Ferrario Daniele, Collotta Angelo, Carfi Maria, Bowe Gerard, Vahter Marie, Hartung Thomas, Gribaldo Laura
ECVAM, Institute for the Health and Consumer Protection, JRC, 21027 Ispra, Italy.
Toxicology. 2009 Jun 16;260(1-3):132-41. doi: 10.1016/j.tox.2009.03.019. Epub 2009 Apr 9.
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.
无机砷（iAs）是一种人类致癌物，是一种众所周知的致染色体断裂化合物。为了评估亚砷酸盐（iAs(III)）毒性的分子机制，我们在体外研究了其对男性和女性人类脐带血细胞的细胞生长、凋亡、端粒长度、端粒酶表达以及活性氧（ROS）形成的影响。用浓度为0.0001微摩尔的iAs(III)孵育可增加端粒酶mRNA和蛋白质表达，维持端粒长度和细胞生长，并诱导癌基因ras和myc的mRNA过表达。我们的结果表明，在低浓度下，女性脐带血细胞比男性脐带血细胞对iAs(III)诱导的端粒酶刺激更敏感，这可能与癌基因ras和myc表达增加有关。相反，在浓度为1微摩尔时，iAs(III)降低了端粒酶表达和端粒长度，并诱导凋亡、坏死和活性氧的产生。谷胱甘肽（GSH）合成抑制剂丁硫氨酸亚砜胺（BSO）显著增加了凋亡细胞的百分比，表明GSH对于脐带血细胞中iAs(III)的解毒至关重要。活性氧（ROS）清除剂5,5-二甲基-1-吡咯啉-N-氧化物（DMPO）可保护脐带血细胞免受iAs(III)毒性，并防止端粒缩短和端粒酶下调。可以得出结论，端粒酶表达和端粒长度与iAs(III)诱导的细胞死亡有关，其通过活性氧的产生，也与iAs(III)对细胞分化过程和细胞生长速率的诱导作用有关。
