Evaluation of pathways involved in pentachlorophenol-induced apoptosis in rat neurons.
Pentachlorophenol (PCP) (C(6)HCl(5)O) is a synthetic toxic organochloride fungicide for humans which exhibit neurotoxic properties. In the present research, we describe the potential pathways implicated in PCP-induced apoptosis in an acute model of toxicity in rat cerebellar granule neurons (CGNs). In our experiments, acute exposure of CGNs to micromolar concentrations of PCP induced the transcriptional activity of genes related to the classical apoptosis pathway (caspase 3, caspase 8, Bad), oxidative stress and glutathione metabolism (glutathione peroxidase-1, catalase, glutathione-S-transferase-3 and superoxide dismutase-1), and mitogenic response (cyclin D1, cdk2, cdk4, cdkn2b). Results from Western blot also shown significative increases in the expression of cyclins D1, E and A and cdk4. The mitogenic response was also related to a significative increase in the phosphorylation of retinoblastoma protein (Rb). PCP would cause apoptosis up-regulating the transcriptional activity of p53 gene and also increasing their activation by phosphorylation, concomitant with a decrease in the sirtuin 1 content. In conclusion, acute exposure of CGNs to PCP induces the classical p53 apoptotic pathway, promotes the up-regulation of several genes related to oxidative stress and the over-expression of molecules involved in the cell cycle control.
Folch
Jaume
J
Unitat de Bioquimica, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus (Tarragona), Spain.
Yeste-Velasco
Marc
M
Alvira
Daniel
D
de la Torre
Aureli Vázquez
AV
Bordas
Meritxell
M
López
Marta
M
Sureda
Francesc X
FX
Rimbau
Victor
V
Camins
Antoni
A
Pallàs
Mercè
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010416:Pentachlorophenol / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; D010416:Pentachlorophenol