Coordination Chemistry Reviews 374 (2018) 376–386
Contents lists available at ScienceDirect
Coordination Chemistry Reviews
journal homepage: www.elsevier.com/locate/ccr
Review
Organ damage by toxic metals is critically determined by the
bloodstream
Sophia Sarpong-Kumankomah, Matthew A. Gibson, Jürgen Gailer ⇑
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada
a r t i c l e
i n f o
Article history:
Received 2 February 2018
Accepted 6 July 2018
Keywords:
Arsenic
Mercury
Cadmium
Selenium
Chronic exposure
Bioinorganic-chemistry
Cancer
a b s t r a c t
Past poisoning epidemics have revealed that the chronic exposure to exceedingly small daily doses of
toxic metal and metalloid species can – over time – severely affect human health. Today, several potentially toxic metals and metalloids have been accurately quantified in the bloodstream of the average population, but the interpretation of these from a public health point of view remains problematic.
Conversely, the biomolecular origin for a multitude of grievous human diseases remains unknown.
Supported by recent epidemiological evidence, these seemingly unrelated facts suggest that human exposure to the aforementioned pollutants may be linked to the etiology of more adverse health effects than
we currently know. Based on the interaction of toxic metal and metalloid species with essential trace elements, plasma and erythrocytes in the bloodstream, we have previously argued that a better understanding of these bioinorganic chemistry processes are destined to provide important new insight into their
mechanisms of chronic toxicity. This perspective provides an update on recent advances to better understand these bioinorganic processes and attempts to integrate these findings with the whole organism in
order to establish connections with the etiology of human diseases. Based on the recent observation of
the arsenite-induced perturbation of the whole-body distribution of selenite in mammals and the mercuration of hemoglobin in erythrocyte cytosol it is argued that bioinorganic processes in the bloodstream
critically determine which metal and/or non-metal containing species will impinge on the toxicological
target organ(s). Accordingly, the bioinorganic chemistry that unfolds in the bloodstream represents a critical bottleneck in terms of linking the exposure of humans to toxic metal species with the etiology of diseases. Furthermore, a better understanding of the blood-based detoxification of environmentally
abundant toxic metal species is of direct practical use to develop palliative treatments to ameliorate
the adverse effect that toxic metal species exert on certain human populations.
Ó 2018 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
Introduction and scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Relevance of blood-based bioinorganic chemistry of toxic metal species in toxicology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.
Increased recognition that environmental factors play in disease etiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.
New insight into the toxicology of metal species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Progress in understanding the bioinorganic chemistry of toxic metal species in the bloodstream . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Essential trace and ultratrace elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Blood plasma: plasma proteins and small molecular weight (SMW) species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Erythrocytes: lipid bilayer membrane and cytosolic constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Mobilization of toxic metal species from organs to the bloodstream . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⇑ Corresponding author.
E-mail address: jgailer@ucalgary.ca (J. Gailer).
https://doi.org/10.1016/j.ccr.2018.07.007
0010-8545/Ó 2018 Elsevier B.V. All rights reserved.
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1. Introduction and scope
An estimated 9 million premature deaths globally were attributed to diseases caused by pollution in 2015 [1]. Since the effects of
chemical pollution on human health are in general poorly defined,
its contribution to the global burden of disease is almost certainly
underestimated and the costs of premature death and disease
caused by pollution continue to rise rapidly [1]. Related to these
facts, a multitude of grievous illnesses that afflict people in developed countries, including Alzheimer’s disease, asthma, autism, diabetes, inflammatory bowel disease, Lou Gehring’s disease, multiple
sclerosis, Parkinson’s disease and rheumatoid arthritis do not
appear to have a genetic origin [2,3]. Considering that every organism – since its conception – is exposed to ‘environmental factors’
that may be present in the inhaled air and/or the ingested food/
drinking water throughout life, their potentially adverse effects
on human health are being increasingly recognized [4–7]. While
environmental factors, such as persistent organic pollutants are
implicated in the in the etiology of type 2 diabetes [8], and intestinal microbiota are linked to lung inflammation [9], it is the unsustainable emission of inorganic pollutants by our high-tech society
into the global environment [10,11] which prompted our previous
perspective entitled ‘‘Probing bioinorganic chemistry processes in
the bloodstream to gain new insights into the origin of human diseases” [12]. Given that this perspective was published in 2010, we
thought it to be useful to provide an update on recent advances
that have been made to better understand the aforementioned
bioinorganic processes and to critically discuss their toxicological
significance. The overall focus of this review will be on studies with
mammalian model organisms and studies that were conducted
with blood plasma and erythrocyte lysates. For the sake of clarity,
the term ‘toxic metal species’ will be used instead of ‘toxic metals
and metalloid species’ throughout this manuscript and chronic
toxicity is defined as the long-term exposure of humans to low
levels of an individual inorganic pollutant or a mixture of inorganic
pollutants.
We will start by briefly re-iterating how toxic metal species
that have invaded the bloodstream can engage in bioinorganic
chemistry processes that are toxicologically relevant. Then we
will provide an update of recent epidemiological studies which
have strengthened the importance of environmental exposuredisease relationships. Thereafter, we will recapture the major
problems that need to be overcome to gain insight into relevant
bioinorganic chemistry-based processes that unfold in the bloodstream. The core of this manuscript is intended to provide a succinct summary of the recent progress that has been made in
terms of better understanding the interaction of toxic metal species with the components of the bloodstream, namely essential
trace and ultratrace elements, plasma proteins/small molecular
weight compounds/metabolites, erythrocytes as well as the mobilization of toxic metal species from organs to the bloodstream.
Some promising avenues for future research will also be identified. The interaction of potentially toxic metal species with erythrocyte cell membranes will not be discussed in depth as this
topic was the focus of an excellent recent review [13]. Likewise,
readers that are interested in the mechanisms by which Cd2+
and AsIII can result in oxidative stress in target organ cells that
may eventually result in diseases are referred to another comprehensive review [14].
1.1. Relevance of blood-based bioinorganic chemistry of toxic metal
species in toxicology
In every human being the dynamic exchange of essential elements between the environment, the bloodstream and internal
organs – which is orchestrated by tightly regulated biochemical
mechanisms throughout life – is inextricably linked to the maintenance of its health and wellbeing [15]. Since the earth’s crust also
contains toxic metals (e.g. Hg, Cd, Pb) and metalloids (e.g. As, Se),
all organisms have been chronically exposed to background concentrations of species of these potentially toxic elements throughout evolution. The onset of the industrial revolution was associated
with an increased production of – amongst other chemicals – As,
Pb, Cd and Hg for various practical end uses [11]. The large scale
production of these particular elements initially resulted in the
occupational exposure of humans in factories and eventually in
the environmental exposure of humans by contaminated food
and drinking water [16] in ways that are still being detailed [17].
The seriousness that is associated with the chronic exposure of
human populations to toxic metal species came to the fore during
a few pollution disasters that involved the aforementioned elements [11]. A couplet by the Indian poet Pandit Chakbast (1881–
1925) probably captures the situation best when he stated: ‘‘What
is life but the emergence of order in the co-mingling of elements?
What is death, but the disintegration of life’s active components.”
Based on the flow of dietary matter through mammalian
organisms, the contained toxic metal species enter the stomach,
the gastrointestinal (GI) tract and – if they are bioavailable –
the bloodstream form where they are then distributed to toxicological target organs (e.g. Cd2+ damages the kidneys [18]). From a
purely bioinorganic chemistry perspective, the bloodstream provides an extremely rich environment of biomolecules for toxic
metal species to interact with. This is because blood plasma contains thousands of proteins [19] some of which have binding sites
for toxic metal species that can compete with essential ones [15]
and because erythrocytes, which constitute 45% of whole blood,
can absorb a variety of toxic metal species [12] which can subsequently undergo toxicologically highly relevant redox-reactions in
their reducing cytosolic environment that are of eminent toxicological relevance [20]. Accordingly, the interactions of toxic metal
species with plasma and erythrocytes will significantly impact
essentially all internal organs ‘downstream’ (Fig. 1) [20,21]. If
we want to explain how exceedingly small daily doses of one
toxic metal species can result in dramatic adverse health effects
[22], however, it behooves us to strive to uncover those particular
biomolecular mechanisms which provide the required ‘leverage’.
Given the biochemical complexity of the bloodstream itself, the
elucidation of these bioinorganic mechanisms can be a rather
daunting task.
The concerted application of advanced spectroscopic tools has
eventually revealed that arsenite (AsIII) and mercuric mercury
(Hg2+) target the metabolism of the essential ultratrace element
selenium [23]. In particular it was demonstrated that the intravenous co-administration of rabbits with each of these toxic metal
species and selenite (SeIV) resulted in the formation of metabolites
with As-Se [24] and Hg-Se [21,25] bonds that are either rapidly
excreted via the bile (Fig. 2A) [26] or are essentially non-toxic
(Fig. 2B) [24]. The formation of the metabolite which contained
an As-Se bond – the seleno-bis(S-glutathionyl) arsinium ion or
[(GS)2AsSe] – is a redox reaction that involves endogenous glutathione (GSH) (Eq. (1) and likely involves a mechanism that is
depicted in Eqs. (2)–(4) [27]:
AsðOHÞ3 þ HSeO3 þ 8GSH ! ðGSÞ2 AsSe þ 3GSSG þ 6H2 O ð1Þ
AsðOHÞ3 þ 2GSH ! ðGSÞ2 As OH þ 2H2 O
ð2Þ
HSeO3 þ 6GSH ! HSe þ 3GSSG þ 3H2 O
ð3Þ
ðGSÞ2 As OH þ HSe ! ðGSÞ2 AsSe
þ H2 O
ð4Þ
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S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386
leverage!
GI-tract
organ
A
essential ultra trace element (E)
toxic metal species (T)
detoxification
E
-T
blood
B
adverse
health
effect/
disease
small dose
bloodstream
Fig. 1. To explain how the exposure to exceedingly small daily doses of toxic metal
species may be linked to processes that may – over time – result in human diseases,
we need to focus on discovering mechanisms that provide the required ‘leverage’.
Since the bloodstream represents a conveyor belt which supplies all organs with life
sustaining nutrients, all simultaneously ingested toxic metal species that decrease
the transport of essential ultra trace elements to their organs for the assembly of
metalloproteins provide the required leverage to link exposure to chronic adverse
health effects that may eventually result in disease. In the context to of this
manuscript disease is defined as as a particular abnormal condition, a disorder of a
structure or function, that affects part or all of an organism.
[(GS)2AsSe] has been shown to chemically react with the
highly toxic species methylmercury (CH3Hg+) in erythrocyte cytosol to form the species (GS)2As-Se-Hg-CH3 (Fig. 2C). The ultimate
fate and biological activity of the metabolites depicted in Fig. 2B
and C, however, is currently unknown [21,25]. While the formation
of these Se-containing metabolites (Fig. 2A–C) will protect internal
organs from the adverse effects of AsIII, Hg2+ and CH3Hg+ in the
short-term [23], the chronic exposure to these latter toxic metal
species is likely to perturb the distribution of the essential ultratrace element Se via the bloodstream to organs because both AsIII
and Hg2+ target HSe [25,27], a critical catabolite of all dietary Se
compounds [28] that is the major building block for the assembly
of selenoproteins [29]. Therefore, the chronic exposure to these
particular toxic metal species will likely result in systemic Sedeficiency in organs over time (Fig. 3A) in the absence of effective
selenium supplementation [30].
If the amount of toxic metal species that invades the bloodstream exceeds the detoxification capacity of the bloodstream,
target
organ
primary
molecular/
cellular
targets
plasma
protein
binding
secondary
hepatocellular/
cyte/
targets
hepatotoxicity
systemic
toxicity
erythrocyte
selective/
systemic
toxicity
kidney
neuronal
cell/
nephro- cell/
toxicity neurotoxicity
selective
toxicity
endothel
cell
blood
vessel
damage
E-T
excretion
Fig. 3. Conceptual depiction of the interaction of essential and toxic element
species that are absorbed from the GI tract into the bloodstream as well as their
disposition to organs and their excretion. Note that the detoxification of toxic metal
species by an essential ultratrace element in the bloodstream protects organs from
their adverse health effects in the short-term (A), but will induce a selenium
deficiency in organs in the long-term, which is referred to as systemic toxicity since
in a first approximation all organs are similarly affected. Any ‘left-over’ toxic metal
species can then interact with erythrocytes, endothelial cells, plasma proteins and
small molecular weight compounds/metabolites that are present in blood plasma,
which can result in selective toxicity (e.g. only a certain target organ is affected).
Since both of these mechanisms are implicated in the etiology of disease processes,
a better understanding of bioinorganic chemical interactions between toxic metals
and various blood constituents represents a viable research strategy to possibly link
the exposure of humans to certain environmental pollutants with specific grievous
human diseases.
any ‘left-over’ AsIII and Hg2+ will subsequently interact with plasma
proteins, small molecular weight compounds/metabolites that are
present in plasma (e.g. L-cysteine, L-glutathione), erythrocytes and
target organs in a manner that is poorly understood at the molecular level (Fig. 3B) [6]. From a biochemical point of view, the formation of the aforementioned Se-containing metabolites in the
bloodstream [20] and/or the liver [31] will abolish selenoprotein
synthesis [32], which provides the required ‘leverage’ in terms of
explaining how the exposure of humans to exceedingly small daily
doses of the corresponding toxic metal species (low lg/day) can
dramatically affect health since the perturbation of the metabolism
of the essential ultratrace Se is associated with severe adverse
health effects [33–35]. From a toxicological point of view, it is
important to recognize that both mechanisms that are depicted
in Fig. 3A and B will determine the toxicological effect at the organ
level when mammals are chronically exposed to toxic metal species
Fig. 2. Structure of metabolites which are formed between the essential ultratrace element selenium and one or more toxic metal species either in erythrocytes (A, C) or in
blood plasma (B). (A) The seleno-bis(S-glutathionyl)arsinium ion, (B) (Hg–Se)100(GS)5 species (GS = glutathione moiety), (C) the methylmercury(II) seleno-bis(S-glutathionyl)
arsinium adduct.
S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386
for months/years. For example, the gradual decrease of the Se status of internal organs [36] will eventually reach a critical threshold
level at which one particular organ may become particularly susceptible to damage either by the selective toxicity of a ‘left-over’
toxic metal species (e.g. a compromised immune system) [37] or
by other environmental factors to trigger the onset of a disease.
This conceptual framework therefore provides a feasible rationale
for the potential involvement of blood-based bioinorganic processes in the etiology of human diseases that are associated with
a long latency period [1]. Furthermore, the biomolecular mechanisms that have been discovered in the bloodstream to date may
represent only the ‘tip of the iceberg’ since CH3Hg+ and Cd2+ are
also known to target the metabolism of Se by mechanisms that
remain elusive [38–40] and since other toxic metal species could
similarly perturb the metabolism and adversely affect the organ
distribution of other essential ultratrace elements, such as cobalt,
molybdenum, cobalt and/or manganese [15]. The novel conceptual
view that is emerging from these considerations is that the interaction of toxic metal species in the bloodstream are emerging to be
critical to understand the toxicological effects of environmentally
abundant toxic metals at the organ level. Specifically, the proven
formation of As-Se, Hg-Se and As-Se-Hg species (Fig. 2A–C) in the
bloodstream may – over months/years – drive certain internal
organs to Se-deficiency. In view of the dietary requirement for
the essential trace element Se of 55 lg/day, chronic human exposure to toxic metal species may therefore result in the damage of
certain organs without the pollutant(s) actually entering the tissue
itself. What is particularly disturbing in this context is the fact that
all individual toxic metal species that target the metabolism/organ
distribution of Se will have a cumulative effect, which would significantly diminish its anticarcinogenic effect [41], even though
sufficient daily doses may be ingested.
Based on these arguments we have previously argued that
increased research efforts should be directed toward two particular
research goals. Firstly, to establish the structural basis of other
blood-mediated interactions that unfold between toxic and essential ultratrace element species in the bloodstream (Fig. 3A) [42]
and secondly, to obtain a deeper understanding of the interaction
of the ‘left over’ toxic metal species (e.g. AsIII, Hg2+, Cd2+, etc.) with
blood plasma constituents and erythrocytes (Fig. 3B) as these processes will not only determine how much of the absorbed toxic
metals species and its metabolites will actually impinge on internal organ(s), but potentially also which organs are ‘targeted’. Considering that the release of toxic metal species into the
environment is projected to increase [6] and that the exposure of
human populations, including children to some of them may be
causally linked to more chronic diseases that we currently know
of [43], it is evident that from a public health point of view further
insight into blood-based bioinorganic processes is urgently needed.
After all, knowledge about the existence of an exposure-disease
interrelationships is the first step to restrict the emission of critical
toxic metal species into the biosphere [44] to decrease disease
prevalence rates [5,45].
1.2. Increased recognition that environmental factors play in disease
etiology
While Hippocrates was already aware that the exposure to
environmental factors is linked to adverse effects on human health
in 400 BCE, we are today confronted with profound knowledge
gaps in terms of understanding exposure-disease interrelationships. This undesirable situation must be attributed to the fact that
the progressive industrialization has resulted in the production of
at least 5000 high volume chemicals that are widely dispersed into
the environment on the one hand and the fact that fewer than half
of them have undergone testing for safety or toxicity [1]. In this
379
context toxic metal species constitute a unique class of pollutants
because they inherently cannot be degraded and they therefore
tend to accumulate in certain environmental compartments [11]
and potentially also in mammals [46,47]. While a few, isolated poisoning epidemics have provided extremely useful insight into the
exposure-disease interrelationship of specific toxic metal species,
such as CH3Hg+ (the culprit in Minamata Disease) [48], epidemiologists have provided important insight in terms of linking the
chronic low-level exposure of humans to the inorganic pollutants
inorganic arsenic (AsIII and AsV) or cadmium (Cd2+) with the etiology of cancer [49].
Based on the fact that it can take years before the chronic exposure to toxic metals species will result in noticeable adverse health
effects [50], it is entirely possible that the etiology of more chronic
diseases than we currently know of may be causally linked to their
exposure [51,52]. Two conceptual arguments can be made to support this possibility. Firstly, there is a multitude of chronic human
diseases for which we do not know their biochemical origin (see
the aforementioned list of human diseases) [2] and while we accurately know the concentration of inorganic (and organic) pollutants in the human bloodstream from biomonitoring studies [53],
we don’t know what these concentrations mean in terms of their
health relevance [12]. Secondly, the effect that environmental pollutants in general have on the disease prevalence of various cancers has been studied by epidemiologists for decades [54], but
only comparatively recent studies have revealed that local cancer
rates of immigrants from different ethnic background converge
[54]. Importantly, these results excluded a genetic explanation in
disease etiology and strongly implicated ‘environmental factors’.
This and other studies [7,8,55–57] have led to an increased recognition of the immensely important role that ‘environmental factors’ play in the etiology of chronic diseases, such as cancer over
the last 10–15 years [43,58–60]. In fact, some researchers estimate
that up to 90% of cancer deaths and half of heart disease mortality
may be linked to environmental factors [59]. Accordingly, the environmentally irresponsible manner by which our high-tech society
disposes of highly toxic and carcinogenic metal species to groundwater (e.g. 80% of electronic waste is landfilled in the US [61])
needs to change [10]. Notable advances have been made in terms
of delineating which daily exposure dose over what time period
can be linked to increased cancer rates in humans for individual
toxic metal species [62]. Considering that Cd is an established
human carcinogen [63], but that exposure to this toxic metal is also
linked to a plethora of other adverse health effects [64–69], it
seems possible that human exposure to this toxic metal may be
causally involved in the etiology of other human diseases [51].
The enormous difficulty that is associated with gaining insight
into exposure-disease interrelationships must be attributed to
the extremely complex interplay between ‘environmental factors’
(i.e. the gut microbiome, persistent organic pollutants, toxic metal
species) and the genetic susceptibility of individuals [58,70,71].
The exposure of individuals to a combination of environmental factors, for example, is determined by their occupation, life style
choices and the geographical location that any given individual
resides within an urban centre [72]. In addition, the nutritional status of the individual as well as age, sex and genetic makeup are
known to affect the susceptibility of individuals to environmental
factors. Last but not least, the biological complexity that is associated with the main components of the bloodstream is also known
to affect the individual susceptibility to toxic metal species. In
principle, three principle contributing factors have to be taken into
account, namely the genetic variability of small molecular weight
metabolites in blood plasma [73], the genetic variability of human
plasma proteins [74], as well as our almost non-existent understanding of the toxicological relevance that known interactions of
toxic metal species with cytosolic metalloproteins within
380
S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386
erythrocytes play in the overall toxicological effect in exposed
organisms [75].
2. Progress in understanding the bioinorganic chemistry of
toxic metal species in the bloodstream
2.1. Essential trace and ultratrace elements
1.3. New insight into the toxicology of metal species
Since we know strikingly little about the role that xenobiotics
[76] and toxic metals species play in the etiology of disease processes [6,11,12], it is useful to briefly re-iterate three fundamental
research problems that must be overcome to improve this undesirable situation [12].
The first problem is our fragmentary understanding of the biotransformation of toxic metal species in vivo [23], which is critical
as it is its molecular form that will interact with the constituents of
the bloodstream and/or the target organ(s) to determine the
ultimate toxic effect (Fig. 3). To this end, one needs to consider
changes of the oxidation state of the species that is absorbed into
the systemic blood circulation (e.g. in erythrocytes AsV is reduced
to AsIII) [77]. In addition, one needs to differentiate between
toxicologically relevant events that unfold between a toxic metal
species in plasma (e.g. plasma protein binding [78]) and those that
unfold in erythrocytes (e.g. the binding of Hg2+ to hemoglobin)
[75]. One also needs to be cognizant that a bioinorganic detoxification process may involve both of these compartments for its
completion. For example, the erythrocyte-mediated formation of
an entirely non-toxic Hg-Se species will subsequently bind to
selenoprotein P in blood plasma [25].
The second problem – one of significantly bigger magnitude – is
biological complexity and the associated difficulty of identifying
the in vivo ‘target(s)’ of any given toxic metal species and/or its
metabolites at all levels of complexity, including the molecular
(e.g. blocking of a receptor, binding to and misfolding a target protein), the cellular (humans are comprised of 200 types of cells),
the organ (neurotoxicity, nephrotoxicity, hepatotoxicity), and –
perhaps most importantly – the systems level (e.g. immunotoxicity, dys-homeostasis of essential elements) [12].
Arguably the biggest problem that we are confronted with is the
fact that every human is exposed to multiple inorganic environmental pollutants [79] and that we need to address this ‘mixture
toxicity’ problem [80–82]. Faced with this almost insurmountably
complex problem, it is becoming clear that the mere quantification
of inorganic pollutants in the bloodstream should be increasingly
complemented by the quantification of select plasma proteins,
which in their entirely may provide an inherently better measure
of the health/disease state of certain organs and therefore – by
inference – the organism itself [22,71,83].
At this point, it is important to point out that in order to predict
in what way bioinorganic chemical events which involve the interaction of toxic metal species with the bloodstream will impact
organ toxicity, one needs to be aware of two distinctly different
toxicological mechanisms of action, namely systemic toxicity and
selective toxicity [84]. The former refers to a mechanism by which
all organs ‘downstream’ of the bloodstream are equally affected.
This can be brought about by a toxic metal species, which cumulatively decreases the organ-availability of a particular essential
ultratrace element (e.g. Se) to eventually result in Se-deficiency
(Fig. 3A). Another way by which this can be brought about is if a
toxic metal species enters erythrocytes and adversely affects the
transport of oxygen to all internal organs (e.g. if the binding of oxygen to hemoglobin is compromised). Selective toxicity, on the
other hand, refers to a mechanism by which any ‘leftover’ toxic
metal species is being uptaken into a target organ (e.g. the liver
[85]) and then exerts an adverse effect by inhibiting critical
enzymes [86] or by inducing epigenetic effects therein (Fig. 3B)
[49].
Sufficient quantities of the gastrointestinally absorbed essential
trace elements Fe, Cu and Zn (daily requirement: 2–10 mg/day)
and the ultra trace elements Co, Se and Mo (daily requirement
<100 mg/day) need to be shuttled by the bloodstream to internal
organs for the subsequent assembly of metalloproteins [87]. Since
many details regarding these highly evolved transport mechanisms
are unknown [88,89], little is also known about their potential disruption by toxic metal species [36], which may – over time – rather
plausibly result in organ-based diseases [15,35].
Using New Zealand white rabbits, we have discovered that the
biomolecular mechanisms by which AsIII and Hg2+ perturb the
metabolism of the essential ultratrace element Se involves the formation of metabolites in the bloodstream which contain As-Se and
Hg-Se bonds (Fig. 2) [22–24,27,30,90]. Intriguingly, the biochemical formation of both of these toxicologically relevant metabolites
is driven by glutathione (GSH) that is present at 2.5 mM concentrations in the cytosol of erythrocytes (Fig. 3A), but which is also
present in the cytosol of essentially all mammalian cells [20].
Although SeIV does not represent a significant fraction of the dietary selenium that is ingested by the general population, its presence in human plasma [91] suggests that it possibly serves a
specific role that has evolved in terms of detoxifying AsIII and
Hg2+ – and possibly other toxic metal species – in the bloodstream
to prevent them from exerting organ damage [30,42]. The toxicological significance of this As-Se antagonism was confirmed in subsequent studies, which involved the intravenous injection of New
Zealand white rabbits with environmentally relevant doses of AsIII
and SeIV followed by the analysis of bile that was collected for 25
min. A dramatically increased biliary excretion of total As and Se
was observed when AsIII and SeIV were simultaneously administered [92]. Intriguingly, these experiments also revealed that when
rabbits were intravenously injected with 50 lg AsIII/kg body
weight, a significant mobilization of endogenous Se from organ tissues to bile occurred. Combined, these findings conclusively
demonstrated that the exposure of rabbits to AsIII will result in
Se-deficiency [92] since [(GS)2AsSe] does not appear to undergo
enterohepatic cycling and therefore represents a true detoxification product [93].
More recently, the AsIII-SeIV antagonism has also been observed
in rats since their intravenous injection with both of these metalloid species resulted in the biliary excretion of [(GS)2AsSe] [94].
The excretion of this metabolite from the liver to the bile is mediated by an ATP-binding cassette transporter protein, multidrug
resistance protein 2 (MRP2) [95]. In view of the fact that rats do
not have a gall bladder, but humans do, the AsIII-SeIV antagonism
was recently confirmed in a mammalian species that more closely
resembles humans in this regard. Using hamsters as an animal
model, advanced synchrotron-based X-ray fluorescence imaging
spectroscopy was applied to determine the distribution of As and
Se in whole animal tissues 30 min after their treatment with either
AsIII, SeIV or both metalloid species [31]. The results revealed that
co-treated animals showed a strong co-localization of As and Se
in the liver, the gall bladder and the small intestine. The fact that
no As and Se was co-localized in the brain of hamsters that were
co-treated implies that [(GS)2AsSe], which rapidly forms in the
bloodstream [20], does not appear to traverse the blood-brainbarrier over the course of the experiment. Importantly, the presence of [(GS)2AsSe] could be verified for the very first time in
intact liver tissue slices. Studies with mice revealed that feeding
a high-Se lentil diet protected them against atherosclerosis
S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386
following the exposure to 200 ppb of AsIII [96]. While an involvement of [(GS)2AsSe] was not verified in this particular study, the
in vivo formation of this species nevertheless provides a feasible
explanation for the obtained results. Thus, the likely unfolding of
the As-Se antagonism in mice combined with its demonstrated
unfolding in hamsters, rabbits and rats strongly suggests that it
is a phenomenon that pertains to all mammals, including humans.
Collectively, these conclusive results establish a biomolecular basis
to explore the use of dietary Se supplements as a possible palliative
treatment to ameliorate the adverse health effects of humans that
are suffering from the chronic low-level arsenic poisoning in certain parts of the world [94]. Since a Phase II trial that was conducted in China has suggested some clinical benefits from Se
supplementation in arsenicosis patients [97], further studies are
required to investigate if the adverse effects that are associated
with the consumption of drinking water that is laced with inorganic arsenic can be effectively mitigated by an inorganic dietary
supplement, sodium selenite [98].
Since [(GS)2AsSe] (Fig. 2A) has been demonstrated to be
assembled from AsIII and SeIV in erythrocytes [20] and considering
that it has also been detected in bile [90], it is important to establish the mechanism by which this species is transported between
these biological compartments. While the mechanism by which
this metabolite is excreted from erythrocytes to plasma is still
unknown [95], the addition of [(GS)2AsSe] to human blood
plasma has most recently revealed that this species can abstract
Zn2+ from Zn-containing plasma proteins, which resulted in the
elution of an As, Se and Zn-containing species in the small molecular weight elution range (Fig. 4) [99]. Similar observations were
made with New Zealand white rabbit blood plasma (data not
shown). These preliminary observations are not unexpected as
Zn2+ is known to coordinate to Se [100], but require further investigations to establish the stoichiometry and the structure of this
apparent [(GS)2AsSe]x-Zn species. Furthermore, these observations
suggest that this novel metabolite may represent the actual species
that is translocated from the blood plasma to the liver for the even-
Fig. 4. Representative Zn-specific chromatogram that was obtained by SEC-ICP-AES
after the analysis of human plasma (dashed line) and As, Se and Zn-specific
chromatograms that were simultaneously obtained after human plasma was spiked
with [(GS)2AsSe] (solid lines). Column: Superdex 200 Increase 10/300 GL (30 1.0
cm I.D., 13 mm particle size), temperature at 22 °C, mobile phase: 150 mM PBS
buffer (pH 7.4), flow-rate: 0.75 mL/min, injection volume: 0.5 mL. The metals and
metalloids were detected at 189.042 nm (As), 196.090 nm (Se) and 213.856 nm
(Zn). Retention times of molecular weight markers are depicted on the top of the
box. [(GS)2AsSe] was synthesized as previously reported [26] and 50 lL of the
obtained solution was added to 2.0 mL human plasma to give a final concentration
of 0.135 mg/mL As and 0.143 mg/mL Se (ethics protocol ID REB15-1138). The slightly
reduced retention time of Zn compared to that of the As and Se peak is attributed to
a dissociation of the Zn2+ complex with [(GS)2AsSe], which has been previously
observed for the related species (GS)2AsSe-Hg-CH3 [21].
381
tual excretion of [(GS)2AsSe] in bile. Studies which aim to establish the biochemical fate of [(GS)2AsSe]x-Zn species would greatly
contribute to establish its toxicological significance. The formation
of this [(GS)2AsSe]x-Zn species in plasma clearly establishes a
biomolecular link between AsIII, SeIV and the essential trace element Zn, which could help to explain the results of previous animal
studies in which the treatment of mice with As2O3 resulted in a
statistically significant decrease in serum Zn over time [36].
In terms of identifying relevant research questions for future
studies based on the aforementioned discussion, it is noteworthy
to point out that 2 billion people worldwide currently suffer from
anaemia [14,101], which could be experimentally induced in animals that were injected with 2.0 mg Cd/kg body weight once a
week for 6–9 months [102]. While the obtained results were
rationalized based on the Cd-mediated reduced production of erythropoietin, it is possible that a bioinorganic chemistry-based
mechanism could be involved, especially since ferrochelatase,
which inserts the Fe2+ into protoporphyrin IX, is inhibited by
Cd2+ [51], but it is unknown if the latter mechanism also unfolds
in vivo. In the same vein anaemia has also been reported in human
populations that were chronically exposed to AsIII (in West Bengal
and Bangladesh) [103] as well as in people that lived in the vicinity
of an abandoned mine and were exposed to Hg2+ [104]. These
observations suggest that other hitherto unknown bioinorganic
chemistry-based mechansisms could exist.
2.2. Blood plasma: plasma proteins and small molecular weight (SMW)
species
After a toxic metal species enters the bloodstream, plasma proteins and SMW species represent the first biomolecules that the
toxic metal will encounter. With regard plasma proteins, HSA –
by far the most abundant plasma protein in blood plasma (concentration 36–54 g/l) [105] – has specific binding sites for Hg2+
[106,107] and Cd2+ [108] (the binding sites for AsIII and CH3Hg+
are unknown, but Cys-34 is a highly likely candidate). Another
highly abundant plasma protein, a2 macroglobulin (2–5 g/L)
has also been found to have a strong affinity for Hg2+ [109] and
Cd2+ [110]. The effect that this binding may have on the homeostasis of this plasma protein is unknown, despite the fact that an
imbalance of its activity contributes to several major human
diseases, including Alzheimer disease [111]. Cd2+ has also been
demonstrated to bind to the pure plasma proteins apotransferrin and ferritin at near physiological conditions [78,110].
We will now briefly elaborate on principle mechansisms by which
the binding of a toxic metal species to plasma proteins may result
in an adverse health effect [12].
The first mechanism involves the toxic metal species-induced
induction of a conformational change of the binding protein, which
may render the misfolded protein incapable of serving its intended
biochemical function (Fig. 5A) [112,113]. Alternatively, the misfolded protein may present neoepitopes that could trigger the production of autoantibodies against it, which has been detected in
human plasma after the exposure to Hg2+ [114]. These latter events
can result in systemic autoimmunity [115], which is associated
with Lupus [116]. A toxic metal species-plasma protein complex
may also be inadvertently transported across a particular bloodorgan barrier via receptor-mediated endocytosis [117] to eventually result in organ based adverse effects, such as Kawasaki Syndrome, which has been reported in children that had been
exposed to Cd2+ and Hg2+ [118].
Another mechanism by which the interaction of a toxic metal
species with a specific plasma metalloprotein protein may result
in an adverse health effect involves the displacement of an essential trace/ultratrace element from its parent plasma transport protein binding site. Under chronic exposure conditions such a
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gastrointestinal tract
PP
CC
plasma
M
PP
A
C
B
impaired
function
TP
TP +
autoimmunity
plasma
organ
endo
cytosis
inflammation?
PP
toxic metal species
PP plasma protein
M
TP
transport protein
essential element
M small molecular weight metabolite
Fig. 5. Overview of biomolecular mechanisms by which an absorbed toxic metal
species may interact with blood plasma proteins to adversely affect internal organs
downstream (A–C). Note that in principle organ damage can be brought about by
three distinctly different mechanisms of toxicity, which are indicated by lightning
bolts in red (effect of misfolded plasma protein on organ including autoimmunity
[114]), orange (induction of an essential element deficiency at the organ level [36])
and yellow (selective toxicity at the organ level [84]). Abbreviations: CC = conformational change or misfolding of a plasma protein.
displacement from an established transport protein would reduce
the ‘flux’ of the essential ultratrace element to organs and eventually result in dyshomeostasis (Fig. 5B) and finally pathologies.
Evidence in support of this mechanism has been obtained for the
displacement of Co2+ from its binding site on HSA by Cd2+ [119],
and the displacement of Zn2+ from HSA by Cd2+ at conditions that
correspond to acute exposure [15]. While the aforementioned biochemical events were observed in plasma, a similar displacement
of the redox-active Fe2+ from its endogenous biological binding
sites has been proposed as the putative mechanism by which
Cd2+-exposure can induce lipid peroxidation in rats despite it not
being redox active [120].
The third conceptual mechanism relates to the fact that blood
plasma not only contains thousands of plasma proteins and buffer
salts to maintain its pH at 7.4, but also >400 SMW species (Fig. 5C),
which includes amino acids, carbohydrates, peptides and nucleotides, just to name a few [73]. Since the relative variability of the
concentrations of these metabolites between individuals appears
to be genetically determined, it has been proposed that these
SMW species could play a critical role in disease processes [73]
and it is therefore important to accurately quantify these species
in human plasma [121]. To this end, Cys and GSH have been found
to alter the distribution of Hg2+ and CH3Hg+ to internal organs,
such as the liver, the brain and the kidneys [122]. In order to gain
insight into how the SMW thiols L-cysteine (Cys), L-glutathione
(GSH), N-acetyl-L-cysteine (NAC) and oxidized glutathione (GSSG)
may affect the metabolism of Cd2+, its abstraction from HSA –
the major Cd2+ transport protein in plasma – was investigated at
near physiological conditions using a liquid chromatographic
approach [123]. As expected, GSSG did not mobilize Cd2+ from
HSA, whereas Cys and GSH did at concentrations >1.0 mM. Since
these concentrations are not physiologically relevant, these investigations were extended to the SMW thiol homo-cysteine (hCys),
which is present in human plasma [124]. The results of these
investigations revealed that 0.5 mM hCys partially mobilized
Cd2+ from HSA [110], which is of potential toxicological relevance
because similar plasma concentrations of hCys have been reported
for hyperhomocysteinemia patients, which suffer from
cardiovascular disease [125]. Although the detailed biomolecular
mechanism(s) by which plasma hCys adversely affects the
cardiovascular system and is linked to stroke, Alzheimer’s disease,
neural tube defects, inflammatory bowel disease and osteoporosis
[124], these in vitro results strongly suggest that in hyperhomocysteinemia patients the distribution of Cd2+ from the bloodstream to
toxicological target organs may be perturbed (Fig. 5C). This finding
may explain the proposed role of this toxic metal in the formation
of atherosclerotic plaques [68]. It remains to be determined
whether the perturbation of the blood-based disposition of Cd2+
may contribute to the overall disease outcome in hyperhomocysteinemia patients. Since the plasma hCys concentration also
increases with age [125], the formation of Cdx-hCysy complexes
in the bloodstream could be involved in biochemical processes that
are related to ageing. Overall, these findings underscore the notion
that the interaction of toxic metal species with plasma proteins can
be significantly altered by tissue-derived SMW species, such as
HCys and possibly others [73] and therefore play an important role
in the translocation of toxic metal species to target organs, including the brain [122].
2.3. Erythrocytes: lipid bilayer membrane and cytosolic constituents
Considering that erythrocytes constitute 45% of whole blood,
they represent another toxicological target for toxic metal species
[126]. Four principle mechanisms can be identified by which the
interaction of a toxic metal species with the cell membrane of erythrocytes can result in toxicologically relevant effects.
The first mechanism of toxicologically relevance involves the
interaction of toxic metal species with the lipid bilayer membrane
of erythrocytes, which can adversely affect their rigidity and permeability (Fig. 6D) [13]. Erythrocytes that were obtained from
jewelry workers in India that had been occupationally exposed to
Cd vapor from soldering, for example, displayed an increased fragility and a significant loss of biconcave shape [127], which could
greatly disturb oxygen transport to tissues and may result in vascular occlusion [128].
Another relevant mechanism that has to be considered is the
toxic metal species-induced inhibition of the uptake of certain
nutrients (Fig. 6E). It is well established that Hg2+, for example,
can inhibit the uptake of glucose [129] and water [130], with the
latter event being most likely attributed to the inhibition of
aquaporin water channels [131]. While the long-term effects of
gastrointestinal tract
E
inhibition of
uptake
GSH
complexation
F
metabolism
D
cell membrane
damage
rigidity/
permeability
changes
red blood cell
G
enzyme
inhibition
metalloprotein
damage
Hb
Hb
hemolysis
Hb
Hb
plasma
+
Hb
Hb
organ
toxic metal species
Hb
Hp haptoglobin
Hb
Hp
Hp
Hb
Hp
plasma
Hb
hemoglobin
glucose, H2O
Fig. 6. Overview of possible biomolecular mechanisms (D–G) by which a gastrointestinally absorbed toxic metal species may adversely affect the integrity of
erythrocytes which may eventually result in systemic toxicity (oxygen transport is
adversely affected) or selective toxicity (lysis will release hemoglobin which may
overwhelm the binding capacity of haptoglobin and result in kidney failure). To this
end, a dimethylarsinous-hemoglobin-haptoglobin complex has been detected in rat
plasma [174].
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V
Hb 17.5 kDa
0
V
i
Hg2+
5 min
2h
6h
Control
Hg Intensity (c/s)
100
80
Hg
Fe
2h
60
40
5 min
2h
20
A
0
Hg Intensity (c/s)
100
CH3Hg+
80
5 min
2h
6h
Control
Hg
Fe
2h
60
40
20
B
0
5 min
2h
6h
Control
THI
100
Hg Intensity (c/s)
these latter biochemical events on the integrity of erythrocytes
have not been investigated in vivo, it is possible that these events
may significantly shorten their lifetime in the bloodstream [12].
Considering that AsIII is taken up by erythrocytes [132], presumably via the glucose transporter GLUT1 [133] and that CH3Hg+ is
rapidly absorbed by erythrocytes by passive diffusion [23], potential bioinorganic chemistry-based interactions of these toxic metal
species with cytosolic constituents must also be considered.
The third mechanism of toxicological relevance entails the
intraerythrocytic metabolism of absorbed toxic metal species followed by the complexation of the generated metabolites with
endogenous biomolecules (Fig. 6F). AsIII and SeIV have been shown
to react with cytosolic GSH to form [(GS)2AsSe] [20], but it is currently unknown how this species is ejected from the erythrocyte
into plasma because no transporter has yet been identified which
accepts this species as a substrate [95]. Interestingly [(GS)2AsSe]
has been demonstrated to react with CH3Hg+ to form (GS)2As-SeHg-CH3 in rabbit erythrocyte cytosol (Fig. 2C), which appears to be
a detoxification product [21]. AsV, which is 1000-fold more toxic to
erythrocytes than AsIII [77] is absorbed into erythrocytes by band
3, which functions as a HCO
3 /Cl exchanger [134] and then reduced
III
to As by mechanisms that involve GSH [135,136]. The generated
AsIII has been demonstrated to react with GSH to form (GS)3As
[137] and to bind to hemoglobin [138]. Another SMW target for toxic
metal species in the bloodstream of fish is Se-containing compound
selenoneine, which was isolated from blood of Bluefin tuna [139]
and plays an important role in the detoxification of CH3Hg+ [140].
This novel Se compound has been detected in the erythrocytes of a
fish eating population in Japan [141] and is the Se-analog of ergothioneine, which is abundantly present (up to 2 mM) in various human
tissues and also in the cytosol of erythrocytes [142].
The last mechanism by which toxic metals species may
adversely affect erythrocytes is by the inhibition of cytosolic
enzymes and/or by the damage of cytosolic metalloproteins, such
as hemoglobin (Hb) (Fig. 6G). Cd2+, for example, has been reported
to inhibit glutathione peroxidase [143]. This will adversely affect
the redox-status of the erythrocyte cytosol (i.e. the GSH:GSSG
ratio), which is of eminent toxicological relevance [144] and may
also shorten the lifetime of erythrocytes, which is 120 days
[12]. To this end, it has been hypothesized that the Hg2+ induced
lysis of erythrocytes could be linked to the inhibition of cytoplasmic enzymes, such as superoxide dismutase and catalase [145].
The lysis of erythrocytes in the bloodstream is directly linked to
kidney damage if the binding capacity of haptoglobin – a plasma
protein which specifically binds Hb – is overwhelmed (Fig. 6G)
[146]. It has long been known that despite the cytosolic concentration of GSH of 2.2 mM [147,148]) hemoglobin, which is present at
concentrations of 5.2 mM [148]) will bind CH3Hg+, AsIII [149–
152] and Cd2+, which implies a high specific binding affinity
[153]. To corroborate these findings, the comparative fate of
Hg2+, CH3Hg+ and thimerosal was recently investigated in rabbit
erythrocyte lysate using a metallomics approach [75]. This study
involved the analysis of treated lysate over a 6 h period by sizeexclusion chromatography (SEC) using a mobile phase which contained 2.5 mM GSH (to simulate the conditions of erythrocyte cytosol) and an inductively coupled plasma atomic emission
spectrometer (ICP-AES) as a detector to simultaneously monitor
the elution of Hg and hemoglobin (Hb), which was monitored by
its iron emission line (Fig. 7). These studies revealed that >92% of
total Hg2+ eluted as a GSxHg complex and that a small fraction
(<1.5%) eluted bound to a cytosolic protein (2h and 6 h), which
was also observed for Cd2+. Interestingly, 4.8–6.9% of Hg2+, 4.3–
5.8% of CH3Hg+ and 4.8–11.8% of thimerosal co-eluted with Hb
(Fig. 7) and the EXAFS analysis of the Hg2+ peak that co-eluted with
Hb revealed two Hg-S distances of 2.316 Å, which implied its binding to two Cys-residues. While one Cys residue can be inferred to
80
Hg
Fe
2h
60
40
20
C
0
600
800
1000
1200
1400
1600
1800
Retention Time (s)
Fig. 7. Hg and Fe-specific chromatograms that were obtained by SEC-ICP-AES after
the analysis of New Zealand white rabbit erythrocyte lysate that had been spiked
with Hg2+ (36 lg of Hg2+/mL) [A], CH3Hg+ (38 lg of CH3Hg+/mL) [B], or thimerosal
(72 lg of thimerosal/mL) [C] at the indicated time points. Column: Superdex 75
10/300 GL (30 1.0 cm I.D., 8.6 mm particle size), Temperature: 22 °C, Mobile
Phase: 100 mM Tris-buffer containing 2.5 mM GSH (pH 7.4), Flow-rate: 0.75 mL/
min, Injection volume: 500 mL, Detector: ICP-AES at 226.502 nm (Cd), 253.652 nm
(Hg) and 259.940 nm (Fe). Retention times of molecular weight markers are
depicted on top.
be from Hb, the nature of the second Cys residue is currently
unknown. The reason for the unexpectedly strong binding of CH3Hg+ and the thimerosal-derived CH3CH2Hg+ species to Hb – in the
presence of 2.5 mM GSH – remains unknown. These experiments
clearly demonstrate that the interaction of all investigated Hgspecies with Hb is considerably stronger than that of Cd2+ [75].
While this difference in the binding of Hg2+ and Cd2+ to Hb can
be rationalized based on the different coordination geometry that
each of these metals prefer [154,155], further studies are needed
to provide insight into the molecular basis for the strong binding
of the methylated Hg-species CH3Hg+ and CH3CH2Hg+ (derived
from thimerosal) to Hb. These in vitro results generally support
observations which have been previously reported in victims of a
CH3Hg+ poisoning epidemic in Iran, who had erythrocyte concentrations 0.03 mM CH3Hg+ and 5.2 mM Hb [48]. In view of the
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lifetime of erythrocytes of 120 days the effect of that the binding
of the aforementioned toxic Hg species to Hb may have on its binding to O2 requires further studies [156]. The observed binding of
Hg2+ to a protein that is different from Hb in erythrocyte cytosol
(Fig. 7; Cd2+ bound to the same protein [75]) is of potential toxicological relevance because it could be one of the 1578 cytoplasmic
proteins [157] some of which constitute a circadian clock [158] and
may therefore adversely affect the associated biochemical processes.
2.4. Mobilization of toxic metal species from organs to the bloodstream
Based on the emerging conceptual framework that is depicted
in Fig. 3, the chronic exposure of human populations to toxic metal
species, such as Hg2+ will result in their bioaccumulation in internal organs (e.g. the liver) [47], and is particularly relevant with
regard to Cd2+, for which there is no mechanism for its excretion
in humans [14]. The tissue concentration of Cd therefore increases
in organs, such as the kidneys [18] and the liver until the age of
50 [159]. One potential problem that is associated with this
inevitable organ accumulation of this as well as other toxic metal
species is the fact that studies with mice have demonstrated that
the administration of acetaminophen (ACM) – the most widely
used analgesic in the United States [160] – can mobilize Cd from
the liver to the kidneys, which was associated with an increased
excretion of Cd via urine and feces and was antagonized by the
administration of Cys [161]. While the ACM dose that was used
in these experiments corresponds to an overdose and the
biomolecular mechanism by which ACM mobilized hepatic Cd to
the kidneys remains unknown, these results are nevertheless relevant from a toxicological point of view since ACM poisoning has
become the most common cause of acute liver failure in both the
United States and the United Kingdom [160]. Thus, these results
suggest that the ingestion of this or other medicinal drugs may
inadvertently result in a redistribution of toxic metal species, such
as Hg2+, CH3Hg+, Cd2+ and AsIII from their storage sites in the liver
to adversely affect the kidneys [162]. Based on this general concept
it has been proposed to orally administer humans with N-acetyl-Lcysteine to mobilize CH3Hg+ from endogenous storage sites to the
urine to assess the exposure of individuals to this established neurotoxin [163].
3. Concluding remarks
Due to the rapidly advancing industrialization of our high
technology-minded society and the associated emission of inorganic pollutants into the global environment, the exposure of certain human populations to toxic metal species is projected to
increase [11,45,72,164]. Although stringent measures have been
put into place to minimize the exposure of human populations to
inorganic pollutants in many countries, considerable levels of these
toxins persist in soils and therefore continue to enter the food chain
[82]. Given that a multitude of human diseases have not been linked
to a genetic origin [2], environmental factors including toxic metal
species are likely to play an important role in their etiology [11].
Since the rapid rise of the disease prevalence rate of pollution
related chronic human diseases poses an increasing burden on the
world economy [1], it will become progressively more important
to better understand exposure-disease inter-relationships as this
represents the first step to impose stricter pollution abatement
strategies for pollutants that are involved in biochemical processes
that can be causally linked to a particular disease.
One way to gain insight into complex exposure-disease relationships is to elucidate how toxic metal species that are absorbed
into the bloodstream interact with essential ultratrace elements,
blood plasma and erythrocytes [12]. Although we are just begin-
ning to understand these processes, this review has underscored
that the bloodstream harbors important bioinorganic detoxification mechanisms (e.g. involving the ultratrace element Se [23])
which protect organs from the adverse effects of certain toxic
metal species. The ‘leftover’ toxic metal species, however, will subsequently interact with plasma proteins, small molecular weight
metabolites, erythrocytes and target organs in a manner that will
ultimately determine which and how much of a toxic metal species
will reach the toxicological target organ(s) to exert an observable
adverse health effect (e.g. kidney failure). At the same time the
involvement of essential trace elements in these detoxification
processes will adversely affect their transport to organs. Based on
this conceptual framework, one needs to recognize that both of
these aforementioned mechanisms (Fig. 3A, B) will collectively
determine the outcome of the exposure of humans to toxic metal
species at the target organ level over time. Given that bioinorganic
process that unfold in the bloodstream may therefore result in
organ-based diseases only after months [165] or potentially years,
they provide a feasible explanation for the long latency period for
chronic toxic metal exposure and may vice versa explain why the
chronic exposure of humans to toxic metals has not yet been linked
to the etiology of more chronic human diseases that we currently
know (e.g. cancer). Advances in terms of linking the exposure of
humans to organ-based adverse health effects will therefore critically depend on furthering our understanding of the bioinorganic
chemistry of toxic metal species in the bloodstream. It is in this
sense that the chronic exposure of human populations to toxic
metal species could be implicated in the etiology of more human
diseases that we currently know [52,67].
A rather practical incentive to discover hitherto unknown
bioinorganic detoxification mechanisms that unfold in the bloodstream and protect organs from the adverse effects of toxic metal
species is the fact that these very mechanisms can be exploited
to develop cheap, palliative solutions to ameliorate the adverse
health effects of people that are suffering from the chronic low
level exposure to toxic metal species in the short term before more
expensive solutions (e.g. the construction of appropriate water
purification systems) are implemented.
An underappreciated concept in the context of better understanding the exposure-disease interrelationships of toxic metal
species is the realization of the important role that SMW species,
such as hCys that are present in plasma may play in their organ
distribution [60,122]. Since the plasma concentration of hCys is
elevated in patients that suffer from hyperhomocysteinemia, it is
possible that a perturbed metabolism (i.e. the organdisposition)
of toxic metal species may contribute the overall outcome and
could possibly be linked to neurodegenerative diseases
[36,122,166]. Relatedly, older people which have an increased
body burden of toxic metal species stored in various organs may
inadvertently mobilize these toxins to the bloodstream following
the ingestion of certain medicinal drugs [161].
Although it is difficult to ascribe causal relationships between
the exposure to toxic metal species and the development of diseases, research that aims to better understand bioinorganic chemical processes that unfold in the mammalian bloodstream is critical
to uncover unknown biomolecular mechanisms which will contribute to establish functional connections between the chronic
exposure of humans to certain inorganic pollutants (e.g. AsIII,
Cd2+, Hg2+ and CH3Hg+ all target the metabolism of Se) [24] and
specific diseases (e.g. Se-deficiency is associated with cardiomyopathy) [35]. This strategic approach requires the application of
appropriate bioanalytical tools to probe relevant interactions
in vitro and/or in vivo and to do this not only in an ‘systems
biology’-oriented manner [83,167], but also under nondenaturing conditions, which metallomics approaches inherently
are capable of [15]. Since a large variety of appropriate metallomics
S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386
tools are now available to probe bioinorganic chemical processes in
complex biological fluids [15], there is every reason to be optimistic that together with modern proteomic methodologies
[22,87] and synchrotron radiation-based techniques (e.g. X-ray
absorption spectrometry [31]) this tool set can now be applied to
obtain fundamentally new insights into bioinorganic chemistryrelated processes that unfold in the bloodstream and to develop
practical solutions to ameliorate adverse human health effects that
are caused by environmentally abundant toxic metals [97,168].
Relatedly, the same tool set can also be applied to modulate the
metabolism of metal-based drugs to improve the treatment of
patients that suffer from environmental pollution related diseases,
such as cancer [169]. Hence, bioinorganic chemists are at the forefront in contributing to solve one of the greatest challenges that
humankind faces in the post-genomic area [170] by helping to find
solutions to decrease the global burden of environmental pollution
induced chronic human diseases in adults [171] as well as children
[172,173].
Acknowledgments
The National Science and Engineering Research Council (NSERC)
of Canada is gratefully acknowledged for funding the research that
is reviewed in this manuscript as well as Richard S. Glass
(Department of Chemistry, University of Arizona) for providing
constructive feedback on the final draft of this manuscript.
References
[1] P.J. Landrigan, R. Fuller, N.J.R. Acosta, O. Adeyi, R. Arnold, N. Basu, A.B. Balde, R.
Bertollini, S. Bose-O’Reilly, J.I. Boufford, T. Chiles, C. Mahidol, A.M. Coll-Seck,
M.L. Cropper, J. Fobil, V. Fuster, M. Greenstone, A. Haines, D. Hanrahan, D.
Hunter, M. Khare, A. Krupnick, B. Lanphear, B. Lohani, K. Martin, K.V.
Mathiasen, M.A. McTeer, C.J.L. Murray, J.D. Ndahimananjara, F. Perera, J.
Potocnik, R.B. Preker, J. Ramesh, J. Rockstroem, C. Salinas, L.D. Samson, K.
Sandilya, P.D. Sly, K.R. Smith, A. Steiner, R.B. Steward, W.A. Suk, O.C.P. van
Schayck, G.N. Yadama, K. Yumkella, M. Zhong, Lancet (2017).
[2] J.D. Marth, Nat. Cell Biol. 10 (2008) 1015–1016.
[3] A. Chakravarti, P. Little, Nature 421 (2003) 412–414.
[4] N.D. Price, A.T. Magis, J.C. Earls, G. Glusman, R. Levy, C. Lausted, D.T.
McDonald, U. Kuseback, C.L. Moss, Y. Zhou, S. Qin, R.L. Moritz, K. Brogaard, G.S.
Omenn, J.C. Lovejoy, L. Hood, Nat. Biotechnol. 35 (2017) 747–756.
[5] L. Trasande, R.T. Zoeller, U. Hass, A. Kortenkamp, P. Grandjean, J.P. Myers, J.
DiGangi, P.M. Hunt, R. Rudel, S. Sathyanarayana, M. Bellanger, R. Hauser, J.
Legler, N.E. Skakkebaek, J.J. Heindel, Andrology 4 (2016) 565–572.
[6] J. Gailer, J. Inorg. Biochem. 108 (2012) 128–132.
[7] J.M. Swanson, S. Entringer, C. Buss, P. Wadhwa, Semin. Reprod. Med. 27
(2009) 391–402.
[8] C.J. Patel, J. Bhattacharya, A.J. Butte, PloS One 5 (2010) e10746.
[9] Y. Huang, K. Mao, X. Chen, M.-A. Sun, T. Kawabe, W. Li, N. Usher, J.-Y. Zhu, J.F.J.
Urban, W.E. Paul, R.N. Germain, Science 359 (2018) 114–119.
[10] R.M. Izatt, S.R. Izatt, R.L. Bruening, N.E. Izatt, B.A. Moyer, Chem. Soc. Rev. 43
(2014) 2451–2475.
[11] P.G.C. Campbell, J. Gailer, Effects of non-essential metal releases on the
environment and human health, in: R.M. Izatt (Ed.), Metal Sustainability:
Global Challenges, Consequences and Prospects, John Wiley & Sons Ltd.,
Chichester, United Kingdom, 2016, pp. 221–252.
[12] E. Zeini Jahromi, J. Gailer, Dalton Trans. 39 (2010) 329–336.
[13] B.J. Payliss, M. Hassanin, E.J. Prenner, Chem. Phys. Lipids 193 (2015) 36–51.
[14] K. Jomova, M. Valko, Toxicology 283 (2011) 65–87.
[15] J.L. Gomez-Ariza, E. Zeini Jahromi, M. Gonzalez-Fernandez, T. Garcia-Barrera,
J. Gailer, Metallomics 3 (2011) 566–577.
[16] A. Borchers, S.S. Teuber, C.L. Keen, M.E. Gershwin, Clin. Rev. Allergy Immunol.
39 (2010) 95–141.
[17] A.E. North, S. Sarpong-Kumankomah, A.R. Bellavie, W.M. White, J. Gailer, J.
Environ. Sci. 57 (2017) 249–257.
[18] N. Johri, G. Jacquillet, R. Unwin, Biometals 23 (2010) 783–792.
[19] N.L. Anderson, N.G. Anderson, Mol. Cell Proteomics 1 (2002) 845–867.
[20] S.A. Manley, G.N. George, I.J. Pickering, R.S. Glass, E.J. Prenner, R. Yamdagni, Q.
Wu, J. Gailer, Chem. Res. Toxicol. 19 (2006) 601–607.
[21] M. Korbas, A.J. Percy, J. Gailer, G.N. George, J. Biol. Inorg. Chem. 13 (2008)
461–470.
[22] S.A. Manley, J. Gailer, Expert. Rev. Proteomics 6 (2009) 251–265.
[23] J. Gailer, Coord. Chem. Rev. 251 (2007) 234–254.
[24] J. Gailer, Appl. Organometal. Chem. 16 (2002) 701–707.
[25] J. Gailer, G.N. George, I.J. Pickering, S. Madden, R.C. Prince, E.Y. Yu, M.B.
Denton, H.S. Younis, H.V. Aposhian, Chem. Res. Toxicol. 13 (2000) 1135–1142.
385
[26] J. Gailer, S. Madden, M.F. Burke, M.B. Denton, H.V. Aposhian, Appl.
Organomet. Chem. 14 (2000) 355–363.
[27] J. Gailer, G.N. George, I.J. Pickering, G.A. Buttigieg, M.B. Denton, R.S. Glass, J.
Organomet. Chem. 650 (2002) 108–113.
[28] C.M. Weekly, H.H. Harris, Chem. Soc. Rev. 42 (2013) 8870–8894.
[29] R.S. Glass, W.P. Singh, W. Jung, Z. Veres, T.D. Scholz, T.C. Stadtman,
Biochemistry 32 (1993) 12554–12559.
[30] J. Gailer, Biochimie 91 (2009) 1268–1272.
[31] O. Ponomarenko, P.F. LaPorte, S.P. Singh, G. Langan, D.E.B. Fleming, J.
Spallholz, M. Alauddin, H. Ahsan, S. Ahmed, J. Gailer, G.N. George, I.J.
Pickering, Metallomics 9 (2017) 1585–1595.
[32] S. Talbot, R. Nelson, W.T. Self, Br. J. Pharmacol. 154 (2008) 940–948.
[33] M.P. Rayman, Lancet 356 (2000) 233–241.
[34] B.N. Ames, Mutat. Res. 475 (2001) 7–20.
[35] W.C. Reeves, S.P. Marcuard, S.E. Willis, A. Movahed, J. Parenter. Enteral. Nutr.
13 (1989) 663–665.
[36] Y. Molin, P. Frisk, N.G. Ilbaeck, Anticancer Drugs 19 (2008) 812–818.
[37] M.L. Ackland, J. Bornhorst, G.V. Dedoussis, R.R. Dietert, J.O. Nriagu, J.M.
Pacyna, J.M. Pettifor, Metals in the environment as risk factors for infectious
diseases gaps and opportunities, in: Trace Metals and Infectious Diseases, MIT
Press, 2015, pp. 271–307.
[38] H.E. Ganther, C. Goudie, M.L. Sunde, M.J. Kopecky, P. Wagner, S.-H. Oh, W.G.
Hoekstra, Science 175 (1972) 1122–1124.
[39] S.A. Gunn, T.C. Gould, W.A.D. Anderson, J. Reprod. Fertil. 15 (1968) 65–70.
[40] K. Sumino, R. Yamamoto, S. Kitamura, Nature 268 (1977) 73–74.
[41] G.N. Schrauzer, Biol. Trace Elem. Res. 33 (1992) 51–62.
[42] C. Sasakura, K.T. Suzuki, J. Inorg. Biochem. 71 (1998) 159–162.
[43] S.M. Rappaport, PloS One (2016) e0154387.
[44] S.P. Mohapatra, I. Nokolova, A. Mitchell, J. Environ. Manage. 83 (2007) 80–92.
[45] N. Steckling, M. Tobollik, D. Plass, C. Hornberg, B. Ericson, R. Fuller, S. BoseO’Reilly, Ann. Glob. Health 83 (2017) 234–247.
[46] Centers of Disease Control and Prevention, Atlanta, GA, USA. http://www.
cdc.gov/exposurereport/pdf/FourthReport.pdf (2009).
[47] H.V. Aposhian, D.C. Bruce, W. Alter, R.C. Dart, K.M. Hurlbut, M.M. Aposhian,
FASEB J. 6 (1992) 2472–2476.
[48] F. Bakir, S.F. Damluji, L. Amin-Zaki, M. Murtafdha, A. Khalidi, N.Y. Al-Rawi, S.
Tikriti, H.I. Dhahir, T.W. Clarkson, J.C. Smith, R.A. Doherty, Science 181 (1973)
230–241.
[49] M.A. Benton, J.E. Rager, L. Smeester, R.C. Fry, BMC Genomics 12 (2011) 173.
[50] W.L. Marcus, A.S. Rispin, Threshold carcinogenicity using arsenic as an
example, in: C.R. Cothern, M.A. Mehlmans, W.L. Marcus (Eds.), Advances in
Modern Environmental Toxicology, Princeton Scientific Publishing Company,
1988, pp. 133–158.
[51] J.-M. Moulis, Biometals 23 (2010) 877–896.
[52] K.E. Cosselman, A. Navas-Acien, J.D. Kaufman, Nat. Rev. Cardiol. 12 (2015)
627–642.
[53] Centers of Disease Control and Prevention, in, Atlanta, GA, 2005.
[54] J. Peto, Nature 411 (2001) 390–395.
[55] H.V. Aposhian, R.A. Zakharyan, E.K. Wildfang, S.M. Healy, J. Gailer, T.R.
Radabaugh, G.M. Bogdan, L.A. Powell, M.M. Aposhian, How is inorganic
arsenic detoxified?, in: W.R. Chappel, C.O. Abernathy, R.L. Calderon (Eds.),
Arsenic Exposure and Health Effects, Elsevier, Lausanne, 1999, pp. 289–297.
[56] S. Wu, S. Powers, W. Zhu, Y.A. Hannun, Nature 529 (2015) 43–47.
[57] P. Lichtenstein, N.V. Holm, P.K. Verkasalo, A. Iliadou, J. Kaprio, M. Koskenvuo,
E. Pukkala, A. Skytthe, K. Hemminki, N. Engl. J. Med. 343 (2000) 78–85.
[58] C.P. Wild, Cancer Epidemiol. Biomarkers Prev. 14 (2005) 1847–1850.
[59] S.M. Rappaport, J. Epidemiol. Community Health 66 (2012) 99–102.
[60] S.M. Rappaport, M.T. Smith, Science 330 (2010) 460–461.
[61] E. Grossman, High tech trash. Digital devices, hidden toxics, and human
health, Island Press, London, 2006.
[62] L. Jarup, A. Akesson, Toxicol. Appl. Pharmacol. 238 (2009) 201–208.
[63] J. Huff, R.M. Lunn, M.P. Waalkes, L. Tomatis, P.F. Infante, Int. J. Occup. Environ.
Health 13 (2007) 202–212.
[64] N. Jayatilake, S. Mendis, P. Maheepala, F.R. Mehta, BMC Nephrol. 14 (180)
(2013) 13.
[65] S. Bar-Sela, S. Reingold, E.D. Richter, Int. J. Occup. Environ. Health 7 (2001)
109–112.
[66] A.A. Saad, K. Gaber, A.I. Youssef, N.M. Amer, M.N. Ashour, M.K. Farag, N.A.M.
Diab, Hum. Ecol. Risk Assess. 17 (2014) 906–914.
[67] A. Bhatnagar, Circ. Res. 99 (2006) 692–705.
[68] M. Knoflach, B. Messner, Y.H. Shen, S. Frotschnig, G. Liu, K. Pfaller, X. Wang, B.
Matosevic, J. Willeit, S. Kiechl, G. Laufer, D. Bernhard, Circ. J. 75 (2011) 2491–
2495.
[69] J.J. Wirth, R.S. Mijal, Syst. Biol. Reprod. Med. 56 (2010) 147–167.
[70] D. Schwartz, F. Collins, Science 316 (2007) 695–696.
[71] L. Hood, A systems approach to medicine will transform healthcare, in: A.H.
Zewail (Ed.), Physical Biology, from Atoms to Medicine, Imperial College
Press, London, 2008, pp. 337–366.
[72] G.M. Filippelli, D. Morrison, D. Cichella, Elements 8 (2012) 439–444.
[73] S.-Y. Shin, E.B. Fauman, A.-K. Petersen, J. Krumsiek, R. Santos, J. Huang, M.
Arnold, I. Erte, V. Forgetta, T.-P. Yang, K. Walter, C. Menni, L. Chen, L. Vasquez,
A.M. Valdes, C.L. Hyde, V. Wang, D. Ziemek, P. Roberts, L. Xi, E. Grundberg,
The Multiple Tissue Human Expression Resource (MuTHER) Consortium, M.
Waldenberger, J.B. Richards, R.P. Mohney, M.V. Milburn, S.L. John, J. Trimmer,
F.J. Theis, J.P. Overington, K. Suhre, M.J. Brosnan, C. Gieger, G. Kastenmueller,
T.D. Spector, N. Soranzo, Nat. Genet. 46 (2014) 543–550.
386
S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386
[74] A. Johansson, S. Enroth, M. Palmblad, A.M. Deelder, J. Bergquist, U. Gyllensten,
Proc. Natl. Acad. Sci. U.S.A. 110 (2013) 4673–4678.
[75] M.A. Gibson, S. Sarpong-Kumankomah, S. Nehzati, G.N. George, J. Gailer,
Metallomics 9 (2017) 1060–1072.
[76] J.K. Nicholson, I.D. Wilson, Nat. Rev. Drug Discov. 2 (2003) 668–676.
[77] S.L. Winski, D.E. Carter, J. Toxicol. Environ. Health 46 (1995) 379–397.
[78] D.J. Price, J.G. Joshi, J. Biol. Chem. 258 (1983) 10873–10880.
[79] R.B. Conolly, Toxicol. Sci. 63 (2001) 1–2.
[80] D.J. Carlin, C.V. Rider, R. Woychik, L.S. Birnbaum, Environ. Health Perspect.
121 (2013) A6–A8.
[81] S.J. Sturla, A.R. Boobis, R.E. FitzGerald, J. Hoeng, R.J. Kavlock, K. Schirmer,
M. Whelan, M.F. Wilks, M.C. Peitsch, Chem. Res. Toxicol. 27 (2014) 314–
329.
[82] C. de Burbure, J.-P. Buchet, A. Leroyer, C. Nisse, J.-M. Haguenouer, A. Mutti, Z.
Smerhovsky, M. Cikrt, M. Trzcinka-Ochocka, G. Razniewska, M. Jakubowski, A.
Bernard, Environ. Health Perspect. 114 (2006) 584–590.
[83] L. Hood, J.R. Heath, M.E. Phelps, B. Lin, Science 306 (2004) 640–643.
[84] J. Gailer, ISRN Chromatogr. 2013 (2013) 21.
[85] R.J. Gerson, Z.A. Shaikh, Biochem. Pharmacol. 33 (1984) 199–203.
[86] S. Lin, W.R. Cullen, D.J. Thomas, Chem. Res. Toxicol. 12 (1999) 924–930.
[87] S.A. Manley, S. Byrns, A.W. Lyon, P. Brown, J. Gailer, J. Biol. Inorg. Chem. 14
(2009) 61–74.
[88] T. Peters, Adv. Protein Chem. 37 (1985) 161–245.
[89] M.G.J. Ford, B.M.F. Pearse, M.K. Higgins, Y. Vallis, D.J. Owen, A. Gibson, C.R.
Hopkins, P.R. Evans, H.T. McMahon, Science 291 (2004) 1051–1055.
[90] J. Gailer, S. Madden, G.A. Buttigieg, M.B. Denton, H.S. Younis, Appl.
Organomet. Chem. 16 (2002) 72–75.
[91] B. Michalke, Selenspeziation mit SAX/ICP-MS und RPLC-ICP-MS, in: K.F.U.D.
Jensen
(Ed.),
Moderne
Techniken
der
Ionenanalyse,
ECOMED
Verlagsgesellschaft AG+Co.KG, Landsberg, Germany, 2002, pp. 50–60.
[92] J. Gailer, L. Ruprecht, P. Reitmeir, B. Benker, P. Schramel, Appl. Organometal.
Chem. 18 (2004) 670–675.
[93] E.M. Leslie, J. Inorg. Biochem. 2012 (2012) 141–149.
[94] G.N. George, J. Gailer, O. Ponomarenko, P.F. LaPorte, K. Strait, M. Alauddin, H.
Ahsan, S. Ahmed, J. Spallholz, I.J. Pickering, J. Inorg. Biochem. 158 (2016) 24–
29.
[95] M.W. Carew, E.M. Leslie, Carcinogenesis 31 (2010) 1450–1455.
[96] R.M. Krohn, M. Lemaire, L.F.N. Silva, C. Lemarie, A. Bolt, K.M. Mann, J.E. Smits,
J. Nutr. Biochem. (2016, 2016,) 9–15.
[97] L. Yang, W. Wang, S. Hou, P.J. Peterson, W.P. Williams, Environ. Geochem.
Health 24 (2002) 359–374.
[98] J.E. Spallholz, L.M. Boylan, M.M. Rahman, Sci. Total Environ. 323 (2004) 21–
32.
[99] E.Z. Jahromi, W. White, Q. Wu, R. Yamdagni, J. Gailer, Metallomics 2 (2010)
460–468.
[100] C. Jacob, W. Maret, B.L. Vallee, Proc. Natl. Acad. Sci. U.S.A. 96 (1999) 1910–
1914.
[101] E. McLean, M. Cogswell, I. Egli, D. Woidyla, B. de Benoist, Publ. Health Nutr. 12
(2008) 444–454.
[102] H. Horiguchi, M. Sato, N. Konno, M. Fukushima, Arch. Toxicol. 71 (1996) 11–
19.
[103] M.M. Rahman, U.K. Chowdhury, S.C. Mukherjee, B.K. Mondal, K. Paul, D. Lodh,
B.K. Biswas, C.R. Chanda, G.K. Basu, K.C. Saha, S. Roy, R. Das, S.K. Palit, Q.
Quamruzzaman, D. Chakraborti, Clin. Toxicol. 39 (2001) 683–700.
[104] N.P.C. Maramba, J.P. Reyes, A.T. Francisco-Rivera, L.C.R. Pananiban, C.
Dioquino, N. Dando, R. Timbang, H. Akagi, M.T. Castillo, C. Quitoriano, M.
Afuang, A. Matsuyama, T. Eguchi, Y. Fuchigami, J. Environ. Manage. 81 (2006)
135–145.
[105] W.Y. Craig, T.B. Ledue, R.F. Ritchie, in: Foundation for Blood Research (Ed.),
Dade Behring Inc., Newark, 2000.
[106] D.C. Carter, J.X. Ho, Adv. Prot. Sci. 45 (1994) 153–203.
[107] S. Lau, B. Sarkar, J. Toxicol. Environ. Health 5 (1979) 907–916.
[108] A.J. Stewart, C.A. Blindauer, S. Berezenko, D. Sleep, P.J. Sadler, Proc. Natl. Acad.
Sci. U.S.A. 100 (2003) 3701–3706.
[109] J. Sundberg, B. Ersson, B. Loennerdal, A. Oskarsson, Toxicology 137 (1999)
169–184.
[110] P. Sagmeister, M.A. Gibson, K.H. McDade, J. Gailer, J. Chromatogr., B 1027
(2016) 181–186.
[111] A. Marrero, S. Duquerroy, S. Trapani, T. Goulas, T. Guevara, G.R. Andersen, J.
Navaz, L. Sottrup-Jensen, F.X. Gomis-Rueth, Angew. Chem. Int. Ed. 51 (2012)
3340–3344.
[112] A. Garza, H. Chavez, R. Vega, E. Soto, Salud Mental 28 (2005) 48–58.
[113] Y.-H. Huang, C.-M. Shih, C.-J. Huang, C.-M. Lin, C.-M. Chou, M.-L. Tsai, T.P. Liu,
J.-F. Chiu, C.-T. Chen, J. Cell. Biochem. 98 (2006) 577–589.
[114] B. Rowley, M. Monestier, Mol. Immunol. 42 (2005) 833–838.
[115] K.M. Pollard, P. Hultman, D.H. Kono, Chem. Res. Toxicol. 23 (2010) 455–466.
[116] P. Bigazzi, Lupus 3 (1994) 449–453.
[117] R.K. Zalups, S. Ahmad, Toxicol. Appl. Pharmacol. 186 (2003) 163–188.
[118] D. Yeter, M.A. Portman, M. Aschner, M. Farina, W.-C. Chan, K.-S. Hsieh, H.-C.
Kuo, Int. J. Environ. Res. Publ. Health 13 (2016) 101.
[119] E. Mothes, P. Faller, Biochemistry 46 (2007) 2267–2274.
[120] E. Casalino, C. Sblano, C. Landriscina, Arch. Biochem. Biophys. 346 (1997)
171–179.
[121] M. Isokawa, T. Kanamori, T. Funatsu, M. Tsunoda, J. Chromatogr., B 964 (2014)
103–115.
[122] D.J. Thomas, J.C. Smith, Toxicol. Appl. Pharmacol. 62 (1982) 104–110.
[123] T.T. Morris, J.L.A. Keir, S.J. Boshart, V.P. Lobanov, A.M.A. Ruhland, N. Bahl, J.
Gailer, J. Chromatogr., B 958 (2014) 16–21.
[124] W. Wang, O. Rusin, X. Xu, K.K. Kim, J.O. Escobedo, S.O. Fakayode, K.A. Fletcher,
M. MLowry, C.M. Schowalter, C.M. Lawrence, F.R. Fronczek, I.M. Warner, R.M.
Strongin, J. Am. Chem. Soc. 127 (2005) 15949–15958.
[125] H. Refsum, P.M. Ueland, O. Nygard, S.E. Vollset, Annu. Rev. Med. 49 (1998)
31–62.
[126] M.J. Warren, J.B. Cooper, S.P. Wood, P.M. Shoolingin-Jordan, Trends Biochem.
Sci. 23 (1998) 217–221.
[127] S. Moitra, B.B. Brashier, S. Sahu, Am. J. Ind. Med. 57 (2014) 1064–1072.
[128] L. Szablewski, A. Sulima, Biol. Chem. 398 (2017) 411–423.
[129] P.G. LeFevre, J. Gen. Physiol. 31 (1948) 505–527.
[130] R.I. Macey, Am. J. Physiol. 246 (1984) C195–C203.
[131] M. Borgnia, S. Nielsen, A. Engel, P. Agre, Annu. Rev. Biochem. 68 (1999) 425–
458.
[132] I. Csanaky, Z. Gregus, Toxicology 186 (2003) 33–50.
[133] Z. Liu, M.A. Sanchez, X. Jiang, E. Boles, S.M. Landfear, B.P. Rosen, Biochem.
Biophys. Res. Commun. 351 (2006) 424–430.
[134] T.-L. Zhang, Y.-X. Gao, J.-F. Lu, K. Wang, J. Inorg. Biochem. 79 (2000) 195–203.
[135] B. Nemeti, Z. Gregus, Toxicol. Sci. 85 (2005) 847–858.
[136] B. Nemeti, I. Csanaky, Z. Gregus, Toxicol. Sci. 74 (2003) 22–31.
[137] N. Scott, K.M. Hatlelid, N.E. MacKenzie, D.E. Carter, Chem. Res. Toxicol. 6
(1993) 102–106.
[138] B. Chen, X. Lu, S. Shen, L.L. Arnold, S.M. Cohen, X.C. Le, Chem. Res. Toxicol. 26
(2013) 952–962.
[139] Y. Yamashita, M. Yamashita, J. Biol. Chem. 285 (2010) 18134–18138.
[140] M. Yamashita, Y. Yamashita, K. Suzuki, Y. Kani, N. Mizusawa, S. Imamura, K.
Takemoto, T. Hara, M.A. Hossain, T. Yabu, K. Touhata, Mar. Biotechnol. 15
(2013) 559–570.
[141] M. Yamashita, Y. Yamashita, T. Ando, J. Wakamiya, S. Akiba, Biol. Trace Elem.
Res. 156 (2013) 36–44.
[142] I.K. Cheah, B. Halliwell, Biochim. Biophys. Acta 1822 (2012) 784–793.
[143] A.G. Splittberger, A.L. Tappel, Arch. Biochem. Biophys. 197 (1979) 534–542.
[144] N. Ballatori, S.M. Krance, S. Notenboom, S. Shi, K. Tieu, C.L. Hammond, Biol.
Chem. 390 (2009) 191–214.
[145] L. Zolla, G. Lupidi, G. Amiconi, Toxicol. In Vitro 8 (1994) 483–490.
[146] R.P. Rother, L. Bell, P. Hillmen, M.T. Gladwin, J. Am. Med. Assoc. 293 (2005)
1653–1662.
[147] J. Gailer, W. Lindner, J. Chromatogr., B 716 (1998) 83–93.
[148] D.L. Rabenstein, A.A. Isab, R.S. Reid, Biochim. Biophys. Acta 696 (1982) 53–64.
[149] D.L. Rabenstein, A.A. Isab, Biochim. Biophys. Acta 721 (1982) 374–384.
[150] M. Delnomdedieu, M.M. Basti, M. Styblo, J.D. Otvos, D.J. Thomas, Chem. Res.
Toxicol. 7 (1994) 621–627.
[151] A. Naganuma, N. Imura, Toxicol. Appl. Pharmacol. 47 (1979) 613–616.
[152] A. Naganuma, Y. Koyama, N. Imura, Toxicol. Appl. Pharmacol. 54 (1980) 405–
410.
[153] W. Kadima, D.L. Rabenstein, J. Inorg. Biochem. 40 (1990) 141–149.
[154] G.N. George, R.C. Prince, J. Gailer, G.A. Buttigieg, M.B. Denton, H.H. Harris, I.J.
Pickering, Chem. Res. Toxicol. 17 (2004) 999–1006.
[155] E.Z. Jahromi, J. Gailer, I.J. Pickering, G.N. George, J. Inorg. Biochem. 136 (2014)
99–106.
[156] J.A. Lukin, G. Kontaxis, V. Simplaceanu, Y. Yauan, C. Ho, Proc. Natl. Acad. Sci,
U.S.A. 100 (2003) 517–520.
[157] P.G. Righetti, E. Boschetti, Mass Spectrom. Rev. 27 (2008) 596–608.
[158] J.S. O’Neill, G. van Ooijen, L.E. Dixon, C. Troein, F. Corellou, F.-Y. Bouget, A.B.
Reddy, A.J. Millar, Nature 469 (2011) 554–558.
[159] H.A. Schroeder, J.J. Balassa, J. Chronic Dis. 14 (1961) 236–258.
[160] A.M. Larson, J. Polson, R.J. Fontana, T.J. Davern, E. Lalani, L.S. Hynan, J.S. Reisch,
F.V. Schiodt, G. Ostapowicz, A.O. Shakil, W.M. Lee, Hepatology 42 (2005)
1364–1372.
[161] G.R. Gale, L.M. Atkins, A.B. Smith, E.M. Walker, E.P. Fody, Toxicol. Appl.
Pharmacol. 82 (1986) 368–377.
[162] J. Coresh, E. Selvin, L.A. Stevens, J. Manzi, J.W. Kusek, P. Eggers, F. Van Lente, A.
S. Levey, J. Am. Med. Assoc. 298 (2007) 2038–2047.
[163] D.A. Aremu, M.S. Madejczyk, N. Ballatori, Environ. Health Perspect. 116
(2008) 26–31.
[164] L.J. Goldwater, Sci. Am. 224 (1971) 15–21.
[165] B. Weiss, T.W. Clarkson, W. Simon, Environ. Health Perspect. 110 (2002) 851–
854.
[166] L. Charlet, Y. Chapron, P. Faller, R. Kirsch, A.T. Stone, P.C. Baveye, Coord. Chem.
Rev. 256 (2012) 2147–2163.
[167] J. van der Greef, P. Stroobant, R. van der Heijden, Curr. Opin. Chem. Biol. 8
(2004) 559–565.
[168] L. Chapman, H.M. Chan, Environ. Health Perspect. 108 (2000) 29–56.
[169] M. Sooriyaarachchi, G.N. George, I.J. Pickering, A. Narendran, J. Gailer,
Metallomics 8 (2016) 1170–1176.
[170] B. Lahner, J. Gong, M. Mahmoudian, E.L. Smith, K.B. Abid, E.E. Rogers, M.L.
Guerinot, J.F. Harper, J.M. Ward, L. McIntyre, J.I. Schroeder, D.E. Salt, Nat.
Biotechnol. 21 (2003) 1215–1221.
[171] P.J. Landrigan, J.L. Sly, M. Ruchirawat, E.R. Silva, X. Huo, F. Diaz-Barriga, H.J.
Zar, M. King, E.H. Ha, K.A. Asante, H. Ahanchian, P.D. Sly, Ann. Glob. Health 82
(2016) 10–19.
[172] M.C. White, L.A. Peipins, M. Watson, K.F. Trivers, D.M. Holman, J.L.
Rodriguesz, J. Adolesc. Health 52 (2013) S1–S7.
[173] D.O. Carpenter, S. Bushkin-Bedient, J. Adolesc. Health 52 (2013) S21–S29.
[174] H. Naranmandura, K.T. Suzuki, Chem. Res. Toxicol. 21 (2008) 678–685.