title: Different modes of synergistic toxicities between metam/copper (II) and metam/zinc (II) in HepG2 cells: apoptosis vs. necrosis.
abstract: Both metam sodium and copper/zinc-containing compounds are widely used as fungicides. They therefore may co-occur in the biosphere. Despite certain studies of individual toxicity for either metam or copper (II)/zinc (II), their synergistic toxicity has not been examined. In this paper, a remarkable synergistic toxicity was observed in HepG2 cells when metam and copper (II)/zinc (II) at non-toxic and sub-toxic levels were combined. Unexpectedly, cell death modes between metam/copper (II) and metam/zinc (II) were different: For metam/copper (II), apoptosis was evident from morphological characteristics including cytoplasm-chromatin condensation, phosphatidylserine (PS) exposure, SubG0/G1DNA fragmentation, mitochondrial membrane potential decrease, pro/anti-apoptotic protein activation, and cytochrome c release; for metam/zinc (II), necrosis was evident from organelle swelling and uncontrolled collapse. To our knowledge, this work first not only demonstrates the synergistic toxicities of metam and both copper (II)/zinc (II), but also verifies the different modes of apoptosis/necrosis between metam/copper (II) and metam/zinc (II). © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1964-1973, 2016.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.|Environmental Engineering, Civil and Environmental Engineering Department, University of Delaware, USA.
authors.forename: Rui-Mei
authors.initials: RM
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
authors.forename: Ben-Zhan
authors.initials: BZ
authors.lastname: Zhu
authors.affiliation: Environmental Engineering, Civil and Environmental Engineering Department, University of Delaware, USA.
authors.forename: Chin-Pao
authors.initials: CP
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Sheng
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.affiliation: Environmental Engineering, Civil and Environmental Engineering Department, University of Delaware, USA.
authors.forename: Ming-Xin
authors.initials: MX
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002413:Cations, Divalent; D016923:Cell Death; D003300:Copper / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D056945:Hep G2 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D009336:Necrosis; D010575:Pesticides / Q000633:toxicity*; D013859:Thiocarbamates / Q000633:toxicity*; D015032:Zinc / Q000633:toxicity*
chemical_list: D002413:Cations, Divalent; D010575:Pesticides; D013859:Thiocarbamates; C008435:methyldithiocarbamate; D003300:Copper; D045304:Cytochromes c; D015032:Zinc
keywords: apoptosis; copper (II); metam; necrosis; synergistic toxicity; zinc (II)