Nonylphenol induces the death of neural stem cells due to activation of the caspase cascade and regulation of the cell cycle.
Endocrine disruptors (EDs) are a great concern throughout the world, because they have adverse effects on human health and wildlife. In the present study, we investigated the effects of EDs on the proliferation and survival of murine neural stem cells (NSCs). In contrast to bisphenol A, phthalic acid benzyl n-butyl ester, phthalic acid di-n-butyl ester and phthalic acid di(2-ethylhexyl) ester, the treatment of NSCs with 4-nonylphenol for 24 h inhibited cell growth in a concentration-dependent manner. In addition, treatment with 4-nonylphenol resulted in nuclear condensation and DNA fragmentation (morphological changes due to apoptosis) in NSCs after 12 h of exposure, and activated caspase-3 after 6 h and 9 h of exposure. Furthermore, an exposure to 4-nonylphenol led to the accumulation of cells at the G2/M phase interface and down-regulated the protein levels of cyclin A and B1, which are the major regulatory proteins at the G2 to M transition of the cell cycle. Together, these results indicate that, in contrast to other EDs, 4-nonylphenol may exhibit a potent cytotoxicity through apoptosis via the caspase cascade and cell cycle arrest at the G2/M phase, and suggest that 4-nonylphenol may affect neurogenesis in the CNS.
Kudo
Chiho
C
Department of Pharmacology, Graduate School of Dentistry, Osaka University, Japan.
Wada
Koichiro
K
Masuda
Tomotake
T
Yonemura
Toshimitsu
T
Shibuya
Atsuhito
A
Fujimoto
Yohko
Y
Nakajima
Atsushi
A
Niwa
Hitoshi
H
Kamisaki
Yoshinori
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D016213:Cyclins; D010636:Phenols; C025256:nonylphenol; D020169:Caspases