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. 377 377 379 380 380 380 381 382 384 384 385 385 377 S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386 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 378 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 382 S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386 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]. 383 S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386 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 384 S. Sarpong-Kumankomah et al. / Coordination Chemistry Reviews 374 (2018) 376–386 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]. 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