Although there are few studies suggested PCP exposure induced developmental and behavioral disorders, however, the occurrence of neurotoxicity and PCP has not been firmly established.
Tetrachlorobenzoquinone (TCBQ) is a reactive metabolite of
environmental pollutant pentachlorophenol (PCP). To the best of our knowledge, there has no information regarding to the neurological toxic effect of TCBQ available. Here, we demonstrated that TCBQ induces cytotoxicity in
pheochromocytoma PC12 cell line, and the mode-of-action analysis indicated the involvement of apoptotic signalings, such as the activation of
caspase family
proteins, the increased expressions of Fas and Fas-associated death domain (FADD), the loss of mitochondrial membrane potential (
MMP), the release of
cytochrome c (Cyt c) and the cleavage of the
caspase substrates
poly(ADP-ribose) polymerase (PARP). BI-6C9, a specific BH3-interacting domain death agonist (Bid) inhibitor, repressed TCBQ-induced Bid truncation, along with the activation of
caspase 3 and the release of Cyt c, suggested the cross-talk of extrinsic and intrinsic apoptotic signalings. Furthermore, the inhibition of
caspase 8 impaired TCBQ-induced the activation of
caspase 3, as well as the release of Cyt c and the cleavage of Bid, suggesting
caspase 8 acting as the upstream molecule of Bid, and TCBQ-induced apoptosis is initiated via
caspase 8, leads to the activation of
caspase 9/3 through Bid-mediated amplification loop. Finally, the pretreatment of
antioxidant NAC ameliorated Fas, FADD and
caspase 8/3 expressions, which illustrated that TCBQ-induced apoptotic signaling is ROS dependent. Taken together, these results indicated that the cleavage of Bid may play an important role in TCBQ-induced neurotoxicity which promotes the cross-talk of extrinsic and intrinsic apoptotic signalings in PC12 cells.