title: 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.
authors.affiliation: Commissariat à l'Energie Atomique (CEA), Laboratoire de Radiobiologie et Oncologie (LRO), Fontenay-aux-Roses, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Pottier
authors.forename: Muriel
authors.initials: M
authors.lastname: Viau
authors.forename: Michelle
authors.initials: M
authors.lastname: Ricoul
authors.forename: Grace
authors.initials: G
authors.lastname: Shim
authors.forename: Marion
authors.initials: M
authors.lastname: Bellamy
authors.forename: Corina
authors.initials: C
authors.lastname: Cuceu
authors.forename: William M
authors.initials: WM
authors.lastname: Hempel
authors.forename: Laure
authors.initials: L
authors.lastname: Sabatier
mesh_terms: D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000187:drug effects*; D004781:Environmental Exposure / Q000009:adverse effects; D006801:Humans; D007854:Lead / Q000009:adverse effects*; D007855:Lead Poisoning / Q000150:complications; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology*; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*
chemical_list: D007854:Lead