by beta-CYP and 3-PBA. The results obtained in the present study provide evidence showing the immunotoxic effects of beta-CYP and 3-PBA on promyelocytic cells as well as its possible underlying mechanism.