Selenium

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Editor
Bernhard Michalke
Research Unit: Analytical BioGeoChemistry
Helmholtz Zentrum München – German Research Center
for Environmental Health GmbH
Neuherberg, Germany

ISSN 2168-4219     ISSN 2168-4235 (electronic)

Molecular and Integrative Toxicology
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Editorial

Selenium

The element Selenium has experienced a unique consideration among elements

relevant to life. Selenium was discovered by the Swedish medical doctor and chemi-
cal scientist Jöns Jakob Berzelius in 1817, and he named the new element after the
Latin expression for moon (Selene).
For long time, selenium was considered to be a toxic substance, since in the
1930s, veterinarians in the Great Plains identified high levels of selenium in plants
fed to cattle for alkalinity and blind ataxia of these animals. Conversely, in the
1950s, a research group reported that selenium prevented necrotic liver degenera-
tion, and another group found selenium deficiency as cause for weakness of calves.
Following such early reports, during several decades, researchers from institutions
all over the world begun studies on the benefits of selenium supplementation on the
performance and health, first of dairy cattle, but then increasingly studying human
health and even more, specific selenium-related molecular mechanisms and path-
ways using animal and cell culture experiments. In parallel, epidemiological study
designs on various population groups, either Se-deficient or Se-exposed, were
reported.
Selenium has been attributed to a couple of health benefits such as prevention of
some cancer forms, heart disease, and other cardiovascular or muscle disorders,
inhibiting viral expression, delaying AIDS symptoms in HIV positive humans,
slowing the aging process, or being involved in male reproduction and immune
function.
This book—being published within the Springer Toxicology Series—is intended
to provide current information on research in the rapidly developing selenium field,
on the one side being centered around the health benefits attributed to selenium but,
on the other side, also reporting about research related to toxicological aspects.
It starts with a comprehensive overview on selenium research and proceeds with
chapters reporting how Se may be taken up, by enlightening its bio-accessibility and
dietary aspects, the latter in turn being related to selenium in soil and plants. A next

v
vi Editorial

section of the book covers selenium related to genes, proteins, pathways, and its
metabolism followed from health effects. These include the involvement in redox
systems and the protective role of Se against oxidative stress, having close correla-
tion to inflammation, thyroid, or disease protection. Neurological aspects are also a
matter of particular interest. Selenium is of paramount importance during infantile
neurodevelopment, and it is discussed being crucial after stroke or in autism.
Respective chapters in this book spot light on these issues. As an interesting coun-
terpoint, a chapter focuses on detrimental effects on peripheral nerves and from an
epidemiological viewpoint about neurotoxicity of some inorganic selenium forms.
A further paragraph with various chapters is centered around selenium and cancer.
The roles of specific seleno-compounds like selenoprotein P or seleno-cysteine in
cancer are discussed aside from aspects of cell proliferation, cytotoxicity, and finally
the action of selenium in radiotherapy. A couple of chapters are dedicated to sele-
nium and various diseases, including cardiovascular diseases, diabetes, muscle dis-
ease, de-balanced immune response, or risks of Se-deficiency. Important aspects of
selenium biology are also addressed regarding new health challenges, e.g., caused
by Se-nanoparticles or interactions of selenium with other trace elements, vitamins,
or pharmaceuticals. It is fundamental for the above chapters to have knowledge
about cellular bioavailability and cytotoxicity, ruled out on cell culture experiments,
and in general, information about reliable selenium analytics. The latter must
include solid analytical approaches, validated selenium speciation techniques, and
biomonitoring studies. Each of these aspects is concerned within individual chap-
ters of this book.
Although this book cannot cover all aspects in the wide selenium field, I think it
nevertheless covers a comprehensive and relevant range of topics being of interest
to the reader. It will be a success of this book when, specifically, young researchers
are motivated to focus their new ideas and research into selenium biochemistry and
related health effects. However, it will be also within the intention of this book to
provide updated information from selenium research to all interested readers, either
being already settled in this fast-growing field or whether still being at the beginning
of their professional career and looking for an interesting research topic for their
scientific journey.

Neuherberg, Germany Bernhard Michalke

Contents

Part I Overview
  1 Selenium in Human Health and Disease: An Overview ����������������������    3
Regina Brigelius-Flohé

Part II Bioaccessibility and Dietary Aspects of Selenium

  2 Selenium in Soils and Crops��������������������������������������������������������������������   29
Philip J. White
  3 Dietary Aspects for Selenium and/or Selenium Compounds ��������������   51
Lutz Schomburg

Part III Genes, Proteins, Pathways, and Metabolism

Related to Selenium
  4 Contribution of the Yeast Saccharomyces cerevisiae
Model to Understand the Mechanisms of Selenium Toxicity��������������   71
Myriam Lazard, Marc Dauplais, and Pierre Plateau
  5 Selenium Metabolism, Regulation,
and Sex Differences in Mammals ����������������������������������������������������������   89
Caroline Vindry, Théophile Ohlmann, and Laurent Chavatte

Part IV The Role of Selenium within Redox Systems,

Inflammation, and Thyroid Interaction
  6 Oxidative Stress, Selenium Redox Systems
Including GPX/TXNRD Families ���������������������������������������������������������� 111
Irina Ingold and Marcus Conrad
  7 Selenium and Inflammatory Mediators������������������������������������������������ 137
Solveigh C. Koeberle and Anna P. Kipp

vii
viii Contents

  8 Selenium and Thyroid Function ������������������������������������������������������������ 157

Mara Ventura, Miguel Melo, and Francisco Carrilho

Part V The Role of Selenium in Neurodevelopment

and Neurological Disorders
  9 Selenium and Neurodevelopment ���������������������������������������������������������� 177
Noelia Fradejas-Villar and Ulrich Schweizer
10 Selenium and Autism Spectrum Disorder �������������������������������������������� 193
Anatoly V. Skalny, Margarita G. Skalnaya, Geir Bjørklund,
Viktor A. Gritsenko, Jan Aaseth, and Alexey A. Tinkov
11 Selenium in Ischemic Stroke ������������������������������������������������������������������ 211
Anatoly V. Skalny, Margarita G. Skalnaya, Lyudmila L. Klimenko,
Aksana N. Mazilina, and Alexey A. Tinkov
12 Selenium Neurotoxicity and Amyotrophic
Lateral Sclerosis: An Epidemiologic Perspective���������������������������������� 231
Tommaso Filippini, Bernhard Michalke, Jessica Mandrioli,
Aristidis M. Tsatsakis, Jennifer Weuve, and Marco Vinceti

Part VI The Role of Selenium in Cancer

13 Therapeutic Potential of Selenium Compounds
in the Treatment of Cancer �������������������������������������������������������������������� 251
Arun Kumar Selvam, Mikael Björnstedt, and Sougat Misra
14 Selenocystine and Cancer������������������������������������������������������������������������ 271
Sougat Misra and Mikael Björnstedt
15 Selenium in Radiation Oncology������������������������������������������������������������ 287
Oliver Micke, Jens Buentzel, and Ralph Mücke

Part VII The Role of Selenium in Various Diseases and Health Issues

16 Selenium and Cardiovascular Disease: Epidemiological
Evidence of a Possible U-Shaped Relationship������������������������������������� 303
Xi Zhang, Xinli Li, Weili Zhang, and Yiqing Song
17 Selenium and Diabetes���������������������������������������������������������������������������� 317
Ji-Chang Zhou, Jun Zhou, Liqin Su, Kaixun Huang,
and Xin Gen Lei
18 Uncovering the Importance of Selenium in Muscle Disease���������������� 345
Alain Lescure, Mireille Baltzinger, and Ester Zito
19 Selenium in Immune Response and Intensive Care������������������������������ 363
Roland Gärtner
Contents ix

20 Selenium and Toxicological Aspects: Cytotoxicity, Cellular

Bioavailability, and Biotransformation of Se Species �������������������������� 373
Franziska Ebert, Sandra M. Müller, Soeren Meyer,
and Tanja Schwerdtle
21 Selenium Nanoparticles: Biomedical Applications ������������������������������ 393
Ivana Vinković Vrček
22 Selenium Interactions with Other Trace Elements,
with Nutrients (and Drugs) in Humans ������������������������������������������������ 413
Josiane Arnaud and Peter van Dael

Part VIII Selenium Analytics, Speciation and Biomonitoring

23 Biomarkers of Se Status�������������������������������������������������������������������������� 451
Kostja Renko
24 Human Biomonitoring of Selenium Exposure�������������������������������������� 467
Thomas Göen and Annette Greiner
25 Bioanalytical Chemistry of Selenium ���������������������������������������������������� 495
Yasumitsu Ogra, Yasumi Anan, and Noriyuki Suzuki

Index������������������������������������������������������������������������������������������������������������������ 513
Contributors

Jan Aaseth Innlandet Hospital Trust, Kongsvinger, Norway

Inland Norway University of Applied Sciences, Terningen Arena, Elverum, Norway
Yasumi Anan Laboratory of Health Chemistry, Showa Pharmaceutical Sciences,
Tokyo, Japan
Josiane Arnaud Institute of Biology and Pathology, University Hospital of
Grenoble and Alpes, Grenoble, France
Mireille Baltzinger Université de Strasbourg, CNRS, Architecture et Réactivité de
l’ARN, IBMC-15, Strasbourg, France
Geir Bjørklund Council for Nutritional and Environmental Medicine, Mo i Rana,
Norway
Mikael Björnstedt Division of Pathology F42, Department of Laboratory
Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge,
Stockholm, Sweden
Regina Brigelius-Flohé German Institute of Human Nutrition Potsdam-
Rehbrücke, Nuthetal, Germany
Jens Buentzel Klinik für Hals-Nasen-Ohren-Heilkunde, Südharz Klinikum,
Nordhausen, Germany
Francisco Carrilho Department of Endocrinology, Diabetes and Metabolism,
Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
Laurent Chavatte Centre International de Recherche en Infectiologie, CIRI,
Lyon, France
Inserm U1111, Lyon, France
CNRS, Ecole Normale Supérieure de Lyon, Université de Lyon 1, UMR5308, Lyon,
France

xi
xii Contributors

Marcus Conrad Helmholtz Zentrum München, Institute of Developmental

Genetics, Neuherberg, Germany
Marc Dauplais Laboratoire de Biochimie, Ecole Polytechnique, CNRS, Université
Paris-Saclay, Palaiseau Cedex, France
Laboratoire de Biochimie, Ecole Polytechnique, CNRS UMR7654, Palaiseau
Cedex, France
Franziska Ebert Department of Food Chemistry, Institute of Nutritional Science,
University of Potsdam, Potsdam, Germany
Tommaso Filippini CREAGEN, Environmental, Genetic and Nutritional
Epidemiology Research Center; Section of Public Health, Department of
Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio
Emilia, Modena, Italy
Noelia Fradejas-Villar Institut für Biochemie und Molekularbiologie, Rheinische
Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Roland Gärtner Klinikum der Universität München—Medizinische Klinik und
Polyklinik IV, Endokrinologie, Munich, Germany
Thomas Göen Friedrich-Alexander-Universität Erlangen-Nürnberg, Institut und
Poliklinik für Arbeits-, Sozial-und Umweltmedizin, Erlangen, Germany
Annette Greiner Friedrich-Alexander-Universität Erlangen-Nürnberg, Institut
und Poliklinik für Arbeits-, Sozial-und Umweltmedizin, Erlangen, Germany
Viktor A. Gritsenko Institute of Cellular and Intracellular Symbiosis, Russian
Academy of Sciences, Orenburg, Russia
Kaixun Huang Hubei Key Laboratory of Bioinorganic Chemistry and Materia
Medica, School of Chemistry and Chemical Engineering, Huazhong University of
Science and Technology, Wuhan, China
Irina Ingold Helmholtz Zentrum München, Institute of Developmental Genetics,
Neuherberg, Germany
Anna P. Kipp Department of Molecular Nutritional Physiology, Institute of
Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
Lyudmila L. Klimenko Institute of chemical Physics of N. N. Semenov of the
Russian Academy of Sciences, Moscow, Russia
Solveigh C. Koeberle Department of Molecular Nutritional Physiology, Institute
of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
Myriam Lazard Laboratoire de Biochimie, Ecole Polytechnique, CNRS,
Université Paris-Saclay, Palaiseau Cedex, France
Laboratoire de Biochimie, Ecole Polytechnique, CNRS UMR7654, Palaiseau
Cedex, France
Contributors xiii

Xin Gen Lei Department of Animal Science, Cornell University, Ithaca, NY, USA
Alain Lescure Université de Strasbourg, CNRS, Architecture et Réactivité de
l’ARN, UPR 9002, IBMC-15, Strasbourg, France
Xinli Li Department of Nutrition and Food Hygiene, School of Public Health,
Medical College of Soochow University, Suzhou, Jiangsu, China
Jessica Mandrioli Department of Neurosciences, Azienda Ospedaliero-­
Universitaria di Modena, Sant Agostino Estense Hospital, Modena, Italy
Aksana N. Mazilina Institute of Chemical Physics of N. N. Semenov of the
Russian Academy of Sciences, Moscow, Russia
Clinical Hospital No 123 Federal Medical-Biological Agency of Russia, Moscow,
Russia
Miguel Melo Department of Endocrinology, Diabetes and Metabolism, Centro
Hospitalar e Universitário de Coimbra, Coimbra, Portugal
Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Instituto de Investigação e Inovação em Saúde (I3S), Porto, Portugal
Institute of Pathology and Immunology of the University of Porto, Porto, Portugal
Soeren Meyer Department of Food Chemistry, Institute of Nutritional Science,
University of Potsdam, Potsdam, Germany
Bernhard Michalke Research Unit: Analytical BioGeoChemistry, Helmholtz
Zentrum München – German Research Center for Environmental Health GmbH,
Neuherberg, Germany
Oliver Micke Klinik für Strahlentherapie und Radioonkologie, Franziskus
Hospital Bielefeld, Bielefeld, Germany
Sougat Misra Division of Pathology F42, Department of Laboratory Medicine,
Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm,
Sweden
Ralph Mücke Strahlentherapie RheinMainNahe, Bad Kreuznach, Germany
Sandra M. Müller Department of Food Chemistry, Institute of Nutritional Science,
University of Potsdam, Potsdam, Germany
Yasumitsu Ogra Laboratory of Toxicology and Environmental Health, Graduate
School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
Théophile Ohlmann Centre International de Recherche en Infectiologie, CIRI,
Lyon, France
Inserm U1111, Lyon, France
CNRS, Ecole Normale Supérieure de Lyon, Université de Lyon 1, UMR5308, Lyon,
France
xiv Contributors

Pierre Plateau Laboratoire de Biochimie, Ecole Polytechnique, CNRS, Université

Paris-Saclay, Palaiseau Cedex, France
Kostja Renko Institut für Experimentelle Endokrinologie, Charité—Universitäts
medizin Berlin, Berlin, Germany
Lutz Schomburg Charité—Universitätsmedizin Berlin, Institut für Experimentelle
Endokrinologie, Berlin, Germany
Ulrich Schweizer Institut für Biochemie und Molekularbiologie, Rheinische
Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Tanja Schwerdtle Department of Food Chemistry, Institute of Nutritional Science,
University of Potsdam, Potsdam, Germany
TraceAge—DFG Research Unit on Interactions of Essential Trace Elements in
Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany
Arun Kumar Selvam Division of Pathology F42, Department of Laboratory
Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge,
Stockholm, Sweden
Margarita G. Skalnaya Peoples’ Friendship University of Russia (RUDN
University), Moscow, Russia
Anatoly V. Skalny Yaroslavl State University, Yaroslavl, Russia
Peoples’ Friendship University of Russia (RUDN University), Moscow, Russia
All-Russian Research Institute of Medicinal and Aromatic Plants (VILAR),
Moscow, Russia
Yiqing Song Department of Epidemiology, Richard M. Fairbanks School of Public
Health, Indiana University, Indianapolis, IN, USA
Liqin Su Department of Soil Quality and Health Monitoring, National Institute of
Environmental Health, Chinese Center for Disease Control and Prevention,
Beijing, China
Noriyuki Suzuki Laboratory of Toxicology and Environmental Health, Graduate
School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
Alexey A. Tinkov Yaroslavl State University, Yaroslavl, Russia
Peoples’ Friendship University of Russia (RUDN University), Moscow, Russia
Institute of Cellular and Intracellular Symbiosis, Russian Academy of Sciences,
Orenburg, Russia
Aristidis M. Tsatsakis Department of Forensic Sciences and Toxicology,
University of Crete, Heraklion, Greece
Peter van Dael DSM Nutritional Products, Kaiseraugst, Switzerland
Contributors xv

Mara Ventura Department of Endocrinology, Diabetes and Metabolism, Centro

Hospitalar e Universitário de Coimbra, Coimbra, Portugal
Marco Vinceti CREAGEN, Environmental, Genetic and Nutritional Epidemiology
Research Center; Section of Public Health, Department of Biomedical, Metabolic
and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
Department of Epidemiology, Boston University School of Public Health, Boston,
MA, USA
Caroline Vindry Centre International de Recherche en Infectiologie, CIRI, Lyon,
France
Inserm U1111, Lyon, France
CNRS, Ecole Normale Supérieure de Lyon, Université de Lyon 1, UMR5308, Lyon,
France
Ivana Vinković Vrček Institute for Medical Research and Occupational Health,
Zagreb, Croatia
Jennifer Weuve Department of Epidemiology, Boston University School of Public
Health, Boston, MA, USA
Philip J. White Ecological Science Group, The James Hutton Institute, Dundee,
UK
Weili Zhang State Key Laboratory of Cardiovascular Disease, FuWai Hospital,
National Center for Cardiovascular Diseases, Peking Union Medical College and
Chinese Academy of Medical Sciences, Beijing, China
Xi Zhang Clinical Research Unit, Xin Hua Hospital Affiliated to Shanghai Jiao
Tong University School of Medicine, Shanghai, China
Ji-Chang Zhou School of Public Health (Shenzhen), Sun Yat-sen University,
Shenzhen, China
Molecular Biology Laboratory, Shenzhen Center for Chronic Disease Control,
Shenzhen, China
Jun Zhou Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica,
School of Chemistry and Chemical Engineering, Huazhong University of Science
and Technology, Wuhan, China
Ester Zito Dulbecco Telethon Institute at IRCCS-Istituto di Ricerche
Farmacologiche Mario Negri, Milan, Italy
 Part I
Overview
Chapter 1
Selenium in Human Health and Disease:
An Overview

Regina Brigelius-Flohé

Abstract Since its detection in 1817 selenium underwent an adventurous trip from
a toxic to an essential element. As integral part of selenoproteins it was assumed that
it is capable to prevent or even cure diseases. The trip was slowed with the findings
that, when overdosed, selenium still can have toxic effects. Thus, an optimal intake
and status had to be evaluated. It became clear that the plasma selenium level should
neither substantially fall below nor exceed a value around 120 μg/L. Success and
failure of human studies undertaken to find a beneficial effect of selenium supple-
mentation in cancer, inflammation and immune response, cardiovascular diseases,
thyroiditis, male fertility, and the surprising adverse effect, diabetes, are shortly
summarized, and functions of involved selenoproteins and underlying mechanisms
discussed. To provide recommendations, more studies with better comparability
regarding form, dosage, and duration of a supplementation are needed and still
unknown functions of selenoproteins identified.

Keywords Cancer · Cardiovascular disease · Diabetes · Inflammation ·

Landmarks of Se research · Male fertility · Se requirements · Selenium · Thyroid

Some Landmarks of Selenium Research in Human Health

Since its detection in 1817 by Jöns Jakob Berzelius, selenium underwent a remark-
able change in its image. It was considered to be a toxic element until Klaus Schwarz
recognized in 1957 (Schwarz and Foltz 1957) that rats fed a highly purified casein
diet deficient in vitamin E and a “factor 3” developed hepatic necrosis which was
prevented by each of these substances. Analysis of a fraction of pig kidney identi-
fied selenium as essential part of factor 3. Having thus recognized that selenium was
an essential trace element, further consequences of selenium deficiency and its
hypothetic ability to prevent diseases were investigated (reviewed in Flohé 2009).

R. Brigelius-Flohé (*)
German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
e-mail: [email protected]

© Springer International Publishing AG, part of Springer Nature 2018 3

B. Michalke (ed.), Selenium, Molecular and Integrative Toxicology,
https://doi.org/10.1007/978-3-319-95390-8_1
4 R. Brigelius-Flohé

Keshan and Kashin-Beck disease were the first diseases recognized to be associ-
ated with selenium deficiency in humans.
The Keshan disease is an endemic cardiomyopathy observed in 1935 in the
Keshan county in the Heilongjiang province in China (Yang et al. 1988), reviewed
in Loscalzo (2014). Samples of heart tissue of patients who had died from Keshan
disease showed similarities with samples from sheep with white muscle disease
appearing when animals were raised on selenium-deficient meadows. The livestock
could be protected from the disease by adding selenium to the diet (Muth et al.
1958). Selenium deficiency was made responsible for the Keshan disease too, and
selenium supplementation as sodium selenite proved to be lifesaving (Ge and Yang
1993). Infection of mice with a Coxsackie virus isolated from a Keshan disease
victim led to a severe heart pathology, especially when the animals were selenium
deficient or had their GPX1 deleted (Ge and Yang 1993). Moreover, under these
conditions the avirulent form of the virus mutated to a virulent form (Beck et al.
1995). This acquisition of virulence could be attributed to point mutations in the
viral genome, presumably resulting from the mutagenic potential of hydroperox-
ides, which were not adequately metabolized in the selenium-deficient animals or
by the lack of GPX1. Collectively, these observations support the conclusion that
selenium, via GPX-dependent hydroperoxide removal, dampens any overreaction
of the innate immune response and also prevents the collateral damage typically
associated with the oxidative burst against bacterial or viral infections.
The Kashin-Beck disease is an endemic degenerative osteoarthropathy present in
selenium-deficient areas, not only in China. The etiology is largely unknown, but
the mycotoxin T-2 (trichothecene mycotoxin) might be an important risk factor
apart from selenium deficiency (Stone 2009). As mechanism, an inhibition of aggre-
can synthesis in chondrocytes, and promotion of aggrecanases and production of
pro-inflammatory cytokines by T-2, which can be blocked by selenium, is being
discussed (Chen et al. 2006).
With the early detection of links between selenium intakes and disease it
became likely that selenium is not only essential for grazing livestock but also for
humans. Also for long known to be toxic, selenium became an issue of fierce
debates about its risks and benefits. The scope of this chapter is to present the
consensus achieved on selenium requirements of humans, to briefly compile the
functions of selenoproteins putatively involved in expected benefits, and to discuss
the underlying mechanisms.

Nutritional Requirements and Recommendations

Dietary reference intakes (DRI) and tolerable upper intake levels (UL) vary
between geographic areas. Up to 2015 the recommendation of the German,
Austrian, and Swiss nutritional societies (DACH) was 30–70 μg/day and then was
enhanced to 60 (female) and 70 (male) μg/day (Kipp et al. 2015). Other European
countries recommend 40–75 μg/day, the UK for example 75 for males and 60 for
1 Selenium in Human Health and Disease: An Overview 5

females. This roughly corresponds to the recommendation of respective institu-

tions in Australia and New Zealand of 2006 (www.nrv.gov.au/nutrients/selenium).
The European Food Safety Authority (EFSA) recommends 55 μg/day (UL 300),
as does the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM)
of the USA (UL 400). The World Health Organization (WHO) suggests 26 for
females and 34 for males.
Patients receiving parenteral nutrition (PN) are at risk to become selenium defi-
cient. Even cardiomyopathic symptoms similar to those seen in Keshan disease
have been observed (Fleming et al. 1982; Johnson et al. 1981). Symptoms could
be reversed by selenium (Reeves et al. 1989). The requirements of patients are
difficult to estimate since it may depend on the illness, surgery, length of hospital
stay, PN at home, and more. The American Society for Parenteral and Enteral
Nutrition (ASPEN) suggests 60–100 μg/day according to a review by Shenkin
(2009). The related European Society (ESPEN) recommends 32–71 μg/day for
adults (Staun et al. 2009).

The Chemical Nature of Selenium Compounds

Main nutritional sources of selenium are crop plants. The Se content varies depend-
ing on the Se content in the soil they are growing on. Cereals contain selenite, sele-
nomethionine (SeMet), and selenocysteine (Sec), wheat contains also Se-methyl-Sec.
Nuts contain mainly SeMet, Brazil nuts up to 2.5 μg/g. Se-rich vegetables are broc-
coli, cabbage, onions, and garlic. They contain Se-methyl-Sec, SeMet, and selenate,
which can be enriched by growing these vegetables on Se-enriched soil (Fairweather-­
Tait et al. 2010; Rayman 2008). Sec and SeMet are present in meat and fish (0.1–4
μg/g), and selenite also in tuna and crustaceans. Selenium-enriched dietary supple-
ments (garlic, yeast) apart from SeMet, Sec, and γ-glutamyl-Se-methyl-Sec also
contain inorganic compounds such as selenite and selenite (Ip et al. 2000). Milk and
dairy products contain Sec and selenate, if cows are supplemented with selenium-­
enriched yeast and also SeMet. Eggs mainly contain Sec and SeMet. The content
depends on the feeding of the hens and can reach up to 0.5 mg/kg (Fairweather-Tait
et al. 2010; Rayman 2008). (For more details see Chaps. 2, 3, 20, and 25)

Selenium as Part of Selenoproteins

Physiologically, selenium and selenium compounds are not effective as such, but
selenium has to be incorporated into proteins as selenocysteine (for details see
Chap. 4). The human genome contains 25 genes for selenoproteins. These proteins
are involved in redox homeostasis, redox regulation of signaling cascades and tran-
scription factors, and thyroid hormone metabolism, but the function is not yet
known for about 50% of them. Known functions are listed and described in
6 R. Brigelius-Flohé

Brigelius-Flohé and Flohé (2017) and Labunskyy et al. (2014). The nomenclature of
selenoproteins has recently been harmonized (Gladyshev et al. 2016). Selenoproteins
with known enzyme function are named according to these functions, as before:
TXNRD1–3 (thioredoxin reductase 1–3), GPX1–4 and 6 (glutathione peroxidases),
DIO1–3 (iodothyronine deiodinase 1–3), MSRB1 (methionine sulfoxide reductase
B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known
functions were previously named “selenoprotein,” followed by a letter. They now
are characterized by the root symbol SELENO followed by the same letter, e.g.,
SELENOP for selenoprotein P.

Biomarkers of the Selenium Status

To get an idea about the selenium status of individuals, plasma selenium levels have
often been used. However, the different forms of selenium found in plasma are func-
tionally not equally identical. Inorganic and organic compounds of selenium
absorbed from food are metabolized in the liver into selenide (H2Se), the selenium
form required for incorporation into selenoproteins as Sec. Also SeMet can be
metabolized into selenide. However, if applied in excess, it is unspecifically incor-
porated into plasma proteins instead of methionine. As such it is functionally not
active, but contributes to the plasma selenium status. In order to get information on
the biologically relevant selenium content, selenoproteins are determined that fulfill
two requirements: (1) responsiveness to already minor selenium deficiency and (2)
easy availability. Two selenoproteins fulfill these criteria: GPX3 and SELENOP, the
main selenoproteins in plasma. Both together constitute a concentration of 80–90
μg selenium/L (Burk et al. 2001). SELENOP can be measured by immunoassay
(Combs Jr. et al. 2011; Hollenbach et al. 2008; Hybsier et al. 2017), and GPX3 via
its activity (Flohé and Günzler 1984). For long plasma GPX3 has been considered
the biomarker of choice. More recently, however, SELENOP has been promoted,
since the selenium level required for reaching the plateau of SELENOP is 110–125
ng/mL, which can be reached by a selenium intake of about 100 μg/day, whereas
that for maximal GPX3 activity was only 70–90 ng/mL (Fairweather-Tait et al.
2011; Hurst et al. 2010). However, the selenium status varies in different parts of the
world and depends on the dietary selenium intake. In a Chinese study with an aver-
age intake of 10 μg/day, 37 μg/day as SeMet was sufficient to optimize GPX3,
whereas of selenite 66 μg was needed. SELENOP did not reach a maximum with
these doses (Xia et al. 2005). In the following study, in subjects with a baseline
intake of 14 μg selenium/day, a supplementation of 49 and 35 μg/day of SeMet was
found to optimize SELENOP and GPX3 levels, respectively. From these findings,
about 75 μg/day as SeMet was postulated for US residents (Xia et al. 2010). Thus,
SELENOP appears to be the most suitable biomarker for the selenium status. (For
more details see Chap. 23)