˜Theœ micronucleus assay in toxicology

682 Pages·2019·15.854 MB·English

by  Fenech, Michael, Knasmüller, Siegfried

The Micronucleus Assay in Toxicology
1
0
0
P
F
4-
0
6
3
1
0
8
8
7
1
8
7
9
9/
3
0
1
0.
1
oi:
d
g |
or
c.
s
s.r
b
u
p
s://
p
htt
n
o
9
1
0
2
y
ul
J
8
1
on
d
e
h
s
bli
u
P
View Online
Issues in Toxicology
Editor-­in-c­hief:
Diana Anderson, University­of­Bradford,­UK
1
00 Series­editors:
P
4-F Michael D. Waters, Michael­Waters­Consulting,­USA
60 Timothy C. Marrs, Edentox­Associates,­UK
3
1
0
8
78 Editorial­advisor:
1
8
7 Alok Dhawan, CSIR-­Indian­Institute­of­Toxicology­Research,­Lucknow,­India
9
9/
3
0
0.1 Titles­in­the­Series:
1
oi: 1: Hair in Toxicology: An Important Bio- monitor
d
g | 2: Male- mediated Developmental Toxicity
or 3: Cytochrome P450: Role in the Metabolism and Toxicity of Drugs and
c.
s.rs other Xenobiotics
b
u 4: Bile Acids: Toxicology and Bioactivity
p
s:// 5: The Comet Assay in Toxicology
p
htt 6: Silver in Healthcare
on 7: In­Silico Toxicology: Principles and Applications
9
1 8: Environmental Cardiology
0
2
y 9: Biomarkers and Human Biomonitoring, Volume 1: Ongoing Programs
ul
8 J and Exposures
1
on 10: Biomarkers and Human Biomonitoring, Volume 2: Selected
d Biomarkers of Current Interest
e
h
s 11: Hormone- disruptive Chemical Contaminants in Food
bli
u 12: Mammalian Toxicology of Insecticides
P
13: The Cellular Response to the Genotoxic Insult: The Question
of Threshold for Genotoxic Carcinogens
14: Toxicological Effects of Veterinary Medicinal Products in Humans:
Volume 1
15: Toxicological Effects of Veterinary Medicinal Products in Humans:
Volume 2
16: Aging and Vulnerability to Environmental Chemicals: Age-r elated
Disorders and their Origins in Environmental Exposures
17: Chemical Toxicity Prediction: Category Formation and Read-a cross
18: The Carcinogenicity of Metals: Human Risk Through Occupational
and Environmental Exposure
19: Reducing, Refining and Replacing the Use of Animals in
Toxicity Testing
20: Advances in Dermatological Sciences
View Online
21: Metabolic Profiling: Disease and Xenobiotics
22: Manganese in Health and Disease
23: Toxicology, Survival and Health Hazards of Combustion Products
24: Masked Mycotoxins in Food: Formation, Occurrence and
Toxicological Relevance
1
0 25: Aerobiology: The Toxicology of Airborne Pathogens and Toxins
0
P
F 26: Chemical Warfare Toxicology, Volume 1: Fundamental Aspects
4-
0 27: Chemical Warfare Toxicology, Volume 2: Management of
6
3
1 Poisoning
0
8
8 28: Toxicogenomics in Predictive Carcinogenicity
7
1
8 29: Human Stem Cell Toxicology
7
9
9/ 30: The Comet Assay in Toxicology, 2nd edition
3
10 31: Computational Systems Pharmacology and Toxicology
0.
1 32: Ecotoxicology and Genotoxicology: Non- traditional
oi:
d Terrestrial Models
org | 33: Ecotoxicology and Genotoxicology: Non- traditional Aquatic Models
sc. 34: Oxidative Stress and Redox Signalling in Parkinson's Disease
bs.r 35: Nanotoxicology: Experimental and Computational Perspectives
u
s://p 36: Regulatory Toxicology in the European Union
p 37: Formaldehyde: Exposure, Toxicity and Health Effects
htt
n 38: Chemical Health Threats: Assessing and Alerting
o
9 39: The Micronucleus Assay in Toxicology
1
0
2
y
ul
J
8
1
on
d
e
h
s
bli
u
P
How­to­obtain­future­titles­on­publication:
A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.
For­further­information­please­contact:
Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: [phone], Fax: [phone]
Email: [email protected]
Visit our website at www.rsc.org/books
View Online
1
0
0
P
F
4-
0
6
3
1
0
8
8
7
1
8
7
9
9/
3
0
1
0.
1
oi:
d
g |
or
c.
s
s.r
b
u
p
s://
p
htt
n
o
9
1
0
2
y
ul
J
8
1
on
d
e
h
s
bli
u
P
View Online
The Micronucleus Assay in
Toxicology
1
0
0
P
F
4-
0
6
3
01 Edited by
8
8
7
1
78 Siegfried Knasmüller
9
39/ Medical­University­of­Vienna,­Austria
0
0.1 Email: [email protected]
1
oi:
d
g | and
or
c.
s.rs Michael Fenech
b
u Genome­Health­Foundation­and
p
s:// HUMN­Project­Coordinating­Group,­Australia
p
htt Email: [email protected]
n
o
9
1
0
2
y
ul
J
8
1
on
d
e
h
s
bli
u
P
View Online
1
0
0
P
F
4-
0
6
3
1
0
8
8
7
1 Issues in Toxicology No. 39
8
7
9
39/ Print ISBN: 978-1 - 78801- 134- 1
0
1 PDF ISBN: 978- 1- 78801-3 60- 4
0.
oi:1 EPUB ISBN: 978- 1- 78801- 849- 4
d Print ISSN: 1757- 7179
org | Electronic ISSN: 1757- 7187
c.
s
s.r A catalogue record for this book is available from the British Library
b
u
p
s:// © The Royal Society of Chemistry 2019
p
htt All­rights­reserved
n
o
9
1 Apart­from­fair­dealing­for­the­purposes­of­research­for­non-c­ommercial­purposes­or­for­
0
y 2 private­study,­criticism­or­review,­as­permitted­under­the­Copyright,­Designs­and­Patents­
Jul Act­1988­and­the­Copyright­and­Related­Rights­Regulations­2003,­this­publication­may­
8
1 not­be­reproduced,­stored­or­transmitted,­in­any­form­or­by­any­means,­without­the­prior­
on permission­in­writing­of­The­Royal­Society­of­Chemistry­or­the­copyright­owner,­or­in­
d
he the­case­of­reproduction­in­accordance­with­the­terms­of­licences­issued­by­the­Copyright­
s
bli Licensing­Agency­in­the­UK,­or­in­accordance­with­the­terms­of­the­licences­issued­by­the­
u
P appropriate­Reproduction­Rights­Organization­outside­the­UK.­Enquiries­concerning­
reproduction­outside­the­terms­stated­here­should­be­sent­to­The­Royal­Society­of­­
Chemistry­at­the­address­printed­on­this­page.
Whilst­this­material­has­been­produced­with­all­due­care,­The­Royal­Society­of­­
Chemistry­cannot­be­held­responsible­or­liable­for­its­accuracy­and­completeness,­nor­
for­any­consequences­arising­from­any­errors­or­the­use­of­the­information­contained­in­
this­publication.­The­publication­of­advertisements­does­not­constitute­any­endorsement­
by­The­Royal­Society­of­Chemistry­or­Authors­of­any­products­advertised.­The­views­and­
opinions­advanced­by­contributors­do­not­necessarily­reflect­those­of­The­Royal­Society­­
of­Chemistry­which­shall­not­be­liable­for­any­resulting­loss­or­damage­arising­as­a­result­
of­reliance­upon­this­material.
The Royal Society of Chemistry is a charity, registered in England and Wales, Number
207890, and a company incorporated in England by Royal Charter (Registered No.
RC000524), registered office: Burlington House, Piccadilly, London W1J 0BA, UK,
Telephone: [phone].
For further information see our web site at www.rsc.org
Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK
7
0
0
P
F
4-
0
6 Preface
3
1
0
8
8
7
1
8
7
9
9/
3
0
1
0.
oi:1 Micronuclei (MN) are at present the most widely used biomarker for the
g | d detection of DNA damage at the chromosomal level in human and eukary-
or otic cells across many species both in vitro and in vivo. They are cellular
sc. structures which contain fragments of chromosomes or whole chromo-
s.r
b somes that have been excluded from replicating nuclei at the late anaphase/
u
p
s:// telophase stage of mitosis. MN containing chromosome fragments are a
http biomarker of DNA breakage, and MN containing whole chromosomes are
n a biomarker of either malfunction of the centromeres or kinetochores of
o
19 chromosomes or damage to the mitotic machinery required to segregate
0
y 2 chromosomes after DNA replication. It is known that chromosomal insta-
Jul bility detected with the MN method is causally related to a wide range of
8
1 diseases, particularly to cancer.
d on MN tests are simple, robust and amenable to automation. Their utility
e
sh in toxicology is underscored by international acceptance as tests for DNA
ubli damage in human and rodent cells caused by genotoxic chemicals and radi-
P
ation and by the development of regulatory guidelines for these purposes.
More than 10 000 papers on the biology of MN generally and at least 3800
scientific papers have been published in peer-r eviewed journals on the use
of MN assays to measure DNA damage. Our aim was to capture this wealth
of knowledge on the MN assay and its application in genetic toxicology into
a single reference book for use by students, lecturers, established scientists,
and health professionals.
The book is divided into three sections: (i) The origins of MN and their
association with diseases (four chapters); (ii) The in vitro and in vivo applica-
tion of MN assays in experiments using cells from humans, rodents and other
species (17 chapters) and (iii) MN assays and their application to study DNA

Issues in Toxicology No. 39
The Micronucleus Assay in Toxicology
Edited by Siegfried Knasmüller and Michael Fenech
© The Royal Society of Chemistry 2019
Published by the Royal Society of Chemistry, www.rsc.org
vii
View Online
viii Preface
damage induced by in vivo exposure to genotoxins in humans (17 chapters).
The second section also includes information on appropriate study design,
statistical analyses of MN data in various research scenarios and the current
status of automated methods for scoring MN in human and rodent cells.
The unique appeal of this book is that each chapter is written by a rec-
7
0 ognised expert in the application of MN assays either in humans or rodents
0
P
F or in other eukaryotic species relevant to application in different ecosystems,
4-
0 such as MN assays in fish, amphibians, reptiles and plants. The chapters in
6
3
1 Section 1 describe how the MN assay evolved from classical metaphase analy-
0
8
8 sis of chromosomes, the molecular origins of DNA damage and defects of the
7
1
8 mitotic machinery that lead to MN formation, the fate of cells with MN and
7
9
9/ the association of increased MN frequencies in human cells in vivo or ex vivo
3
10 with infertility, pregnancy complications, developmental diseases, inflam-
0.
1 mation and age-r elated chronic diseases, cardiovascular and neurological
oi:
d diseases, premature ageing syndromes and cancer, for which the current evi-
org | dence for plausibility and causality is strongest.
sc. The chapters in Section 2 provide the most relevant aspects of the MN assay
bs.r methodology that are used across a wide range of cell types and species. This
u
s://p includes a brief description of the biology of the cell types and why they are
p used in MN experiments, a succinct description of the method concerning
htt
n the most critical aspects such as cell collection, and its timing relative to
o
9 exposure, fixation as well as staining and scoring methods, a photo gallery of
1
0
2 cells with MN and other nuclear anomalies accompanied by line diagrams of
y
ul the cells, a description of scoring criteria, common technical problems and
J
18 how to overcome them, knowledge and technological gaps that need to be
on addressed in the future, and references to the key papers that describe the
d
he method in greater detail for those who want to establish the assay in their
s
bli laboratory.
u
P
Section 3 includes a selection of papers that systematically review the
results of the application of the MN assay to measure DNA damage in humans
exposed occupationally or via their lifestyle to a wide range of genotoxins
(e.g. heavy metals, industrial organic chemicals, cytotoxic drugs, coal dust,
asbestos, pesticides, ionising and non-i onising radiation, tobacco, etc.) and
critically identify the strength and weaknesses of currently available data.
Meta- analyses of previous studies are reported depending on the quality and
heterogeneity of study design.
The purpose of this book is to provide a strong foundation to further
improve the MN assay and broaden its application by using the emerging
cytome approaches that include additional biomarkers such as nucleoplas-
mic bridges and nuclear buds as well centromere detection in MN that com-
plement the conventional MN assays. These novel ancillary biomarkers and
their close mechanistic relationship with MN are described in some of the
chapters in the book.
View Online
Preface ix
The deeper understanding of the MN assay that this book provides should
stimulate the evolution of better application of MN assays across species
for the detection of genotoxic agents in the environment and to define their
dose–response characteristics (independently or interactively with other fac-
tors such as genotype, co- exposure with other genotoxins, nutritional defi-
7
0 ciency or excess).
0
P
F The editors are very thankful to all of the authors of the chapters in this
4-
0 book for the dedication of their time to this important endeavour. We are
6
3
1 also grateful to Armen Nersesyan for assisting with the review of chapters
0
8
8 contributed to this book. Finally, we appreciate very much working with the
7
1
8 Royal Society of Chemistry via their Commissioning Editors Rowan Frame
7
9
9/ and Robin Driscoll and Editorial Assistant Katie Morrey, without whom this
3
10 book could not have been realised.
0.
1
oi: Siegfried Knasmüller and Michael Fenech
d
g |
or
c.
s
s.r
b
u
p
s://
p
htt
n
o
9
1
0
2
y
ul
J
8
1
on
d
e
h
s
bli
u
P
1
1
0
P
F
4-
0
6 Contents
3
1
0
8
8
7
1
8
7
9
9/
3
0 Section 1: The Origins of Micronuclei and their Association
1
0.
1 with Disease
oi:
d
g |
or
c. Chapter 1 A Short Personal History of Micronuclei 3
s
s.r John Heddle
b
u
p
s:// References 6
p
htt
n
9 o Chapter 2 Mechanisms by Which Genotoxins Cause Micronuclei and
1
0 Other Nuclear Anomalies 8
2
uly Michael Fenech
J
8
1
on 2.1 Introduction 8
d
e 2.2 Molecular Mechanisms by Which Genotoxins Induce
h
s
bli MN and Other Nuclear Anomalies 10
u
P 2.2.1 The Molecular Mechanisms by Which DNA
and Protein Lesions Induced by Genotoxins
in Circulating Lymphocytes In Vivo can be
Expressed as MN and Other Nuclear
Anomalies Ex Vivo 13
2.2.2 Important Knowledge Gaps Regarding
Mechanisms by Which Genotoxic Chemicals
Induce MN in Lymphocytes In Vivo and Ex Vivo 17
2.2.3 Conclusions 18
2.2.4 Further Reading 18
References 19

Issues in Toxicology No. 39
The Micronucleus Assay in Toxicology
Edited by Siegfried Knasmüller and Michael Fenech
© The Royal Society of Chemistry 2019
Published by the Royal Society of Chemistry, www.rsc.org
xi