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Published on 27 November 2014 on http://pubs.rsc.org | doi:10.1039/9781782622383-FP001
Manganese in Health and Disease

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Issues in Toxicology
Series Editors:
Professor Diana Anderson, University of Bradford, UK
Dr Michael Waters, Integrated Laboratory Systems Inc, NC, USA

Dr Timothy C Marrs, Edentox Associates, Kent, UK
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Alok Dhawan, Ahmedabad University, India
Titles in the Series:

1: Hair in Toxicology: An Important Bio-Monitor
2: Male-mediated Developmental Toxicity
3: Cytochrome P450: Role in the Metabolism and Toxicity of Drugs and
other Xenobiotics
4: Bile Acids: Toxicology and Bioactivity
5: The Comet Assay in Toxicology
6: Silver in Healthcare
7: In Silico Toxicology: Principles and Applications
8: Environmental Cardiology
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9: Biomarkers and Human Biomonitoring, Volume 1: Ongoing Programs

and Exposures
10: Biomarkers and Human Biomonitoring, Volume 2: Selected Biomarkers
of Current Interest
11: Hormone-Disruptive Chemical Contaminants in Food
12: Mammalian Toxicology of Insecticides
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-related
Disorders and their Origins in Environmental Exposures
17: Chemical Toxicity Prediction: Category Formation and Read-Across
18: The Carcinogenicity of Metals: Human risk through occupational and
environmental exposure
19: Reducing, Refining and Replacing the Use of Animals in Toxicity
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22: Manganese in Health and Disease
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Published on 27 November 2014 on http://pubs.rsc.org | doi:10.1039/9781782622383-FP001 View Online
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Manganese in Health and

Disease
Edited by
Lucio G. Costa
University of Washington, Seattle, WA, USA
Email: lgcosta@u.washington.edu
Michael Aschner
Albert Einstein College of Medicine, Bronx, NY, USA
Email: michael.aschner@einstein.yu.edu
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Issues in Toxicology No. 22
Print ISBN: 978-1-84973-943-6

PDF eISBN: 978-1-78262-238-3
ISSN: 1757-7179
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A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2015
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For further information see our web site at www.rsc.org

Preface
Manganese (Mn) is the twelfth most abundant element in the Earth’s crust
and present in drinking water and in food. As an essential trace element, Mn
is required for multiple biochemical and cellular reactions, and is a neces-
sary component for numerous metallo-enzymes, such as Mn superoxide
dismutase, arginase, phosphoenol-pyruvate decarboxylase, and glutamine
synthase, to name a few.
Despite its essentiality, exposures to high levels of Mn from occupational,
iatrogenic, medical, and environmental exposures may contribute to human
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morbidity. Excessive Mn accumulation in the brain, primarily in basal

ganglia, may cause clinical signs and morphological lesions analogous to
those seen in Parkinson’s disease (PD). Other tissues may be affected as well.
Mn intoxication cases were originally described over two centuries ago.
Manganism, resulting from exposure to exceedingly high levels of this metal,
was originally described by James Couper (1837), providing insight into the
adverse neurological effects in five Scottish men employed in grinding Mn
dioxide ore. As Mn began to be used more widely in the steel alloy industry,
more cases were recognized, with stronger epidemiological evidence impli-
cating Mn in a number of neurological diseases. Contemporary exposures to
Mn at levels described by Couper are rare, yet concerns about the health
effects of Mn remain, given its abundant occurrence and the potential ex-
posures throughout various life-stages.
This book, to our knowledge, is the first multidisciplinary scientific en-
deavor to address the health effects of Mn. It aims to provide state-of-the-art
information and deepen the understanding of Mn’s adverse health effects. It
commences with a description on various pathways for Mn absorption (lung,
gastrointestinal tract, olfactory pathway), followed by its nutritional needs,
toxicokinetics and toxicodynamics. A large section of the book is devoted to
its adverse effects, emphasizing cellular and molecular mechanisms of

Edited by Lucio G. Costa and Michael Aschner
Published by the Royal Society of Chemistry, www.rsc.org
vii
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viii Preface
toxicity in a host of tissues and organs, particularly the nervous system, with
emphasis on sensitivity to Mn at various life-stages. We conclude with a list
of research needs that will further improve our understanding of the role of
Mn both in health and disease.
We called upon internationally recognized experts on Mn to address

and facilitate the understanding of its role in health and disease, making
a valiant attempt to provide as broad and multidisciplinary approach as
possible. Our goal was to assemble a series of chapters that advance the
latest developments and scientific breakthroughs in this fast-paced research
area, and to provide information that should be of interest to risk assessors,
neurobiologists, and neurotoxicologists, as well as metal and trace element
biologists. We are hopeful that the book offers the reader appreciation and
renewed sense on contemporary issues in Mn research. We are indebted to
the authors for their contributions and hope that, as a reader, whether you
are a novice or a seasoned Mn researcher, the knowledge amassed herein
will stimulate and transform your novel ideas into better understanding on
the role of this unique metal in health and disease.
Michael Aschner
Lucio G. Costa
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Contents
Chapter 1 Manganese Transport, Trafficking and Function in

Invertebrates 1
Amornrat Naranuntarat Jensen and Laran T. Jensen
1.1 Introduction 1
1.2 Function of Manganese in Biological Systems 2
1.2.1 Manganese Metalloenzymes 2
1.2.2 Non-Protein Manganese Antioxidants 2
1.2.3 Manganese and Bacterial Virulence 4
1.3 Manganese Transport in Bacteria 4
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1.3.1 Bacterial Manganese Uptake Systems 4

1.3.2 Bacterial Manganese Efflux 8
1.3.3 Regulation of Bacterial Manganese Transport 8
1.4 Manganese Transport in Yeast 10
1.4.1 Yeast High Affinity Manganese Uptake,
Smf1p and Smf2p 10
1.4.2 Manganese and Phosphate Coupled Uptake
in Yeast, Pho84p 12
1.4.3 Intracellular Manganese Distribution in Yeast 13
1.4.4 Regulation of Yeast Manganese Transporters 15
1.5 Manganese Transport in the nematode
Caenorhabditis elegans 19
1.5.1 Nramp Manganese Transporters in C. elegans 19
1.5.2 Regulation of C. elegans Nramp Transporters
by Manganese 20
1.5.3 Intracellular Manganese Transporters in
C. elegans 20
1.6 Conclusions 21
References 21

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x Contents
Chapter 2 Nutritional Requirements for Manganese 34
Jeanne H. Freeland-Graves, Tamara Y. Mousa and
Namrata Sanjeevi
2.1 Introduction 34
2.2 Food Sources 35
2.3 Absorption, Transport and Excretion 36
2.4 Approaches to Assessing Mn Requirements 36
2.4.1 Metabolic Balance 37
2.4.2 Blood Levels of Mn 42
2.4.3 Other Biomarkers 43
2.4.4 Extrapolation to Usual Diet Intake 44
2.5 Deficiencies 45
2.6 Nutritional Recommendations for Mn 50
2.6.1 Life Stage and Gender 50
2.6.2 Infants 51
2.6.3 Children and Adolescents 52
2.6.4 Pregnancy 53
2.6.5 Lactation 54
2.6.6 International Variability of Requirements
and Dietary Levels for Mn 55
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2.7 Influence of Bioavailability 56

2.7.1 Fiber and Phytate 57
2.7.2 Mineral Interactions 58
2.7.3 Fat and Protein 61
2.7.4 Polyphenolic Compounds 61
2.8 Toxicity 61
2.8.1 Parenteral Nutrition 62
2.9 Conclusions 63
References 64
Manganese: Toxicokinetics and Toxicodynamics
Chapter 3 Manganese Superoxide Dismutase 79

Kinsley K. Kiningham
3.1 Introduction 79
3.2 Manganese Incorporation into SOD2 82
3.3 Manganese Superoxide Dismutase is Essential for Life 82
3.4 Post-Translational Modification of MnSOD 85
3.4.1 Nitration of MnSOD Compromises
Mitochondrial Function in Various Disease
States 85
3.4.2 Phosphorylation of MnSOD can Enhance
Activity and Stability 88
3.4.3 Acetylation of MnSOD Reduces Enzymatic
Activity 88
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Contents xi
3.5 MnSOD and Redox Signaling 89
3.6 Transcriptional Regulation of MnSOD Expression 92
3.7 MnSOD and Disease 95
3.7.1 Cancer 95
3.7.2 Cardiovascular Disease 97

3.7.3 Neurodegenerative Disorders 98
3.7.4 MnSOD Polymorphisms and Disease 99
3.8 Future Directions 100
Abbreviation List 101
References 102
Chapter 4 Olfactory Transport of Manganese: Implications

for Neurotoxicity 119
David C. Dorman and Melanie L. Foster
4.1 Introduction 119

4.2 Anatomical Features of the Olfactory System 120
4.3 Scientific Evidence in Support of Olfactory Transport
of Manganese 121
4.3.1 Manganese Transport Kinetics 124
4.4 Manganese-Enhanced Magnetic Resonance Imaging
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(MEMRI) of the Olfactory System 125

4.5 Toxicological Significance of Olfactory Transport of
Manganese 125
4.5.1 Olfactory System Pathology 126
4.5.2 Biochemical Effects 126
4.5.3 Olfactory Function 127
4.5.4 Species Differences 127
4.6 Conclusions 127
References 128
Chapter 5 Manganese Transport Across the Pulmonary

Epithelium 133
Khristy J. Thompson, Jonghan Kim and
Marianne Wessling-Resnick
5.1 The Air–Blood Barrier 133

5.1.1 Microanatomy of the Lungs 133
5.1.2 Lung Manganese Exposures 134
5.2 Overview of Manganese Transport 135
5.2.1 Divalent Metal Transporter-1 (Slc11a2) 135
5.2.2 Ferroportin (Slc40a1) 136
5.2.3 Transferrin/Transferrin Receptor (CD71) 137
5.2.4 Other Manganese Transporters:
Non-Selective Ion Channels 137
5.2.5 Hypothetical Model for Pulmonary
Manganese Transport 138
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xii Contents
5.3 Interplay Between Manganese and Iron Status 138
5.3.1 Pulmonary Manganese Uptake and Iron
Deficiency 140
5.3.2 Iron Overload and Lung Manganese
Absorption 142
5.3.3 Roles for Tf and the Tf Receptor in the Lungs 142
5.4 Non-Selective Ion Channels 143
5.5 Toxic Effects of Manganese on Lung Epithelial Cells 144
5.6 Infection and Manganese in the Lungs 145
5.7 Future Directions 146
Acknowledgements 148
References 148
Chapter 6 Are There Distinguishable Roles for the Different

Oxidation States of Manganese in Manganese Toxicity? 158
Thomas E. Gunter

6.2 A Brief Review of the Inorganic Chemistry of Mn21
and Mn31 159
6.3 Current Physical Techniques Useful in Mn
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Speciation 160
6.3.1 UV-Visible Spectroscopy 160
6.3.2 XANES Spectroscopy 161
6.3.3 Electron Paramagnetic Resonance
Spectroscopy (EPR) 163
6.4 Studies Most Relevant to Mn Speciation 164
6.5 Studies of Biological Effects of Exposure to Mn21 or
Mn31 Complexes 166
6.6 Is Mn21 Oxidized to Mn31 within Cells or
Mitochondria? 170
6.7 Transport of Mn31 via the Transferrin Mechanism 171
6.8 The Toxicologically Important Steps of a
Mn21-Inhibited Process 172
6.9 Effects of Exposure to Nanoparticles Containing a
Range of Mn Oxidation States 173
6.10 Conclusions 174
References 176
Chapter 7 Effect of Manganese on Signaling Pathways 182

Tanara V. Peres, Fabiano M. Cordova, Mark W. Lopes,
Ana Paula Costa and Rodrigo Bainy Leal

7.2 Manganese may Alter Cell Signaling in the Striatum 183
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Contents xiii
7.3 Manganese Modulation of Tyrosine Hydroxylase
Activity 187
7.4 Alteration in MAPK and AKT Signaling Induced by
Manganese 188
7.5 Manganese Action on GSK-3b and the Canonical

Wnt/b-Catenin Pathway 191
7.6 Final Considerations 192
References 192
Chapter 8 Manganese and Oxidative Stress 199

Daiana Silva Ávila, Marcelo Farina,
João Batista Teixeira da Rocha and Michael Aschner

8.2 Mechanisms Mediating Mn-Induced Oxidative
Stress and Toxicity 201
8.2.1 Mn and Mitochondria 201
8.2.2 Manganese and Dopamine Oxidation 204
8.2.3 Manganese and Antioxidant Homeostasis 205
8.2.4 Manganese and Protein Aggregates 205
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8.3 Antioxidant Approach against Manganism 207

8.4 Concluding Remarks 209
References 210
Chapter 9 Mutual Neurotoxic Mechanisms Controlling Manganism

and Parkisonism 221
Jerome A. Roth

9.2 Parkin 224
9.3 DJ-1 226
9.4 PINK1 229
9.5 ATP13A2 230
9.6 LRRK2 233
9.7 a-Synuclein 234
9.8 VPS35 236
9.9 Others 237
9.10 Conclusion 238
References 239
Chapter 10 Mechanism of Manganese-Induced Impairment of

Astrocytic Glutamate Transporters 258
Pratap Karki, Keisha Smith, Michael Aschner and Eunsook Lee

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xiv Contents
10.2 Mn Neurotoxicity 259
10.2.1 Sources of Human Exposure to Mn and its
Transport to the Central Nervous
System 259
10.2.2 Cellular Mechanisms of Mn Neurotoxicity 260

10.3 Role of Astrocytes in Mn Neurotoxicity 262
10.3.1 Mn-induced astrocyte swelling 262
10.3.2 Glial Cell-derived Neuroinflammation in
Mn Neurotoxicity 263
10.3.3 Astrocytic Glutamate Transporters in
Neurological Disorders 263
10.3.4 Mn Reduces Expression and Function of
Astrocytic Glutamate Transporters 264
10.4 Mechanism of Mn-induced Impairment
of Astrocytic Glutamate Transporters 264
10.4.1 Mn-activated Signaling Pathways in
Astrocytes 264
10.4.2 Mn-induced Transcriptional Regulation of
Glutamate Transporter GLT-1: Role of
Yin Yang 1 265
10.5 Summary 268
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References 268
Chapter 11 Impairment of Glutamine/Glutamate-c-aminobutyric

Acid Cycle in Manganese Toxicity in the Central Nervous
System 279
Marta Sidoryk-Wegrzynowicz and Michael Aschner
11.1 Glutamine Content and Regional Distribution and

its Role in the Central Nervous System 279
11.2 Glutamine Transporting Systems in General 280
11.3 Glutamate: Role in Central Nervous System and
Transporters 281
11.4 The Glutamine/Glutamate-g-Aminobutyric Acid 283
11.5 Manganese 284
11.5.1 Essentiality and Toxicity 284
11.5.2 Transporting System 284
11.5.3 Manganese Effects on Astrocytes Function
and Astrocyte–Neuronal Integrity 285
11.5.4 Manganese Involvement in PKCd
Signalling 286
11.6 Manganese and GGC 287
11.6.1 Manganese and Glutamate Transporting
System 287
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Contents xv
11.6.2 Manganese and Glutamine Turnover 288
11.6.3 Manganese Involvement in SNAT3
Expression and Function 289
11.7 Summary 290
References 291
Chapter 12 Manganese and Neuroinflammation 297

Kelly A. Kirkley and Ronald B. Tjalkens

12.2 Astrocytes 298
12.2.1 Description and Distribution of Astrocytes 298
12.2.2 Functional Roles of Astrocytes 298
12.3 Microglia 300
12.3.1 Description and Distribution of Microglia 300
12.3.2 Functional Roles of Microglia 301
12.4 Neuroinflammation 301
12.4.1 Overview of Neuroinflammation in the
CNS 301
12.4.2 Role of Astrocytes in Neuroinflammation 303
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12.4.3 Role of Microglia in Neuroinflammation 303

12.4.4 NF-kB Signaling in Neuroinflammatory
Injury from Manganese 304
12.5 Neuroinflammation in Diseases of the CNS 305
12.5.1 Seizure 305
12.5.2 Parkinson’s Disease 306
12.5.3 Manganism 308
12.6 Conclusion 313
References 313
Chapter 13 Modeling Manganese Kinetics for Human Health Risk

Assessment 322
Miyoung Yoon, Michael D. Taylor, Harvey J. Clewell and
Melvin E. Andersen

13.2 Key Findings from Mn Pharmacokinetic Studies 323
13.3 Pharmacokinetic Modeling of Mn 328
13.3.1 Initial Development 328
13.3.2 Mn PBPK Models 329
13.3.3 Inter-species Extrapolation to Non-human
Primates 334
13.3.4 Development of Human PBPK Models
for Mn 336
13.3.5 Life Stage Extrapolation 338
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xvi Contents
13.4 Application of PBPK Models in Human Health Risk
Assessment 343
13.5 Suggested Research 345
References 346
Chapter 14 Significance and Usefulness of Biomarkers of Exposure to

Manganese 355
Perrine Hoet and Harry A. Roels

14.2 Biological Matrices and Reference Values 356
14.2.1 Mn in Blood 356
14.2.2 Mn in Urine 357
14.2.3 Mn in Hair and Nail 357
14.2.4 Mn in Brain 358
14.2.5 Reference Values 359
14.3 Occupationally Exposed Subjects 366
14.3.1 External–Internal Exposure Relationship:
Ambient Air-Biomarker 366
14.3.2 Internal Exposure – Effect Relationship 383
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14.4 Non-Occupational Exposure 384

14.4.1 Environmental Exposure 384
14.4.2 Other Mn Exposures 385
14.5 Conclusion 386
References 387
Manganese: Health Effects

Chapter 15 Manganese and Parenteral Nutrition 405
Judy L. Aschner and Nathalie L. Maitre
15.1 Parenteral Nutrition and Manganese (Mn)

Supplementation 405
15.2 Existing Guidelines for Parenteral Manganese
Supplementation 406
15.2.1 Adult Guidelines 406
15.2.2 Pediatric Guidelines 407
15.3 Risk Factors for Manganese Excess and Toxicity 410
15.3.1 Disease States 410
15.3.2 Nutritional Iron Status 411
15.4 Consequences of Excessive Parenteral Mn 411
15.4.1 Adults: Manganism and other
Neuropsychiatric Disorders 411
15.4.2 Infants and Children: Cognition and
Neurodevelopment 412
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Contents xvii
15.5 Detection of Manganese Body Burden 414
15.5.1 Mn Measurements in Blood 414
15.5.2 Magnetic Resonance Imaging (MRI) 415
15.6 Future Directions for Optimizing Mn in Parenteral
Nutrition 416
15.6.1 Knowledge Gaps and Research Priorities 416
15.6.2 Recommendations for Clinical Practice
Modifications 416
References 417
Chapter 16 Developmental Effects of Manganese 426

Scott M. Langevin and Erin N. Haynes

16.2 Manganese Deficiency and Development 427
16.3 Manganese Toxicity and Development 427
16.3.1 Brain Development 428
16.3.2 Birth Outcomes 430
16.3.3 Onset of Puberty 431
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References 433
Chapter 17 The Effects of Manganese on Female Pubertal

Development 437
William L. Dees, Jill K. Hiney and Vinod K. Srivastava

17.2 Critical Events Associated with the Normal Onset of
Female Puberty 438
17.3 Acute Effects of Mn on Puberty-Related Hormones:
A Hypothalamic Site of Action 439
17.4 Chronic Effects of Mn on Puberty-Related
Hormones and the Timing of Puberty 440
17.5 Downstream Mechanism(s) of Mn Action on GnRH
Release 442
17.6 Effect of Mn on GnRH Gene Expression 443
17.7 Upstream Mechanisms of Mn Action in the Control
of GnRH Neuronal Activity 447
17.7.1 Mn Action on Kiss-1 Gene Expression 447
17.7.2 A Potential Role for Divalent Metal
Transporter-1 449
17.8 Low Level Mn Exposure and Precocious Puberty 450
References 453
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xviii Contents
Chapter 18 A Decade of Studies on Manganese Neurotoxicity in
Non-Human Primates: Novel Findings and Future
Directions 459
Tomás R. Guilarte
18.1 The Early Studies on Manganese Neurotoxicity in

Non-Human Primates 459
18.2 Early Behavioral and Neuroimaging Findings 461
18.2.1 Behavioral Findings 461
18.2.2 Positron Emission Tomography Findings 462
18.2.3 Magnetic Resonance Spectroscopy and
T1-Weighted Magnetic Resonance Imaging
Findings 463
18.3 Chronic Mn Exposure Impairs Dopamine Neuron
Function in the Striatum and Produces Extensive
Degeneration in the Frontal Cortex 464
18.3.1 Effects of Chronic Mn Exposure on
Dopaminergic Neuron Terminals in the
Striatum Measured by PET and
Confirmation by Ex Vivo Methods 464
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18.3.2 Effects of Chronic Mn Exposure on the

Glutamatergic and GABAergic Systems 466
18.3.3 The Frontal Cortex in Mn-Exposed
Non-Human Primates: Alzheimer’s
Disease-like Pathology and
Neurodegeneration 467
18.4 Behavioral Studies Reveal Significant Impairment
in Working Memory and Visuospatial Paired
Associative Learning in Mn-Exposed Non-Human
Primates 469
18.5 Novel Findings and Future Directions 470
Dedication 472
References 472
Chapter 19 Imaging Modalities for Manganese Toxicity 477

Ulrike Dydak and Susan R. Criswell

19.2 Magnetic Resonance Imaging 478
19.2.1 Basics of MRI 478
19.2.2 Manganese as MRI Contrast Agent 479
19.2.3 Morphological Changes Assessed
by MRI 485
19.2.4 Magnetic Resonance Spectroscopy 486
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Contents xix
19.2.5 Diffusion Weighted Imaging 489
19.2.6 Functional MRI 490
19.3 PET and SPECT Imaging 491
19.3.1 PET Studies in Non-Human Primates 492
19.3.2 PET Studies in Human Subjects 493

19.3.3 SPECT Studies 496
19.4 X-Ray Fluorescence 497
References 501
Chapter 20 Epidemiological Studies of Parkinsonism in

Welders 513
Harvey Checkoway, Susan Searles Nielsen and
Brad A. Racette
20.1 Parkinsonism: Clinical, Pathological, and

Epidemiological Features 513
20.2 Manganese and Parkinsonism: Historical
Background 514
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20.3 Epidemiological Studies of PS/PD among Welders 515

20.4 Discussion 515
References 520
Chapter 21 Cognitive Effects of Manganese in Children and Adults 524

Roberto Lucchini and Silvia Zoni

21.2 Cognitive Effects in Children 525
21.2.1 Reduction of IQ 528
21.2.2 Executive Functions 528
21.2.3 Memory 529
21.2.4 Academic Achievement 529
21.2.5 Mental Development 530
21.3 Cognitive Effects in Adults 530
21.3.1 Occupational Studies 530
21.3.2 Environmental Studies 532
References 533
Chapter 22 Manganese and Huntington Disease 540

Andrew M. Tidball, Terry Jo Bichell and Aaron B. Bowman
22.1 Huntington Disease Pathobiology and

Environmental Influence 540
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xx Contents
22.2 A History of HD and Metal Ions 541
22.2.1 Manganese and HD 542
22.2.2 Iron Homeostasis and HD 543
22.2.3 Copper and HD 545
22.3 Manganese Essentiality and Toxicity in HD Related

Phenotypes 545
22.3.1 Regulation of Amines and Nitric
Oxide 546
22.3.2 Glutamate Excitotoxicity 547
22.3.3 Mitochondrial Dysfunction: Oxidative
Stress and Energetics 551
22.3.4 IGF/PI3K/AKT Signaling in HD and
Manganese Exposure 554
22.3.5 p53 Pathway 556
References 559
Chapter 23 Manganese and Prion Disease 574

Huajun Jin, Dilshan S. Harischandra, Christopher Choi,
Dustin Martin, Vellareddy Anantharam, Arthi Kanthasamy
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and Anumantha G. Kanthasamy

23.2 Prion Diseases 576
23.2.1 Creutzfeldt–Jakob Disease (CJD) 576
23.2.2 Kuru 577
23.2.3 Gerstmann–Sträussler–Scheinker
Syndrome 578
23.2.4 Fatal Familial Insomnia 578
23.3 Prion Protein (PrPC) 580
23.3.1 Structure of PrPC 580
23.3.2 Physiological Function of Prion
Protein 581
23.4 Metals and Prion Diseases 583
23.4.1 Manganese 583
23.4.2 Manganese Binding to PrPC 584
23.4.3 Role of Manganese in the Pathogenesis of
Prion Disease 585
23.4.4 Role of Manganese in the Physiological
Function and Expression of PrPC 588
23.4.5 Role of other Metals in Prion
Disease 589
References 590
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Contents xxi
Chapter 24 DNA Damage Induced by Manganese 604
Julia Bornhorst and Tanja Schwerdtle
24.1 Genotoxic Lesions Induced by Manganese 604

24.1.1 Damage Induced by Manganese at the

Chromosomal Level 604
24.1.2 Damage Induced by Manganese at the DNA
Level 608
24.1.3 Mutations Induced by Manganese 609
24.2 Sources of the Genotoxic Potential of Manganese 610
24.3 Consequences of DNA Damage Induced by
Manganese 613
References 614
Post-face 621
Subject Index 624

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Published on 27 November 2014 on http://pubs.rsc.org | doi:10.1039/9781782622383-00001
CHAPTER 1
Manganese Transport,
Trafficking and Function in
Invertebrates
AMORNRAT NARANUNTARAT JENSENa AND
LARAN T. JENSEN*b
a
Department of Pathobiology, Faculty of Science, Mahidol University,
Bangkok, Thailand; b Department of Biochemistry, Faculty of Science,
Downloaded on .
Mahidol University, Bangkok, Thailand

*Email: laran.jen@mahidol.ac.th
1.1 Introduction
Manganese is a biologically important trace metal and is required for the
growth and survival of most, if not all, living organisms. It is perhaps best
known for its prominent role as a redox-active cofactor in free radical de-
toxifying enzymes.1–8 However, the utilization of manganese in biological
systems is substantially more diverse. The uptake and distribution of man-
ganese is critical for proper function of manganese-requiring enzymes;
however, this same metal can have deleterious effects in biological systems if
homeostasis is disrupted.9–12 In order to prevent toxicity, cells maintain
manganese under tight homeostatic control. Adding complexity to the cel-
lular control of manganese homeostasis is the presence of multiple types of
manganese transporter that participate in the specific transport of manga-
nese or in general divalent metal ion transport.

1
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2 Chapter 1
Cells appear to transport manganese solely as the divalent cation and

several classes of manganese transporters have been characterized. These
include Nramp H1-manganese transporters,13–16 ATP-binding cassette (ABC)
manganese permeases,17–21 manganese transporting P-type ATPases,22,23
cation diffusion facilitators (CDFs),24–26 and inorganic phosphate transpor-

ters with high affinity for Mn–HPO4 complexes.27–29 Bacteria typically con-
tain one or more of these types of transporter, and these classes of
transporter are also present in eukaryotic cells.30,31 These transporters
comprise both high and low affinity manganese uptake systems and the
transporter utilized depends on the concentration of manganese in the en-
vironment. The homeostatic range for manganese is quite wide, with cellular
levels of manganese between 0.04 and 2.0 mM under optimal growth
conditions.10,16,29,32,33 Cells rarely experience optimal environmental
levels of manganese and often face extreme conditions of either manganese
deficiency or excess.34 Cells activate stress response mechanisms in an at-
tempt to return manganese levels to the homeostatic range. The response
typically results in the upregulation or downregulation of cell surface
and intracellular transport systems. The regulation of manganese uptake,
distribution, and efflux can occur at both the transcriptional and post-
translational levels, although the specific route of regulation varies in
different organisms.
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1.2 Function of Manganese in Biological Systems

1.2.1 Manganese Metalloenzymes
Manganese metalloenzymes are involved in a wide range of cellular func-
tions, including detoxification of reactive oxygen species, protein glycosyla-
tion, polyamine biosynthesis, DNA biosynthesis, nucleic acid degradation,
phospholipid biosynthesis and processing, polysaccharide biosynthesis,
protein catabolism, the urea cycle, photosynthesis, and sugar catabol-
ism.2,35–45 Manganese-dependent enzymes that participate in these pro-
cesses typically utilize manganese in Lewis acid–base reactions or as a
reduction/oxidation center to facilitate catalysis. These types of reaction
are exemplified by arginase (Lewis acid) and Mn superoxide dismutase
(reduction/oxidation),2,3,46,47 and the role of manganese in these reactions is
shown in Figure 1.1.
1.2.2 Non-Protein Manganese Antioxidants

The importance of manganese in biological systems is not limited to
enzyme-mediated catalysis. Non-enzymatic manganese is involved in the
formation of bacterial products, including secreted antibiotics,48 and con-
tributes to the stabilization of bacterial cell walls.49 In addition, the accu-
mulation of non-protein complexes of manganese can function in the
removal of reactive oxygen species (ROS), especially superoxide.50–53 These
View Online
Manganese Transport, Trafficking and Function in Invertebrates 3

Figure 1.1 Typical chemistry performed by manganese in enzymes. (A) Di-nuclear

manganese center of arginase. The manganese cofactor of arginase does
not participate in redox reactions but instead functions as a Lewis acid to
accept a pair of electrons from the bound water molecule, allowing
deprotonation and increasing its reactivity. (B) Catalytic detoxification of
superoxide anions by manganese superoxide dismutase (Mn-Sod) en-
zymes. The catalytic cycle for Mn-Sod has been called a ‘‘ping–pong’’
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reaction in which the manganese cofactor alternates between the oxi-

dized and reduced forms.
Mn-antioxidants are divalent manganese complexes of small metabolites,

and while the nature of the intracellular Mn-complexes has not been clearly
defined, phosphate and lactate Mn-complexes have been shown to display
the capacity to react efficiently with superoxide in vitro.52,54,55 Complexes of
both iron and copper exhibit superoxide scavenging activity, however these
metal ions also exhibit pro-oxidant activity.56–59 In contrast, manganese ions
react poorly with hydrogen peroxide and do not generate the highly toxic
hydroxyl radical, providing a beneficial antioxidant activity without the pro-
oxidant side effects of other redox active metals.50,60
It appears that Mn-antioxidants can serve to enhance oxidative stress
protection when enzymatic antioxidants are insufficient in various organ-
isms.53,61–63 A critical role for Mn-antioxidants has been demonstrated in
Deinococcus radiodurans, a bacterium that is extremely resistant to radiation
and desiccation. In this organism, survival under extreme exposure to ra-
diation and other oxidative stress conditions is not dependent on anti-
oxidant enzymes but instead relies on the accumulation of millimolar
concentrations of manganese and the subsequent formation of Mn-
antioxidants.50,51,60,63 Interestingly, Lactobacillus plantarum, while resistant
to oxidative stress, does not express the antioxidant enzyme superoxide
dismutase.64,65 Indeed, L. plantarum appears to rely exclusively on Mn-
antioxidants for protection against oxidative stress,54,66,67 highlighting the
power of this alternative ROS detoxification pathway.
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4 Chapter 1
The majority of the information on manganese antioxidants has come

from investigation of bacterial and yeast systems; however, it is also likely
that these complexes are present in multicellular organisms. Elevated
manganese accumulation in the nematode Caenorhabditis elegans enhances
thermotolerance and oxidative stress resistance, and extends life span.68,69

The mechanism of the enhanced stress resistance due to manganese sup-
plementation in C. elegans has not been fully elucidated but is suspected to
involve elevated antioxidant activity.
1.2.3 Manganese and Bacterial Virulence

Manganese is either known or proposed to be important for virulence in
bacterial species such as Salmonella enterica, Mycobacterium tuberculosis,
Staphylococcus aureus, Yersinia pestis, and Streptococcus pneumoniae.19,30,31
Invasion and initial survival within host cells is not dependent on manga-
nese; however, extended survival appears to require the element.70,71 The
expression of manganese transporters is required to enhance bacterial sur-
vival when challenged by host defenses.15,18,70,72–74 Whether different classes
of manganese transporter are redundant or involved at different stages of
infection is not known. Models have been proposed in which manganese
transporters, as well as iron transporters, are essential for virulence because
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of competition between the infecting bacterium and host cells for metal
ions.31,71 The need for manganese in bacterial virulence appears to go
beyond its role as a cofactor in ROS detoxifying enzymes such as Mn-
superoxide dismutase and catalase. Enterobacteria are capable of rapidly
increasing uptake of manganese in response to stress, and can accumulate
millimolar levels of manganese.17 This concentration of manganese far
exceeds the level needed to supply Mn-superoxide dismutase with its
cofactor. It appears that the formation of non-protein Mn-antioxidant
complexes may also be an important virulence factor in some bacterial
species. The additional protection against reactive oxygen species generated
by the host cells may allow invading bacteria to survive the initial stages of
infection, and thus promote colonization.
1.3 Manganese Transport in Bacteria

1.3.1 Bacterial Manganese Uptake Systems
In prokaryotic cells, which lack internal compartmentalization, metal ion
homeostasis is maintained primarily by tight regulation of metal cation flux
across the cytoplasmic membrane. Manganese uptake in bacteria pre-
dominantly involves members of two transporter families, Nramp (MntH)
and cation-transporting ABC permeases (MntABCD and related), with many
species containing both types of transport system.17,20,70,73,75,76 In addition,
utilization of other transport systems for manganese, such as a P-type
adenosine triphosphatase (ATPase) by Lactobacillus species (MntP) and
View Online

23,77
Mycobacterium tuberculosis (CtpC), has also been observed. Exposure to
excess manganese leads to repression of these dedicated manganese trans-
port systems.20,74 However, the tight control of manganese influx can be
bypassed via other transporters that are capable of facilitating the uptake of
manganese but escape regulation by this metal. An example of this is PitA,

an inorganic phosphate transporter with high affinity for Mn–HPO4 com-
plexes that appears to be a major source of manganese uptake during con-
ditions of excess.28
1.3.1.1 Bacterial Nramp Manganese Transporter, MntH

Members of the Nramp (natural resistance-associated macrophage protein)
transporter family were first identified in yeast and mammalian cells and
subsequently found to play a major role in metal ion homeostasis.78–80
Nramp proteins function in general metal ion transport, and members of
this transporter family have been shown to facilitate the movement of di-
valent metal ions including manganese, zinc, copper, iron, cadmium, nickel,
cobalt, and lead.14,81–85 Transport of metal ions through Nramp is energized
by the symport of protons (Figure 1.2).15,86
The majority of bacterial Nramp1 homologues, typically designated as
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MntH,15,20,23,80,87 appear to function in manganese homeostasis.15,73,74 The

MntH transporters are commonly found in bacterial species, although
examples of bacteria lacking Nramp transporters have been described.30
Metal accumulation studies revealed that overexpression of Staphylococcus
Figure 1.2 Typical manganese transporters in bacterial cells. (A) During conditions
of manganese deficiency the high affinity transporters MntH, MntABCD,
and MntP facilitate manganese uptake. However, these manganese
transporters are not present in all bacterial species. (B) Manganese
excess inhibits expression of the high affinity transporters and induces
the manganese efflux protein MntE. Uptake of manganese–phosphate
complexes may be a source of manganese when cells are exposed to toxic
concentrations of this metal.
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6 Chapter 1
aureus MntH resulted in increased cell-associated manganese but not cal-

cium, copper, iron, magnesium or zinc, indicating that this Nramp1 trans-
porter was selective for the uptake of manganese.20 Consistent with these
observations, mutants of mntH in Bacillus subtilis exhibited impaired growth
in metal-depleted media that could be rescued by the addition of manga-

nese.74 Direct transport assays also indicated a preference for manganese in
MntH from Salmonella enterica serovar Typhimurium and Escherichia coli. The
affinity for manganese far exceeds that for iron in these MntH proteins,
demonstrating the role of Nramp transporters in bacterial manganese
uptake.30
Species differences in MntH metal ion specificity have been observed, with
some MntH homologues appearing to function in the transport of other
metals in addition to manganese. While S. enterica, E. coli, and B. subtilis
MntH exhibit a strong preference for manganese,30,74 the M. tuberculosis
MntH homologue, Mramp, appears to transport not only manganese but
also significant amounts of iron and zinc.88 Roles for Nramp transporters in
the uptake of other metal ions, especially iron, have been documented in
both prokaryotic and eukaryotic organisms.16,73,80,89–91 Multiple Nramp
isoforms can be present in a single species, and these Nramp transporters,
although highly similar, may have divergent metal ion preferences. Pseudo-
monas aeruginosa expresses two distinct Nramp transporters capable
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of transporting manganese, and multiple Nramp isoforms are present in

Burkholderia species, although the metal ion preferences of these transpor-
ters have not been determined.30 While the most physiologically relevant
substrate for the majority of bacterial MntH transporters appear to be
manganese, it is clear that these transporters have the capacity to facilitate
the uptake of other metals when they are present in excess. This broad metal
ion selectivity in Nramp transporters also appears to enhance the uptake of
toxic metal ions, such as cadmium and lead.74,85,92
1.3.1.2 Bacterial ABC-Type Manganese Permeases

The ATP-binding cassette (ABC) transporter superfamily is one of the largest
classes of transporter, and this transporter family utilizes hydrolysis of ATP
to facilitate the import or export of diverse substrates, ranging from ions to
macromolecules.93–95 These transporters are present in the plasma mem-
brane or inner membrane of Gram-negative bacteria,93,95,96 and are well
known for their involvement in multi-drug resistance in both prokaryotic
and eukaryotic cells by enhancing the export of toxins and drugs.97,98
However, ABC transporters functioning as importers have only been de-
scribed in prokaryotic systems.93,95,96 Metal ion transporting ABC permeases
have been identified with important roles in manganese acqui-
sition.19,70,76,99,100 The cation selectivity of manganese ABC-type permeases
extends to other divalent metal ions including iron, zinc, cobalt, nickel,
molybdenum, and cadmium; however, the typical affinities for these metal
ions are 10- to 100-fold lower than for manganese.100–103
View Online
Examples of bacterial ABC transporters involved in manganese import

include, but are not limited to, MntABCD (Bacillus subtilis, Staphylococcus
aureus), SitABCD (Shigella flexneri), PsaABCD (Streptococcus pneumoniae), and
YfeABCD (Yersinia pestis),17,18,21,31,70,74,104,105 and these transporters exhibit
similar subunit organization and function. The manganese transporter

complex MntABCD (see Figure 1.2) consists of three subunits: MntC and
MntD are integral membrane proteins that form the permease subunit and
mediate cation import; MntB is the ATPase subunit; and MntA functions as a
cation binding protein that delivers manganese to the permease com-
plex.17,19,93,95,106 MntA is present as a soluble periplasmic protein in
Gram-negative bacteria.94 In Gram-positive bacteria MntA is a lipoprotein
anchored to the extracellular side of the plasma membrane,31,74,107 because
these bacteria do not possess an outer membrane. Similar organization is
also present in the operons of other manganese ABC transporters such as
sitABCD, yfeABCD, and psaABCD.17,19,21,31,70
1.3.1.3 Bacterial P-Type Manganese Transporting ATPases

P-type ATPases form a large superfamily of cation and lipid pumps and are
distinct from the ABC class of ATPases in that ATP hydrolysis is coupled to
transport within a single protein chain.108 A manganese/cadmium trans-
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porting P-type ATPase, MntP (also known as MntA, although distinct from
MntABCD) from Lactobacillus plantarum, was identified and proposed to be
the major source of manganese for this organism.23 Subsequent analysis of
the L. plantarum genome revealed the presence of three Nramp transporters
as well as a manganese ABC transporter.109 Mutations of L. plantarum mntP
or the Nramp and ABC transporters did not alter intracellular manganese
concentrations under either manganese deficiency or excess.109 A primary
role for MntP in manganese acquisition in L. plantarum is not certain;
however, Nramp and manganese ABC transporters were also not essential
for manganese uptake. It appears that L. plantarum is highly adaptive in
maintaining manganese uptake even in the absence of known transporters
and additional, yet uncharacterized, transporters may participate in man-
ganese accumulation. Three additional putative P-type calcium/manganese
ATPases are present in L. plantarum and have been proposed as possible
sources of manganese uptake in this bacterium.109
1.3.1.4 Bacterial Transport of Manganese–Phosphate Complexes

In Salmonella lacking both the Nramp and manganese ABC transporters,
manganese uptake activity has been observed, although at low levels.30 The
proposed source of this residual manganese uptake is PitA, a low affinity
phosphate transporter.27,110 The substrate for PitA is a neutral metal phos-
phate (metal–HPO4) complex, and this transporter has a preference for
phosphate complexes of magnesium, calcium, cobalt, and manganese.27 In
environments rich in metals and phosphate, PitA and related transporters
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Manganese in Health and Disease

Dr Michael Waters, Integrated Laboratory Systems Inc, NC, USA

Advisor to the Board:

Titles in the Series:

9: Biomarkers and Human Biomonitoring, Volume 1: Ongoing Programs

20: Advances in Dermatological Sciences

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Manganese in Health and

Issues in Toxicology No. 22

Print ISBN: 978-1-84973-943-6

r The Royal Society of Chemistry 2015

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morbidity. Excessive Mn accumulation in the brain, primarily in basal

Issues in Toxicology No. 22

We called upon internationally recognized experts on Mn to address

Chapter 1 Manganese Transport, Trafficking and Function in

1.3.1 Bacterial Manganese Uptake Systems 4

Issues in Toxicology No. 22

2.7 Influence of Bioavailability 56

Manganese: Toxicokinetics and Toxicodynamics

Chapter 3 Manganese Superoxide Dismutase 79

3.7.2 Cardiovascular Disease 97

Chapter 4 Olfactory Transport of Manganese: Implications

4.1 Introduction 119

(MEMRI) of the Olfactory System 125

Chapter 5 Manganese Transport Across the Pulmonary

5.1 The Air–Blood Barrier 133

Chapter 6 Are There Distinguishable Roles for the Different

6.1 Introduction 158

Chapter 7 Effect of Manganese on Signaling Pathways 182

7.1 Introduction 182

7.5 Manganese Action on GSK-3b and the Canonical

Chapter 8 Manganese and Oxidative Stress 199

8.1 Introduction 199

8.3 Antioxidant Approach against Manganism 207

Chapter 9 Mutual Neurotoxic Mechanisms Controlling Manganism

9.1 Introduction 221

Chapter 10 Mechanism of Manganese-Induced Impairment of

10.1 Introduction 258

10.2.2 Cellular Mechanisms of Mn Neurotoxicity 260

Chapter 11 Impairment of Glutamine/Glutamate-c-aminobutyric

11.1 Glutamine Content and Regional Distribution and

Chapter 12 Manganese and Neuroinflammation 297

12.1 Introduction 297

12.4.3 Role of Microglia in Neuroinflammation 303

Chapter 13 Modeling Manganese Kinetics for Human Health Risk

13.1 Introduction 322

Chapter 14 Significance and Usefulness of Biomarkers of Exposure to

14.1 Introduction 355

14.4 Non-Occupational Exposure 384