BioMetals (v.23, #5)

New perspectives in cadmium toxicity: an introduction by Jean-Marc Moulis; Frank Thévenod (763-768).

Cadmium exposure in the population: from health risks to strategies of prevention by Tim S. Nawrot; Jan A. Staessen; Harry A. Roels; Elke Munters; Ann Cuypers; Tom Richart; Ann Ruttens; Karen Smeets; Herman Clijsters; Jaco Vangronsveld (769-782).
We focus on the recent evidence that elucidates our understanding about the effects of cadmium (Cd) on human health and their prevention. Recently, there has been substantial progress in the exploration of the shape of the Cd concentration-response function on osteoporosis and mortality. Environmental exposure to Cd increases total mortality in a continuous fashion without evidence of a threshold, independently of kidney function and other classical factors associated with mortality including age, gender, smoking and social economic status. Pooled hazard rates of two recent environmental population based cohort studies revealed that for each doubling of urinary Cd concentration, the relative risk for mortality increases with 17% (95% CI 4.2–33.1%; P < 0.0001). Tubular kidney damage starts at urinary Cd concentrations ranging between 0.5 and 2 μg urinary Cd/g creatinine, and recent studies focusing on bone effects show increased risk of osteoporosis even at urinary Cd below 1 μg Cd/g creatinine. The non-smoking adult population has urinary Cd concentrations close to or higher than 0.5 μg Cd/g creatinine. To diminish the transfer of Cd from soil to plants for human consumption, the bioavailability of soil Cd for the plants should be reduced (external bioavailability) by maintaining agricultural and garden soils pH close to neutral (pH-H2O of 7.5; pH-KCL of 6.5). Reducing the systemic bioavailability of intestinal Cd can be best achieved by preserving a balanced iron status. The latter might especially be relevant in groups with a lower intake of iron, such as vegetarians, and women in reproductive phase of life. In exposed populations, house dust loaded with Cd is an additional relevant exposure route. In view of the insidious etiology of health effects associated with low dose exposure to Cd and the current European Cd intake which is close to the tolerable weekly intake, one should not underestimate the importance of the recent epidemiological evidence on Cd toxicity as to its medical and public health implications.
Keywords: Cadmium; Epidemiology; Kidney; Prevention; Mortality; Osteoporosis; Toxic metals

Heavy metal poisoning: the effects of cadmium on the kidney by Nikhil Johri; Grégory Jacquillet; Robert Unwin (783-792).
The heavy metal cadmium (Cd) is known to be a widespread environmental contaminant and a potential toxin that may adversely affect human health. Exposure is largely via the respiratory or gastrointestinal tracts; important non-industrial sources of exposure are cigarette smoke and food (from contaminated soil and water). The kidney is the main organ affected by chronic Cd exposure and toxicity. Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule. Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd2+ into the cytosol, where it can generate reactive oxygen species (ROS) and activate cell death pathways. An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP) (also a receptor-mediated process in the proximal tubule) such as retinol binding protein (RBP). This so-called ‘tubular proteinuria’ is a good index of proximal tubular damage, but it is not usually detected by routine clinical dipstick testing for proteinuria. Continued and heavy Cd exposure can progress to the clinical renal Fanconi syndrome, and ultimately to renal failure. Environmental Cd exposure may be a significant contributory factor to the development of chronic kidney disease, especially in the presence of other co-morbidities such as diabetes or hypertension; therefore, the sources and environmental impact of Cd, and efforts to limit Cd exposure, justify more attention.
Keywords: Cadmium; Kidney; Nephrotoxicity; Low molecular weight protein; Proximal tubule; Fanconi syndrome

Early biomarkers of cadmium exposure and nephrotoxicity by Walter C. Prozialeck; Joshua R. Edwards (793-809).
As the risks of cadmium (Cd)-induced kidney disease have become increasingly apparent, much attention has been focused on the development and use of sensitive biomarkers of Cd nephrotoxicity. The purpose of this review is to briefly summarize the current state of Cd biomarker research. The review includes overviews of the toxicokinetics of Cd, the mechanisms of Cd-induced proximal tubule injury, and mechanistic summaries of some of the biomarkers (N-acetyl-β-d-glucosamidase; β2-microglubulin, metallothionein, etc.) that have been most widely used in monitoring of human populations for Cd exposure and nephrotoxicity. In addition, several novel biomarkers (kidney injury molecule-1, α-glutathione-S-transferase and insulin) that offer the potential for improved biomonitoring of Cd-exposed populations are discussed.
Keywords: Cadmium; Biomarkers; Kidney; Nephrotoxicity; Proximal tubule

Today cardiovascular diseases (CVDs) are the killer number one world wide. In 2004 an estimated 17.1 million people died due to CVDs and this number will further increase to an estimated 23.6 million by 2030. Importantly, currently known risk factors, like hypertension, and hypercholesterolemia, can only be made responsible for about 50–75% of all CVDs, highlighting the urgent need to search for and define new CVD risk factors. Cadmium (Cd) was shown to have the potential to serve as one such novel risk factor, as it was demonstrated—in vitro, in animal studies, and in human studies—that Cd causes atherosclerosis (the basis of most CVDs). Herein, we discuss the molecular and cellular biological effects of Cd in the cardiovascular system; we present concepts on the pathophysiology of Cd-caused atherosclerosis, and provide data that indicate an epidemiological relevance of Cd as a risk factor for CVDs.
Keywords: Cadmium; Endothelial; Smooth muscle cell; Necrosis; Apoptosis; Lipid; Cadherin; Divalent metal transporter 1; Zinc; Inflammation; DNA damage

Cadmium and transport of ions and substances across cell membranes and epithelia by Emmy Van Kerkhove; Valérie Pennemans; Quirine Swennen (823-855).
Toxic metals such as cadmium (Cd2+) pose serious risks to human health. However, even though the importance of Cd2+ as environmental health hazards is now widely appreciated, the specific mechanisms by which it produces its adverse effects have yet to be fully elucidated. Cd2+ is known to enter cells, it binds and interacts with a multitude of molecules, it may indirectly induce oxidative stress and interfere with gene expression and repair of DNA. It also interacts with transport across cell membranes and epithelia and may therefore disturb the cell’s homeostasis and function. Interaction with epithelial transport, especially in the kidney and the liver, may have serious consequences in general health. A lot of research still needs to be done to understand the exact way in which Cd2+ interferes with these transport phenomena. It is not always clear whether Cd2+ has primary or secondary effects on cell membrane transport. In the present review we try to summarize the work that has been done up to now and to critically discuss the relevance of the experimental work in vitro with respect to the in vivo situation.
Keywords: Na+K+-ATPase; Ion channels; Glucose; Amino acids; Organic anions and cations; Endocytosis; Epithelial junctions

Cadmium (Cd2+) is a nonessential divalent metal ion that causes toxicity in multiple organs in humans. In order for toxicity to occur Cd2+ must first enter cells by utilizing transport pathways for essential metals. This review focuses on studies in which Cd2+ transport was directly demonstrated by electrophysiological, radiotracer or Cd2+-sensitive fluorescent dye techniques. The chemistry of Cd2+ and metal ions in general is addressed in the context of properties relevant for transport through membrane proteins, such as hydration energy. Apart from transport by the ZIP transporters SLC39A8 and SLC39A14, which is not topic of the review, uptake of free Cd2+ has been demonstrated for the Fe2+/H+ cotransporter divalent metal transporter 1. Moreover, the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis. The role of ATP binding cassette transporters in Cd2+ efflux from cells is also discussed. Both the multidrug resistance-associated protein 1 and cystic fibrosis transmembrane conductance regulator are likely to transport cadmium–glutathione complexes out of cells, whereas transport of free Cd2+ by the multidrug resistance P-glycoprotein remains controversial. Finally, arguments for and against Cd2+ transport by Ca2+ channels are presented. Most N- and L-type Ca2+ channels are closed at resting membrane potential (with the exception of CaV1.3 channels) and therefore unlikely to allow significant Cd2+ influx under physiological conditions. CaV3.1 and CaV3.2 T-type calcium channels are permeated by divalent metal ions, such as Fe2+ and Mn2+ because of considerable “window” currents close to resting membrane potential and could be responsible for tonic Cd2+ entry. TRPM7 and the mitochondrial Ca2+ uniporter are other likely candidates for Cd2+ transporters, whereas the role of Orai proteins, the store-operated calcium channels carrying Ca2+ release-activated Ca2+ current, in Cd2+ influx remains to be investigated.
Keywords: Calcium channels; ABC transporters; Standard enthalpy of hydration; 24p3/NGAL/lipocalin-2 receptor; Epithelial transport

The widespread occurrence of cadmium in the environment continues to pose a threat to human health despite attempts at limiting its technological uses. The biologically significant ionic form of cadmium, Cd2+, binds to many bio-molecules and these interactions underlie the toxicity mechanisms of cadmium. Some of the molecules specialized in the handling of alkaline earth (Mg2+, Ca2+) and transition metal ions (e.g. Zn2+, Cu2+/+, Fe3+/2+) should be particularly sensitive to the presence of Cd2+, because they enclose cationic sites to which the toxic metal can bind. The possible molecular targets of this kind for cadmium are considered herein. Whereas in vitro evidence for native cation replacement by Cd2+ in bio-molecules has been largely provided, the demonstration of such occurrences in vivo is scarce, with the notable exception of metallothionein. One reason might be that realistic low-level Cd2+ contaminations involve cellular concentrations far smaller than those of endogenous cations that usually saturate their binding sites. It is very likely that cadmium toxicity is most often mediated by biological systems amplifying the signals triggered by the presence of Cd2+. The interference of Cd2+ with redox sensitive systems acting at the transcriptional and post-transcriptional levels is instrumental in such processes. A better understanding of cadmium toxicity to tackle the environmental challenges lying ahead thus requires properly designed studies implementing biologically relevant cadmium concentrations on different cell types, improved knowledge of the homeostasis of essential metals, and use of these data in a theoretical framework integrating all cellular aspects of cadmium effects.
Keywords: Transition metals; Iron; Copper; Manganese; Reactive oxygen species; Regulation; Resistance mechanism

Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs by Ivan Sabolić; Davorka Breljak; Mario Škarica; Carol M. Herak-Kramberger (897-926).
Metallothioneins are cysteine-rich, small metal-binding proteins present in various mammalian tissues. Of the four common metallothioneins, MT-1 and MT-2 (MTs) are expressed in most tissues, MT-3 is predominantly present in brain, whereas MT-4 is restricted to the squamous epithelia. The expression of MT-1 and MT-2 in some organs exhibits sex, age, and strain differences, and inducibility with a variety of stimuli. In adult mammals, MTs have been localized largely in the cell cytoplasm, but also in lysosomes, mitochondria and nuclei. The major physiological functions of MTs include homeostasis of essential metals Zn and Cu, protection against cytotoxicity of Cd and other toxic metals, and scavenging free radicals generated in oxidative stress. The role of MTs in Cd-induced acute and chronic toxicity, particularly in liver and kidneys, is reviewed in more details. In acute toxicity, liver is the primary target, whereas in chronic toxicity, kidneys are major targets of Cd. The intracellular MTs bind Cd ions and form CdMT. In chronic intoxication, Cd stimulates de novo synthesis of MTs; it is assumed that toxicity in the cells starts when loading with Cd ions exceeds the buffering capacity of intracellular MTs. CdMT, released from the Cd-injured organs, or when applied parenterally for experimental purposes, reaches the kidneys via circulation, where it is filtered, endocytosed in the proximal tubule cells, and degraded in lysosomes. Liberated Cd can immediately affect the cell structures and functions. The resulting proteinuria and CdMT in the urine can be used as biomarkers of tubular injury.
Keywords: Antioxidants; Heavy metals; Hepatotoxicity; Nephrotoxicity; Oxidative stress; Reactive oxygen species; Urine metallothionein

Cadmium stress: an oxidative challenge by Ann Cuypers; Michelle Plusquin; Tony Remans; Marijke Jozefczak; Els Keunen; Heidi Gielen; Kelly Opdenakker; Ambily Ravindran Nair; Elke Munters; Tom J. Artois; Tim Nawrot; Jaco Vangronsveld; Karen Smeets (927-940).
At the cellular level, cadmium (Cd) induces both damaging and repair processes in which the cellular redox status plays a crucial role. Being not redox-active, Cd is unable to generate reactive oxygen species (ROS) directly, but Cd-induced oxidative stress is a common phenomenon observed in multiple studies. The current review gives an overview on Cd-induced ROS production and anti-oxidative defense in organisms under different Cd regimes. Moreover, the Cd-induced oxidative challenge is discussed with a focus on damage and signaling as downstream responses. Gathering these data, it was clear that oxidative stress related responses are affected during Cd stress, but the apparent discrepancies observed in between the different studies points towards the necessity to increase our knowledge on the spatial and temporal ROS signature under Cd stress. This information is essential in order to reveal the exact role of Cd-induced oxidative stress in the modulation of downstream responses under a diverse array of conditions.
Keywords: Cadmium; Glutathione; Oxidative stress; Signaling; Thiol; Antioxidative defense; Reactive oxygen species

The oxidative stress: endoplasmic reticulum stress axis in cadmium toxicity by Masanori Kitamura; Nobuhiko Hiramatsu (941-950).
Cadmium preferentially accumulates in the kidney, the major target for cadmium-related toxicity. Several underlying mechanisms are postulated, and reactive oxygen species (ROS) have been considered as crucial mediators for tissue injuries. In addition to oxidative stress, we recently disclosed that endoplasmic reticulum (ER) stress also plays a critical role. Cadmium causes ER stress in vitro and in vivo and mediates induction of apoptosis in target tissues. In this article, we describe a role for ER stress and involvement of particular branches of the unfolded protein response (UPR) in cadmium-triggered tissue injury, especially nephrotoxicity. We also discuss relationship between oxidative stress and ER stress, and involvement of selective ROS in the induction of pro-apoptotic branches of the UPR.
Keywords: Cadmium; Endoplasmic reticulum stress; Unfolded protein response; Reactive oxygen species; Apoptosis; Nephrotoxicity

Cadmium is an environmental pollutant, with relevant exposures at workplaces and in the general population. The carcinogenicity has been long established, most evident for tumors in the lung and kidney, but with increasing evidence also for other tumor locations. While direct interactions with DNA appear to be of minor importance, the interference with the cellular response to DNA damage, the deregulation of cell growth as well as resistance to apoptosis have been demonstrated in diverse experimental systems. With respect to DNA repair processes, cadmium has been shown to disturb nucleotide excision repair, base excision repair and mismatch repair; consequences are increased susceptibility towards other DNA damaging agents and endogenous mutagens. Furthermore, cadmium induces cell proliferation, inactivates negative growth stimuli, such as the tumor suppressor protein p53, and provokes resistance towards apoptosis. Particularly the combination of these multiple mechanisms may give rise to a high degree of genomic instability in cadmium-adapted cells, relevant not only for tumor initiation, but also for later steps in tumor development. Future research needs to clarify the relevance of these interactions for low exposure conditions in humans.
Keywords: Cadmium; DNA repair; Gene expression; Cell cycle control; Apoptosis; Genomic instability