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Updated: May 26, 2026
Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Protein phosphatases 2A as well as reactive oxygen species involved in tributyltin-induced apoptosis in mouse livers
Yali Zhang1, Yonggang Chen, Lijun Sun
1Department of Biochemistry and Genetics, School of medicine, Zhejiang University, 866th Yu Hang Tang Road, 310058, Hangzhou, China.
Abstract:
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.
Insights
Tributyltin (TBT) exposure in mice induces liver apoptosis by inhibiting protein phosphatase 2A (PP2A) and increasing reactive oxygen species (ROS). This triggers MAPK activation, leading to caspase-3 mediated cell death.
Area of Science:
- Environmental Toxicology
- Cellular Biology
- Molecular Mechanisms
Background:
- Tributyltin (TBT) is a toxic environmental pollutant with known in vitro effects.
- Previous studies indicated TBT induces apoptosis via PP2A inhibition and JNK activation in human cells.
Purpose of the Study:
- To validate in vitro findings on TBT-induced apoptosis in an in vivo mouse model.
- To elucidate the molecular signaling pathway of TBT toxicity in mouse livers.
Main Methods:
- Mice were orally administered varying doses of TBT (0-60 mg/kg).
- Liver tissues were analyzed for PP2A activity, ROS, MAPK (ERK, JNK, p38) activation, Bax/Bcl-2 ratio, and caspase-3 levels.
- Apoptosis was assessed using the TUNEL assay.
Main Results:
- TBT exposure inhibited PP2A activity and increased ROS levels in mouse livers.
- MAPK activation (ERK, JNK, p38) and an elevated Bax/Bcl-2 ratio were observed.
- Caspase-3 activation and significant apoptosis were detected in TBT-treated livers.
Conclusions:
- TBT-induced liver apoptosis involves PP2A inhibition and ROS elevation, activating MAPKs.
- MAPK activation leads to altered Bax/Bcl-2 expression and caspase-3 activation, culminating in apoptosis.
- This study details a novel in vivo mechanism for TBT-induced hepatotoxicity.
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