title: Endosulfan induces COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways.
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.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
authors.forename: Young Ran
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
authors.forename: Tilak
authors.initials: T
authors.lastname: Khanal
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
authors.forename: Minh Truong
authors.initials: MT
authors.lastname: Do
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea.
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Jin
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Han
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-Gu, Daejeon, 305-764, Republic of Korea. hgjeong@cnu.ac.kr.
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015232:Dinoprostone / Q000378:metabolism; D004726:Endosulfan / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D015232:Dinoprostone; D004726:Endosulfan; D000111:Acetylcysteine
keywords: COX-2; Endosulfan; NADPH oxidase; ROS