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Arch Toxicol. 2015 Nov;89(11):2039-50. doi: 10.1007/s00204-014-1359-7. Epub 2014 Sep 9.

Endosulfan induces COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways.

Author information

1
Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
2
Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
3
Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea. hgjeong@cnu.ac.kr.

Abstract

Endosulfan (1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-en-2,3-ylenebismet-hylene) is correlated with endocrine disruption, reproductive, and immune dysfunctions. Recently, endosulfan was shown to have an effect on inflammatory pathways, but its influence on cyclooxygenase-2(COX-2) expression is unclear. This study investigated the effects of COX-2 and molecular mechanisms by endosulfan in murine macrophage RAW 264.7 cells. Endosulfan significantly induced COX-2 protein and mRNA levels, as well as COX-2 promoter-driven luciferase activity and the production of prostaglandin E2, a major COX-2 metabolite. Transfection experiments with several human COX-2 promoter constructs revealed that endosulfan activated NF-κB, C/EBP, AP-1, and CREB. Moreover, Akt and mitogen-activated protein kinases (MAPK) were significantly activated by endosulfan. Moreover, endosulfan increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2, and NOX3. Endosulfan-induced Akt/MAPK pathways and COX-2 expression were attenuated by DPI, a specific NOX inhibitor, and the ROS scavenger N-acetylcysteine. These results demonstrate that endosulfan induces COX-2 expression via NADPH oxidase, ROS, and Akt/MAPK pathways. These findings provide further insight into the signal transduction pathways involved in the inflammatory effects of endosulfan.

KEYWORDS:

COX-2; Endosulfan; NADPH oxidase; ROS

PMID:
25199686
DOI:
10.1007/s00204-014-1359-7
[Indexed for MEDLINE]

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