Autophagy is the predominant process induced by arsenite in human lymphoblastoid cell lines.
Arsenic is a widespread environmental toxicant with a diverse array of molecular targets and associated diseases, making the identification of the critical mechanisms and pathways of arsenic-induced cytotoxicity a challenge. In a variety of experimental models, over a range of arsenic exposure levels, apoptosis is a commonly identified arsenic-induced cytotoxic pathway. Human lymphoblastoid cell lines (LCL) have been used as a model system in arsenic toxicology for many years, but the exact mechanism of arsenic-induced cytotoxicity in LCL is still unknown. We investigated the cytotoxicity of sodium arsenite in LCL 18564 using a set of complementary markers for cell death pathways. Markers indicative of apoptosis (phosphatidylserine externalization, PARP cleavage, and sensitivity to caspase inhibition) were uniformly negative in arsenite exposed cells. Interestingly, electron microscopy, acidic vesicle fluorescence, and expression of LC3 in LCL 18564 identified autophagy as an arsenite-induced process that was associated with cytotoxicity. Autophagy, a cellular programmed response that is associated with both cellular stress adaptation as well as cell death appears to be the predominant process in LCL cytotoxicity induced by arsenite. It is unclear, however, whether LCL autophagy is an effector mechanism of arsenite cytotoxicity or alternatively a cellular compensatory mechanism. The ability of arsenite to induce autophagy in lymphoblastoid cell lines introduces a potentially novel mechanistic explanation of the well-characterized in vitro and in vivo toxicity of arsenic to lymphoid cells.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA.
Alicia M
AM
Bolt
Randi M
RM
Byrd
Walter T
WT
Klimecki
D017209:Apoptosis; D018053:Arsenites / Q000633:toxicity*; D001343:Autophagy; D002460:Cell Line; D003603:Cytotoxins / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure; D008954:Models, Biological; D017670:Sodium Compounds / Q000633:toxicity; D018675:Toxicity Tests
D018053:Arsenites; D003603:Cytotoxins; D004785:Environmental Pollutants; D017670:Sodium Compounds; C017947:sodium arsenite; C015001:arsenite