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

Michael Fenech, Siegfried Knasmueller, Claudia Bolognesi, Stefano Bonassi, Nina Holland, Lucia Migliore, Fabrizio Palitti, Adayapalam T. Natarajan, Micheline Kirsch-Volders

Research output: Contribution to journalReview article

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.

Original languageEnglish
Pages (from-to)12-25
Number of pages14
JournalMutation Research - Reviews in Mutation Research
Volume770
DOIs
Publication statusPublished - Oct 1 2016

Fingerprint

Lymphocytes
Chromosomes
DNA Breaks
Mutagens
Micronucleus Tests
Cytokinesis
Cell Nucleus Division
Chromosomal Instability
Anaphase
Spindle Apparatus
DNA Adducts
Nanostructures
Centromere
DNA Replication
Human Body
Mitosis
Malnutrition
DNA Damage
Epithelium
Membranes

Keywords

  • Chemical
  • Ex vivo
  • Exogenous
  • Exposure
  • Genotoxins
  • Humans
  • In vivo
  • Lymphocytes
  • Mechanisms
  • Micronucleus
  • Molecular

ASJC Scopus subject areas

  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this

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. / Fenech, Michael; Knasmueller, Siegfried; Bolognesi, Claudia; Bonassi, Stefano; Holland, Nina; Migliore, Lucia; Palitti, Fabrizio; Natarajan, Adayapalam T.; Kirsch-Volders, Micheline.

In: Mutation Research - Reviews in Mutation Research, Vol. 770, 01.10.2016, p. 12-25.

Research output: Contribution to journalReview article

Fenech, Michael ; Knasmueller, Siegfried ; Bolognesi, Claudia ; Bonassi, Stefano ; Holland, Nina ; Migliore, Lucia ; Palitti, Fabrizio ; Natarajan, Adayapalam T. ; Kirsch-Volders, Micheline. / 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. In: Mutation Research - Reviews in Mutation Research. 2016 ; Vol. 770. pp. 12-25.
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