Lindane and cell death: at the crossroads between apoptosis, necrosis and autophagy.
Lindane, a persistent organochlorine pesticide, is recognized as a major public health concern because of its potential toxic effects on human health. Despite observations pointing to the toxicity of lindane, mechanisms underlying its deleterious effects in liver have yet to be understood. In this study, we investigated the effects of lindane on autophagic, apoptotic and necrotic cell death in primary cultured rat hepatocytes. We found that lindane deregulated the autophagic process as demonstrated by (1) the formation of enlarged acidic vesicles labeled with LC3, Rab7 and LAMP1 (specific markers of autophagic vacuole maturation), (2) the conversion of LC3-I (the cytosolic form) into LC3-II (membrane bound), (3) the deregulation of the Beclin 1 protein expression and (4) the enhanced formation of the Bcl-xL/Beclin 1 complex. Lindane induced vacuolization together with the inhibition of spontaneous and intrinsic apoptosis. This disruption of cell suicide was linked to Bcl-xL up-regulation, Bax down-expression, prevention of cytochrome c release, and inhibition of caspase-9 and -3 activities. Lindane-induced disruption of apoptosis and autophagy occurred in parallel with necrosis induction in rat hepatocytes. In consequence, we proposed that lindane toxicity in primary rat hepatocytes could be jointly attributed to the disruption of autophagic process, the inhibition of apoptotic cell death and the induction of necrosis. These events account, at least in part, for the involvement of both cytotoxic and carcinogenic signaling pathways in the action of lindane in the liver.
Zucchini-Pascal
Nathalie
N
Laboratoire de Toxicologie Cellulaire, Moléculaire et Génomique, INRA, UMR 1089, 06903 Sophia Antipolis, France. zucchini@sophia.inra.fr
de Sousa
Georges
G
Rahmani
Roger
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers; D015153:Blotting, Western; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects*; D002469:Cell Separation; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000473:pathology / Q000648:ultrastructure; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D047468:Immunoprecipitation; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015415:Biomarkers; D007306:Insecticides; D001556:Hexachlorocyclohexane; D012313:RNA; D045304:Cytochromes c; D020169:Caspases