Signaling pathways of bisphenol A-induced apoptosis in hippocampal neuronal cells: role of calcium-induced reactive oxygen species, mitogen-activated protein kinases, and nuclear factor-kappaB.
In the present study, we investigated the neurotoxicity of bisphenol A [BPA; 2,2-bis-(4 hydroxyphenyl) propane] and the underlying mechanisms of action in mouse hippocampal HT-22 cells. BPA, known to be a xenoestrogen, is used in the production of water bottles, cans, and teeth suture materials. BPA-treated HT-22 cells showed lower cell viability than did controls at concentrations of BPA over 100 microM. BPA induced apoptotic cell death as indicated by staining with Hoechst 33258, costaining with Annexin V/propidium iodide, and activation of caspase 3. BPA regulated the generation of reactive oxygen species (ROS) by increasing intracellular calcium. BPA activated phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor (NF)-kappaB. Pretreatment with specific inhibitors for calcium, ROS, ERK, and JNK decreased BPA-induced cell death; however, inhibitor for NF-kappaB increased BPA-induced cell death. The results suggest that calcium, ROS, ERK, and JNK are involved in BPA-induced apoptotic cell death in HT-22 cells. In contrast, an NF-kappaB cascade was activated for survival signaling after BPA treatment.
CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Joong-gu, Daegu, Republic of Korea.
Soyoung
S
Lee
Kyoungho
K
Suk
In Kyeom
IK
Kim
Il-Sung
IS
Jang
Jin-Woo
JW
Park
Victor J
VJ
Johnson
Taeg Kyu
TK
Kwon
Byung-Ju
BJ
Choi
Sang-Hyun
SH
Kim
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010636:Phenols / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002118:Calcium; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009498:Neurotoxins; D010636:Phenols; D017382:Reactive Oxygen Species; C006780:bisphenol A; D000098826:Bisphenol A Compounds