title: The hormesis effect of BDE-47 in HepG2 cells and the potential molecular mechanism.
abstract: Polybrominated diphenyl ethers (PBDEs) had been used extensively in electrical and electronic products as brominated flame retardants. PBDEs are widely distributed in environment media and wildlife since they are lipophilic and persistent, resulting in bioaccumulation and bioamplification through food chains. Accumulation of PBDEs in the environment and human tissues will consequently cause potential negative effects on the ecological environment and human health. To date, some in vitro and in vivo studies have reported that PBDEs possess neurotoxicity, hepatotoxicity, immunotoxicity, reproduction toxicity, endocrine disrupting activity and carcinogenicity. BDE-47 is one of the most predominant PBDE congeners detected in human tissues. The objective of this study is to investigate whether low concentration of BDE-47 could cause hormesis effect in the human hepatoma HepG(2) cells, and to explore the possible molecular mechanism. The results showed that low concentration of BDE-47 (10(-10), 10(-9) and 10(-8) M) could promote cell proliferation and cause no obvious change in DNA damage or cell apoptosis, while the high concentration significantly inhibit cell proliferation. Meanwhile, the reactive oxygen species (ROS) in low concentration BDE-47 (10(-10), 10(-9) and 10(-8) M) treated groups significantly elevated compared with the control group. After low concentration BDE-47 treatment, the expression of proliferating cell nuclear antigen (PCNA), Cyclin D1, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylated protein kinase B (p-Akt) in the HepG(2) cells was markedly up-regulated. However, in DNA-PKcs inhibited cells, the promotion effect on cell proliferation was significantly suppressed. Cell cycle analysis showed a significant decrease in G1 phase after exposure to low concentration of BDE-47. Moreover, pre-exposure to low concentration BDE-47 seemed alleviate the negative effects of high concentration (50 μM) exposure to cause DNA damage and apoptosis. These results suggested that BDE-47 has a hormesis effect in HepG(2) cells and DNA-PKcs/Akt pathway may be involved in regulation of cell proliferation and apoptosis.
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China.
authors.forename: Liulin
authors.initials: L
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Zou
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhong
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Minghong
authors.initials: M
authors.lastname: Wu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D020552:Comet Assay; D019938:Cyclin D1 / Q000378:metabolism; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005411:Flame Retardants / Q000008:administration & dosage / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers; D056945:Hep G2 Cells; D059165:Hormesis / Q000187:drug effects*; D006801:Humans; D011075:Polybrominated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls; D018809:Proliferating Cell Nuclear Antigen; C511295:2,2',4,4'-tetrabromodiphenyl ether; D019938:Cyclin D1; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt