title: The role of lysosomes in BDE 47-mediated activation of mitochondrial apoptotic pathway in HepG2 cells.
abstract: Polybrominated diphenyl ethers (PBDEs) are a group of widely used flame retardants. The rising presence of PBDEs in human tissues has received considerable concerns with regard to potential health risks. While the mitochondrial-apoptotic pathway has been suggested in PBDEs-induced apoptosis, the role of lysosomes is yet to be understood. In the present study, HepG2 cells were exposed to BDE 47 at various concentrations and durations to establish the causal and temporal relationships among various cellular events, such as cell viability, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, and expression of cytochrome C and caspase 3. The involvement of lysosomes was simultaneously studied by evaluating lysosomal membrane permeability (LMP) and changes in the expression of cathepsin B, a lysosome hydrolase. In addition, a cathepsin B inhibitor (10 μM CA-074) was used to determine the involvement of lysosomes and potential interactions between lysosomes and mitochondria. Our results showed that ROS production was an initial response of HepG2 to BDE 47 exposure, followed by a decreased MMP; a loss of MMP caused additional ROS generation which acted to induce LMP; an increased LMP resulted in a release of cathepsin B which aggravated the loss of MMP leading to release of cytochrome C and caspase 3 and subsequent apoptosis. Pretreatment with CA-074 did not abolish the initial ROS generation, however, all downstream events were dramatically alleviated. Taken together, our data indicate that lysosomes might be involved in BDE 47-mediated mitochondrial-apoptotic pathway in HepG2 cells, possibly through feedback interactions between mitochondria and lysosomes.
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China.
authors.forename: Chengquan
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Qian
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China; Dalian Key Laboratory of Hematology, Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Institute of Stem Cell Transplantation of Dalian Medical University, Dalian 116027, China. Electronic address: jshao@uw.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Shao
authors.affiliation: Dalian Key Laboratory of Hematology, Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Institute of Stem Cell Transplantation of Dalian Medical University, Dalian 116027, China. Electronic address: yanjsdmu@126.com.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Yan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D004785:Environmental Pollutants; D055768:Halogenated Diphenyl Ethers; C511295:2,2',4,4'-tetrabromodiphenyl ether
keywords: Apoptosis; Feedback interactions; Lysosomes; Mitochondria; PBDEs