Lead Exposure Induces Telomere Instability in Human Cells

Abstract

Lead (Pb) is an important environmental contaminant due to its widespread use over many centuries. While it affects primarily every organ system of the body, the most pernicious effects of Pb are on the central nervous system leading to cognitive and behavioral modification. Despite decades of research, the mechanisms responsible for Pb toxicity remain poorly understood. Recent work has suggested that Pb exposure may have consequences on chromosomal integrity as it was shown that Pb exposure leads to the generation of γH2Ax foci, a well-established biomarker for DNA double stranded break (DSB formation). As the chromosomal localization of γH2Ax foci plays an important role in determining the molecular mechanism responsible for their formation, we examined the localization of Pb-induced foci with respect to telomeres. Indeed, short or dysfunctional telomeres (uncapped or damaged telomeres) may be recognized as DSB by the DNA repair machinery, leading to “telomere-Induced Foci” (TIFs). In the current study, we show that while Pb exposure did not increase intra-chromosomal foci, it significantly induced TIFs, leading in some cases, to chromosomal abnormalities including telomere loss. The evidence suggests that these chromosomal abnormalities are likely due to perturbation of telomere replication, in particular on the lagging DNA strand. We propose a mechanism by which Pb exposure leads to the loss of telomere maintenance. As numerous studies have demonstrated a role for telomere maintenance in brain development and tissue homeostasis, our results suggest a possible mechanism for lead-induced neurotoxicity.

Heavy metals in the cell nucleus - role in pathogenesis

“…K + or Na + , in previously formed G-quadruplexes and induce formation of additional Gquadruplex structures. The authors suggested that such G-quadruplexes may persist during telomere replication which results in telomere instability and perturbations in their maintenance (Pottier et al, 2013). Similar results were reported by Liu and coworkers (2004), who studied the effects of heavy metals on hepatocytes.…”

Telomere length in children environmentally exposed to low-to-moderate levels of lead

“…In in vitro studies, Pottier et al showed that Pb exposure leads to telomere instability and telomere loss due to the induction of γH2Ax foci, which are biomarkers of DNA double-strand breaks, at the end of chromosomes, near telomeres (Pottier et al, 2013). Such DNA breaks were previously reported in lead-exposed humans using the comet assay (Olewińska et al, 2010) or the micronuclei formation cytokinesis-block test (Kapka et al, 2007).…”

“…Because guanosine-rich telomeres form G-quadruplexes (Lu et al, 2013), one possible explanation for the observed shortening is the displacement of physiological ions by lead ions, which leads to more compacted G-quadruplex formation and in turn results in telomere instability and telomere maintenance impairment during replication (Pottier et al, 2013). In in vitro studies, Pottier et al showed that Pb exposure leads to telomere instability and telomere loss due to the induction of γH2Ax foci, which are biomarkers of DNA double-strand breaks, at the end of chromosomes, near telomeres (Pottier et al, 2013).…”

Molecular mechanisms of lead toxicity

“…It was proposed that the DNA damage inducing the formation of γH2Ax foci resulted from a direct interaction between Pb 2+ and chromosomal DNA (Gastaldo et al, 2007). An analysis of the lead-induced γH2Ax foci revealed that they are primarily associated with the telomeric regions (Pottier et al, 2013), suggesting the presence of uncapped or shortened telomeres recognized by the protein complexes responsible for repairing DNA damage as doublestrand breaks. An increased telomere loss and doublet formation in lead-treated cells were observed due to the presence of dysfunctional telomeres, possibly resulting from defects in the replication of the lagging strand (Pottier et al, 2013).…”