title: The "adaptive responses" of low concentrations of HBCD in L02 cells and the underlying molecular mechanisms.
abstract: This study aimed to investigate the "adaptive responses" of hexabromocyclododecanes (HBCD) at environmentally relevant concentrations in human hepatocytes L02. L02 cells were pre-treated with low concentrations of HBCD (10(-13)-10(-11) M), followed by treatment with high concentrations of HBCD, α-hexachlorocyclohexane (α-HCH), polychlorinated biphenyls (PCBs), or polybrominated diphenyl ether-47 (BDE47). The results showed that the pre-treatment with low concentrations of HBCD induced "adaptive responses" to high concentrations of HBCD/α-HCH exposure (but not to PCBs and BDE47), as evidenced by attenuation of survival inhibition, reactive oxygen species (ROS) over-production, and deoxyribonucleic acid (DNA) damage induction. The "adaptive responses" induced by low concentrations of HBCD, which depended on the activation of the phosphatidylinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, reduced the phosphorylation of adenosine monophosphate-activated kinase (AMPK) and enhanced the phosphorylation of p38 mitogen-activated protein kinases (p38 MAPK). The observations were further confirmed by the experiments with inhibitors. Moreover, the evaluation on the changes of metabolic enzymes revealed that HBCD and α-HCH shared a similar pattern of cytochrome P450 induction (CYP2B6), which was different from those of PCBs and BDE47 (CYP1A1 and CYP2B6). These results indicated that low concentrations of HBCD could induce "adaptive responses" to the subsequent treatment with high concentrations of HBCD/α-HCH in L02 cells, which was associated with the PI3K/Akt pathway, and AMPK and p38 MAPK signaling. The "adaptive responses" seemed to be dependent on the types of chemicals in terms of the metabolic patterns and chemical structures.
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China. Electronic address: peace74839@shu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Guo
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, PR China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000222:Adaptation, Physiological; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000494:pharmacology*; D055768:Halogenated Diphenyl Ethers / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D055768:Halogenated Diphenyl Ethers; D006842:Hydrocarbons, Brominated; D017382:Reactive Oxygen Species; C511295:2,2',4,4'-tetrabromodiphenyl ether; C040534:alpha-hexachlorocyclohexane; D001556:Hexachlorocyclohexane; C089796:hexabromocyclododecane; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; HBCD; L02 cells; PI3K/Akt pathway; p38 MAPK