Inhibitory effects of ochratoxin A on nerve growth factor-induced neurite extension through downregulation of p38 MAP kinase and AP-1 activation in cultured pheochromocytoma cells.
Ochratoxin A (OTA) induces microcephaly in animals and in vitro cultured whole embryos. Inhibition of neuronal cell differentiation was proposed as underlying mechanisms responsible for OTA-induced microcephaly. Previously it was found that OTA inhibited differentiation of cultured rat embryonic midbrain cells into neurons. In this study, the influence of OTA on differentiation in PC-12 cells, a widely accepted model cells for study of neuronal differentiation was examined. Cell differentiation was assessed by measurement of neurite extension and quantified by the number of neurites extended. OTA decreased serum and nerve growth factor (NGF)-induced neurite extension in a concentration-dependent manner. Since MAP kinase and transcription factors have been implicated in cell differentiation of neuronal cells, and our previous study demonstrated that p38 MAP kinase and AP-1 are activated during PC 12 cell differentiation, the effect of OTA on NGF-induced p38 MAP kinase and transcription factor activation was examined. Co-treatment of OTA with NGF resulted in inhibition of NGF-induced p38 MAP kinase and AP-1 activation. Moreover, SB203580, a specific inhibitor of p38 MAP kinase blocked p38 MAP kinase and AP-1 activation accompanied by further inhibition of neurite extension. The present study shows that OTA inhibited cell differentiation of PC-12 cells, and this inhibitory effect may be related to inhibition of the activation of the p38 MAP kinase in conjunction with transcription factors AP-1. This finding suggests that the inhibitory effect on neuronal cell differentiation by OTA might be a mechanism responsible for OTA-induced microcephaly.
Oh
Jae Ho
JH
Korea Food and Drug Administration, Seoul, Korea.
Jung
Hai Kwan
HK
Park
Yun Ju
YJ
Kim
Cheul Kyu
CK
Chung
Soo Youn
SY
Park
Nam Gyu
NG
Yun
Young Won
YW
Kim
Dae Joong
DJ
Ha
Tae Youl
TY
Song
Yuen Sook
YS
Lee
Yoot Mo
YM
Oh
Ki wan
Kw
Hong
Jin Tae
JT
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002454:Cell Differentiation; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D016501:Neurites / Q000187:drug effects; D009793:Ochratoxins / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases
D002273:Carcinogens; D009793:Ochratoxins; C025589:ochratoxin A; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases