Oxidative Stress Contributes to Arsenic-induced Telomere Attrition, Chromosome Instability, and Apoptosis

Abstract

The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an antitumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome endto-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.Arsenic is a significant environmental concern worldwide because millions of people are at risk of drinking water contaminated by arsenic (1, 2). Epidemiological data show that chronic exposure of humans to inorganic arsenic is associated with hepatic injury, peripheral neuropathy, and increased rates of a wide variety of cancers, particularly of the skin, lung, bladder, and liver (3-5). Arsenic also produces toxic effects on the female reproductive system, including ovarian dysfunction (6), aberrant embryo development and lethality (7,8), and postnatal growth retardation (9). Interestingly, it also has proven useful for anti-cancer therapy (10 -12), although the mechanisms underlying its paradoxical (antineoplastic) effects remain unclear.Many possible modes of arsenic action have been proposed, including chromosomal abnormalities, oxidative stress, altered DNA repair and DNA methylation patterns, altered cell proliferation, abnormal gene amplification, and inhibition of p53 and telomerase (5, 13-18). In particular, arsenic exerts its toxicity by generating reactive oxygen species (ROS) 1 (19 -22). Mitochondria, the main source of ROS production, which also play a crucial role in the control of apoptosis (23, 24), have been implicated in arsenite-induced apoptosis (21, 25). Thus, mitochondrial dysfunction may explain the cytotoxicity and degenerative effects induced by arsenic. How ROS links arsenic exposure to carcinogenesis is still not well understood.Vertebrate telomeres consist of tandem repeats of G-rich sequence that cap the ends of chromosomes, protecting them from fusion and chromosomal instability...

Genome Integrity Is Regulated by theCaenorhabditis elegansRad51D Homologrfs-1

“…Over the past 10 years, it has become increasing clear that oxidative stress can induce telomeric shortening (Liu et al 2002(Liu et al , 2003Von Zglinicki 2002;Tchirkov and Lansdorp 2003) although the mechanism by which this occurs is not fully understood. Oxidative stress can both increase DNA lesions in telomeric DNA (Petersen et al 1998;Von Zglinicki et al 2000) and also disrupt the association of the essential telomere binding proteins, TRF1 and TRF2, which protect the ends from fusion (Opresko et al 2005).…”

“…Oxidative stress can both increase DNA lesions in telomeric DNA (Petersen et al 1998;Von Zglinicki et al 2000) and also disrupt the association of the essential telomere binding proteins, TRF1 and TRF2, which protect the ends from fusion (Opresko et al 2005). Other stresses including hyperoxia and heavy metal exposure also induce telomeric shortening (Von Zglinicki et al 1995;Liu et al 2003). In vivo studies have also suggested that stress can accelerate telomere shortening, although the heterogeneity of telomere lengths in normal tissues has precluded definitive proof of these events (reviewed in Von Zglinicki and Martin-Ruiz 2005).…”

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

“…It was recently found that in addition to the above actions, high doses of arsenic cause chromosomal abnormalities that can promote either genomic instability and carcinogenesis or cell death. [19][20][21] These effects result in most cases from the induction of an altered telomere state by oxidative stress due to the generation of reactive oxygen species (ROS) by As 2 O 3 treatment. [22][23][24] An inhibition of hTERT gene transcription leading to a decrease in telomerase activity (TA) has also been reported.…”

Increased hepatic telomerase activity in a rat model of iron overload: A role for altered thiol redox state?

“…Telomerase expression is reported to enhance resistance to apoptotic cell death in a variety of cell types, including those in which apoptosis is stimulated by exposure to oxidants [36][37][38][39][40][41]. Although the precise mechanisms accounting for resistance to apoptosis have not been elucidated, this effect of telomerase may be important in experimental liver injury.…”