Tris (1,3-dichloro-2-propyl) phosphate induces toxicity by stimulating CaMK2 in PC12 cells.
Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is one of the widely used organophosphorus flame retardants (OPFRs), which are regarded as suitable substitutes for brominated flame retardants (BFRs). Previously, we have validated the toxicity of TDCIPP in PC12 cells owing to the induced alterations in GAP43, NF-H, CaMK2a/2b, and tubulin α/β proteins; however, limited information is currently available on the toxicity and mechanism of TDCIPP. In the present study, cytotoxicity effects were evaluated by exposing PC12 cells to different concentrations of TDCIPP (0-50 μM) for 4 days. To explore the possible mechanisms through which cytotoxicity is induced, changes in intracellular [Ca2+]ilevels and the activation of calmodulin dependent protein kinase 2 (CaMK2), c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases (ERK1/2), and p38 mitogen-activated protein kinases (MAPK) pathways were evaluated. Furthermore, PC12 cells were pretreated with CaMK2 inhibitor KN93 to investigate the relationship between TDCIPP-induced phosphorylation of CaMK2 and activation of JNK, ERK1/2, and p38 MAPK pathways. Our results indicate that TDCIPP-induced toxicity might be associated with the overload of [Ca2+]ilevels, increased phosphorylation of CaMK2, and activation of the JNK, ERK1/2, and p38 MAPK pathways, the lattermost of which was further demonstrated to be partially elicited by the CaMK2 phosphorylation.
Department of Toxicology, A Key Laboratory of Risk Assessment and Control for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin, China.|Department of Chronic Disease Prevention and Treatment, Mentougou Center for Disease Prevention and Control, Beijing, China.
Chaonan
C
Li
Department of Toxicology, A Key Laboratory of Risk Assessment and Control for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin, China.
Li
L
Li
Department of Toxicology, A Key Laboratory of Risk Assessment and Control for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin, China.
Bencheng
B
Lin
Department of Toxicology, A Key Laboratory of Risk Assessment and Control for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin, China.
Yanjun
Y
Fang
Department of Toxicology, A Key Laboratory of Risk Assessment and Control for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin, China.
Honglian
H
Yang
Department of Toxicology, A Key Laboratory of Risk Assessment and Control for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin, China.
Huanliang
H
Liu
Department of Toxicology, A Key Laboratory of Risk Assessment and Control for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin, China.
Zhuge
Z
Xi
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005411:Flame Retardants / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000633:toxicity*; D016716:PC12 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005411:Flame Retardants; D009943:Organophosphorus Compounds; C016805:tris(1,3-dichloro-2-propyl)phosphate; D017346:Protein Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
calmodulin dependent protein kinase; intracellular calcium ions; mitogen-activated protein kinases; toxicity; tris (1,3-dichloro-2-propyl) phosphate