title: Endosulfan inhibits proliferation through the Notch signaling pathway in human umbilical vein endothelial cells.
abstract: Our previous research showed that endosulfan triggers the extrinsic coagulation pathway by damaging endothelial cells and causes hypercoagulation of blood. To identify the mechanism of endosulfan-impaired endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) with different concentrations of endosulfan, with and without an inhibitor for Notch, N-[N-(3, 5-difluorophenacetyl)-1-alanyl]S-Phenylglycinet-butylester (DAPT, 20 μM), or a reactive oxygen species (ROS) scavenger, N-Acetyl-l-cysteine (NAC, 3 mM), for 24 h. The results showed that endosulfan could inhibit cell viability/proliferation by increasing the release of lactate dehydrogenase (LDH), arresting the cell cycle in both S and G2/M phases, and inducing apoptosis in HUVECs. We also found that endosulfan can damage microfilaments, microtubules, and nuclei; arrest mitosis; remarkably increase the expressions of Dll4, Notch1, Cleaved-Notch1, Jagged1, Notch4, Hes1, and p21; and significantly induce ROS and malondialdehyde production in HUVECs. The presence of DAPT antagonized the above changes of cycle arrest, proliferation inhibition, and expressions of Dll4, Notch1, Cleaved-Notch1, Hes1, and p21 caused by endosulfan; however, NAC could attenuate LDH release; ROS and malondialdehyde production; apoptosis; and the expression levels of Dll4, Notch1, Cleaved-Notch1, Notch4, and Hes1 induced by endosulfan. These results demonstrated that endosulfan inhibited proliferation through the Notch signaling pathway as a result of oxidative stress. In addition, endosulfan can damage the cytoskeleton and block mitosis, which may add another layer of toxic effects on endothelial cells.
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Jialiu
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Lianshuang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Junchao
authors.initials: J
authors.lastname: Duan
authors.affiliation: National Research Centre for Environmental Toxicology (Entox), Member of Queensland Alliance for Environmental Health Science (QAEHS), The University of Queensland, Coopers Plains, 4108, Brisbane, QLD, Australia.
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, 100069, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, 100069, Beijing China. Electronic address: xqzhou@ccmu.edu.cn.
authors.forename: Xianqing
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004726:Endosulfan / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007306:Insecticides; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D004726:Endosulfan; D000111:Acetylcysteine
keywords: Cell cycle arrest; Cytoskeleton; Endosulfan; HUVECs; Notch signaling pathway