Protein phosphatases 2A as well as reactive oxygen species involved in tributyltin-induced apoptosis in mouse livers.
Tributyltin (TBT), a highly toxic environmental contaminant, has been shown to induce caspase-3-dependent apoptosis in human amniotic cells through protein phosphatase 2A (PP2A) inhibition and consequent JNK activation. This in vivo study was undertaken to further verify the results derived from our previous in vitro study. Mice were orally dosed with 0, 10, 20, and 60 mg/kg of body weight TBT, and levels of PP2A, reactive oxygen species (ROS), mitogen-activated protein kinase (MAPK), Bax/Bcl-2, and caspase-3 were detected in the mouse livers. Apoptosis was also evaluated using the TUNEL assay. The results showed that PP2A activity was inhibited, ROS levels were elevated, and MAPKs including ERK, JNK, and p38 were activated in mouse livers treated with the highest dose of TBT. Additionally, the ratio of Bax/Bcl-2 was increased, caspase-3 was activated, and apoptosis in mouse livers could be detected in the highest dose group. Therefore, a possible signaling pathway in TBT-induced apoptosis in mouse livers involves PP2A inhibition and ROS elevation serving a pivotal function as upstream activators of MAPKs; activation of MAPKs in turn leads to an increase in the Bax/Bcl-2 ratio, ultimately leading to the activation of caspase-3. The results give a comprehensive and novel description of the mechanism of TBT-induced toxicity.
Department of Biochemistry and Genetics, School of medicine, Zhejiang University, 866th Yu Hang Tang Road, 310058, Hangzhou, China.
Yali
Y
Zhang
Yonggang
Y
Chen
Lijun
L
Sun
Jing
J
Liang
Zonglou
Z
Guo
Lihong
L
Xu
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014220:Trialkyltin Compounds / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014220:Trialkyltin Compounds; D014874:Water Pollutants, Chemical; D051028:bcl-2-Associated X Protein; C011559:tributyltin; D020928:Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D053148:Caspase 3