Methylmercury-induced toxicity is mediated by enhanced intracellular calcium through activation of phosphatidylcholine-specific phospholipase C

Journal Article · Sun Oct 15 00:00:00 EDT 2006 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.04.016· OSTI ID:20850441

Kang, Mi Sun ^[1]; Jeong, Ju Yeon ^[1]; Seo, Ji Heui ^[1]; Jeon, Hyung Jun ^[1]; Jung, Kwang Mook ^[1]; Chin, Mi-Reyoung ^[1]; Moon, Chang-Kiu ^[2]; Bonventre, Joseph V ^[3]; Jung, Sung Yun ^[1]; Kim, Dae Kyong ^[1]

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1. Department of Environmental and Health Chemistry, College of Pharmacy, Chung-Ang University, Seoul, 221 Huksuk-Dong, Dongjak-Ku, Seoul 156-756 (Korea, Republic of)
2. College of Pharmacy, Seoul National University, Seoul (Korea, Republic of)
3. Renal Unit, Brigham Women's Hospital, Harvard Medical School, Boston, MA (United States)

Methylmercury (MeHg) is a ubiquitous environmental toxicant to which humans can be exposed by ingestion of contaminated food. MeHg has been suggested to exert its toxicity through its high reactivity to thiols, generation of arachidonic acid and reactive oxygen species (ROS), and elevation of free intracellular Ca{sup 2+} levels ([Ca{sup 2+}]{sub i}). However, the precise mechanism has not been fully defined. Here we show that phosphatidylcholine-specific phospholipase C (PC-PLC) is a critical pathway for MeHg-induced toxicity in MDCK cells. D609, an inhibitor of PC-PLC, significantly reversed the toxicity in a time- and dose-dependent manner with concomitant inhibition of the diacylglycerol (DAG) generation and the phosphatidylcholine (PC)-breakdown. MeHg activated the group IV cytosolic phospholipase A{sub 2} (cPLA{sub 2}) and acidic form of sphingomyelinase (A-SMase) downstream of PC-PLC, but these enzymes as well as protein kinase C (PKC) were not linked to the toxicity by MeHg. Furthermore, MeHg produced ROS, which did not affect the toxicity. Addition of EGTA to culture media resulted in partial decrease of [Ca{sup 2+}]{sub i} and partially blocked the toxicity. In contrast, when the cells were treated with MeHg in the presence of Ca{sup 2+} in the culture media, D609 completely prevented cell death with parallel decrease in [Ca{sup 2+}]{sub i}. Our results demonstrated that MeHg-induced toxicity was linked to elevation of [Ca{sup 2+}]{sub i} through activation of PC-PLC, but not attributable to the signaling pathways such as cPLA{sub 2}, A-SMase, and PKC, or to the generation of ROS.

• OSTI ID: 20850441
• Journal Information: Toxicology and Applied Pharmacology, Vol. 216, Issue 2; Other Information: DOI: 10.1016/j.taap.2006.04.016; PII: S0041-008X(06)00154-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
ARACHIDONIC ACID
CALCIUM IONS
CULTURE MEDIA
EGTA
ENZYMES
INGESTION
LECITHINS
METHYLMERCURY
THIOLS
TOXICITY