Comparative toxicity and apoptosis induced by diorganotins in rat pheochromocytoma (PC12) cells
1School of Pharmaceutical Science, Shanxi Medical University, No. 56, Xinjian Nan Road, Taiyuan 030001, Shanxi, People's Republic of China.
Abstract:
As ubiquitous environmental toxicants, organotin (IV) compounds (OTC) accumulate in the food chain and potential effects on human health are disquieting. The present study compared the cytotoxicity of three diorganotins, namely, dimethyltin (DMT), dibutyltin (DBT) and diphenyltin (DPT), in rat pheochromocytoma (PC12) cells, and the molecular mechanisms responsible for their cytotoxic effects were also explored. Twenty-four hours exposure of PC12 cells to DBT and DPT resulted in a concentration-dependent decrease in cell viability with median lethal concentration (LC₅₀) of 2.97 μM and 7.24 μM, respectively. However, DMT at concentrations up to 128 μM had no obvious effect on cell viability. The mechanistic study revealed that the extent of apoptosis was greater for DBT than that for DPT, followed by DMT, as evidenced by acridine orange/ethidium bromide (AO/EB) fluorescent staining method and annexin V-FITC/PI staining flow cytometry analysis, as well as generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) disruption, release of cytochrome c (Cyt c), and consequent activation of caspase-9, and -3. These investigations suggested that the cytotoxic potency of three diorganotins in PC12 cells was in the order of DBT>DPT≫DMT, and these compounds could induce PC12 cells apoptosis through ROS mediated mitochondrial pathway.
Insights
Dibutyltin (DBT) and diphenyltin (DPT) exhibit significant cytotoxicity in PC12 cells, inducing apoptosis via reactive oxygen species (ROS) and mitochondrial pathways. Dimethyltin (DMT) showed minimal toxicity.
Area of Science:
- Environmental toxicology
- Cellular toxicology
- Neuroscience research
Background:
- Organotin compounds (OTC) are widespread environmental toxicants with potential human health impacts.
- Diorganotins, including dimethyltin (DMT), dibutyltin (DBT), and diphenyltin (DPT), are of particular concern.
- Understanding their cytotoxic mechanisms in neuronal cells is crucial.
Purpose of the Study:
- To compare the cytotoxicity of DMT, DBT, and DPT in rat pheochromocytoma (PC12) cells.
- To elucidate the molecular mechanisms underlying their toxic effects.
- To establish the relative toxicity order of these diorganotins.
Main Methods:
- PC12 cells were exposed to varying concentrations of DMT, DBT, and DPT.
- Cell viability was assessed using median lethal concentration (LC₅₀) determination.
- Apoptosis was evaluated through acridine orange/ethidium bromide staining, annexin V-FITC/PI flow cytometry, intracellular reactive oxygen species (ROS) detection, mitochondrial membrane potential (MMP) assessment, cytochrome c (Cyt c) release, and caspase activation (caspase-9, -3).
Main Results:
- DBT and DPT significantly reduced PC12 cell viability in a concentration-dependent manner (LC₅₀: DBT = 2.97 μM, DPT = 7.24 μM).
- DMT showed no significant cytotoxicity even at high concentrations (up to 128 μM).
- Apoptosis induction was highest for DBT, followed by DPT, and then DMT, involving ROS generation, MMP disruption, Cyt c release, and caspase activation.
Conclusions:
- The cytotoxic potency of the tested diorganotins in PC12 cells follows the order: DBT > DPT ≫ DMT.
- Organotin compounds induce apoptosis in PC12 cells through a ROS-mediated mitochondrial pathway.
- These findings highlight the differential toxicity of diorganotins and their potential neurotoxic effects.
