Arsenic induces telomerase expression and maintains telomere length in human cord blood cells.
Inorganic arsenic (iAs) is a human carcinogen, well known as a clastogenic compound. To evaluate the molecular mechanism of arsenite (iAs(III)) toxicity, we investigated the effects on cell growth and apoptosis, telomere length, telomerase expression, as well as the formation of reactive oxygen species (ROS) in male and female human cord blood cells in vitro. Incubation with iAs(III) at the concentration of 0.0001 microM increased telomerase mRNA and protein expression maintained both telomere length and cellular growth, and induced mRNA over-expression of the two oncogenes ras and myc. Our results suggest that female cord blood cells are more sensitive than male ones to iAs(III) induced telomerase stimulation at low concentrations, possibly related to the increased expression of ras and myc oncogenes. On the contrary, at the concentration of 1 microM, iAs(III) decreased telomerase expression and telomere length, and induced apoptosis, necrosis and production of reactive oxygen species. Buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, markedly increased the percentage of apoptotic cells, suggesting that GSH is fundamental for detoxification of iAs(III) in cord blood cells. The reactive oxygen species (ROS) scavenger, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), protected cord blood cells from iAs(III) toxicity, and prevented telomere shortening and telomerase down-modulation. It can be concluded that telomerase expression and telomere length are associated with iAs(III) induced cell death, via production of reactive oxygen species, as well as with iAs(III) induced effects on cell differentiation processes and rate of cell growth.
Ferrario
Daniele
D
ECVAM, Institute for the Health and Consumer Protection, JRC, 21027 Ispra, Italy.
Collotta
Angelo
A
Carfi
Maria
M
Bowe
Gerard
G
Vahter
Marie
M
Hartung
Thomas
T
Gribaldo
Laura
L
D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005312:Fetal Blood / Q000187:drug effects* / Q000201:enzymology; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D017670:Sodium Compounds / Q000633:toxicity*; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
D018053:Arsenites; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; C017947:sodium arsenite; D019328:Buthionine Sulfoximine; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D019098:Telomerase; D018631:ras Proteins; D005978:Glutathione