title: Molecular mechanisms by which in vivo exposure to exogenous chemical genotoxic agents can lead to micronucleus formation in lymphocytes in vivo and ex vivo in humans.
abstract: The purpose of this review is to summarise current knowledge on the molecular mechanisms by which in vivo exposure to exogenous chemical genotoxins in humans induces micronuclei (MNi) and other nuclear anomalies in lymphocytes in vivo and ex vivo after nuclear division in vitro. MNi originate from acentric chromosome fragments and/or whole chromosomes that are unable to engage with the mitotic spindle and/or fail to segregate properly to the daughter nuclei during anaphase. The lagging fragments or whole chromosomes are surrounded by membrane and become MNi. Acentric fragments are caused by failure of repair or mis-repair of DNA strand breaks which may be induced by chemicals that (i) damage the phosphodiester backbone of DNA, and/or (ii) inhibit the DNA damage response mechanisms or repair of DNA strand breaks and/or (iii) cause DNA replication stress due to DNA adduct or cross-link formation. MNi originating from lagging whole chromosomes may be induced by chemicals that cause defects in centromeres or the mitotic machinery. Mis-repair of chemically-induced DNA breaks may also cause formation of dicentric chromosomes and nucleoplasmic bridges (NPBs) between daughter nuclei in mitosis. NPBs may break and initiate recurring breakage-fusion-bridge cycles and chromosomal instability. The review also explores knowledge on (i) the routes by which lymphocytes in the human body may be exposed to genotoxic chemicals, (ii) kinetics of MNi expression in lymphocytes in vivo and ex vivo in the lymphocyte cytokinesis-block micronucleus (L-CBMN) assay and (iii) current evidence on the efficiency of the L-CBMN assay in detecting in vivo exposure to chemical genotoxins and its concordance with MNi expression in epithelial tissues. The review also identifies important knowledge gaps (e.g. effect of nanomaterials; interactions with nutritional deficiencies etc.) regarding mechanisms by which in vivo chemical genotoxin exposure may cause MNi formation in lymphocytes in vivo and ex vivo in lymphocytes.
authors.affiliation: Commonwealth and Scientific Industrial Research Organization, Genome Health and Personalised Nutrition Laboratory, Food and Nutrition Flagship, Adelaide, South Australia 5000, Australia. Electronic address: michael.fenech@csiro.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Fenech
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Knasmueller
authors.affiliation: Environmental Carcinogenesis Unit, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale Ricerca sul Cancro, Largo Rosanna Benzi 10, Genova 16132, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bolognesi
authors.affiliation: Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonassi
authors.affiliation: School of Public Health, University of California, Berkeley, CA, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Holland
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Migliore
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, Via San Camillo de Lellis snc, 01100 Viterbo, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Palitti
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, Via San Camillo de Lellis snc, 01100 Viterbo, Italy.
authors.forename: Adayapalam T
authors.initials: AT
authors.lastname: Natarajan
authors.affiliation: Laboratory of Cell Genetics, Faculty of Science and Bio-Engineering, Free University of Brussels (VUB), Pleinlaan 2, 1050 Brussel, Belgium.
authors.forename: Micheline
authors.initials: M
authors.lastname: Kirsch-Volders
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D048629:Micronuclei, Chromosome-Defective; D009153:Mutagens / Q000633:toxicity*
chemical_list: D009153:Mutagens
keywords: Chemical; Ex vivo; Exogenous; Exposure; Genotoxins; Humans; In vivo; Lymphocytes; Mechanisms; Micronucleus; Molecular