title: Hexachlorobenzene induces deregulation of cellular growth in rat liver.
abstract: Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the biosphere. The aim of the present study was to investigate the effect of HCB on the homeostasis of liver cell growth, analyzing parameters of cell proliferation and apoptosis, in HCB (0.1, 1, 10 and 100 mg/kg body weight)-treated rats, during 4 weeks. Cell proliferation and ERK1/2 phosphorylation, associated with survival mechanisms, were increased at HCB 100 mg/kg. The pesticide increased the number of apoptotic cells, and the activation of caspase-3, -9 and -8, in a dose-dependent manner, suggesting that HCB-induced apoptosis is mediated by caspases. Increased Fas and FasL protein levels indicate that the death receptor pathway is also involved. This process is associated with decreased Bid, and increased cytosolic cytochrome c protein levels. Transforming growth factor-beta1 (TGF-β1) intervenes in apoptotic and/or proliferative processes in hepatocytes. TGF-β1 cDNA and protein levels are dose-dependently increased, suggesting that this cytokine might be involved in HCB-induced dysregulation of cell proliferation and apoptosis. In conclusion, this study reports for the first time that HCB induces loss of the homeostatic balance between cell growth and cell death in rat liver. Induced apoptosis occurs by mechanisms involving signals emanating from death receptors, and the mitochondrial pathway.
authors.affiliation: Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, CP 1121, Argentina. lauragiribaldi@hotmail.com
authors.forename: Laura
authors.initials: L
authors.lastname: Giribaldi
authors.forename: Florencia
authors.initials: F
authors.lastname: Chiappini
authors.forename: Carolina
authors.initials: C
authors.lastname: Pontillo
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Randi
authors.forename: Diana L
authors.initials: DL
authors.lastname: Kleiman de Pisarev
authors.forename: Laura
authors.initials: L
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006581:Hexachlorobenzene / Q000633:toxicity*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D010575:Pesticides; D053773:Transforming Growth Factor beta1; D006581:Hexachlorobenzene; D012313:RNA; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases