Trichlorfon [O,O-dimethyl-(2,2,2-trichloro-1-hydroxyethyl)], a kind of organophosphorus pesticides, has been used as an insecticide on a large scale in crop protection and in the field of hygiene since 1952. In veterinary medicine it has been used against ecto- and endoparasites and in aquaculture against salmonlice. In human medicine trichlorfon (metrifonate) was used in the treatment against schistosomiasis, and it was in clinical trials for symptomatic treatment of Alzheimer's disease in the 20th century. In addition to acute cholinergic effects, trichlorfon is capable of causing a progressive delayed neurological deficit called organophosphate-induced delayed neurotoxicity (OPIDN), as well as chronic symptoms that persists for years after exposure. It was found that both light and electron microscopic changes in cerebellar cortex after trichlorfon treatment were characteristic of apoptosis and an increased level of apoptosis after trichlorfon treatment. However, the mechanism involved in this process remains unclear.
Professor Yi-Jun Wu and his team, Laboratory of Molecular Toxicology, Institute of Zoology, Chinese Academy of Sciences, have investigated trichlorfon toxicity and studied the mechanism involved in the trichlorfon-induced cell death using the SH-SY5Y human neuroblastoma cell line as a model system. In this study, they investigated the role of the endoplasmic reticulum pathway in apoptosis induced by trichlorfon in SH-SY5Y human neuroblastoma cells. Flow cytometric analysis demonstrated that trichlorfon and its degradation product dichlorvos induced apoptosis in a dose-dependent manner and Hoechst 33342 staining experiments revelaed trichlorfon/dichlorvos-induced nucleus condensation. Western blot analysis indicated decreased expression of caspase-12 and increased activated caspase-12 in trichlorfon-treated cells compared to a control, suggesting trichlorfon may induce apoptosis in SH-SY5Y partly via the endoplasmic reticulum. Intracellular Ca2+ level ([Ca2+]i) in SH-SY5Y cells increased after treatment with trichlorfon but was significantly reduced by pre-treatment with a combination of a calcium channel blocker, an inositol trisphosphate receptor inhibitor, and a ryanodine receptor inhibitor. Percent apoptosis and activated caspase-3 and caspase-12 decreased in pre-treated cells compared to those treated with trichlorfon alone. Trichlorfon induced apoptosis was also inhibited by the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA). These results suggest that endoplasmic reticulum stress, which is related to calcium, may be involved in the cytotoxicity of trichlorfon.
The results of this work were published in Chemico-Biological Interactions (Liu CY, Chang PA, Wu YJ*. Trichlorfon induces apoptosis in SH-SY5Y neuroblastoma cells via the endoplasmic reticulum? Chem-Biol Interact. 2009, 181:37-44).
The 5th International Conference on Rodent Biol...
