Cellular mechanisms of cadmium toxicity related to the homeostasis of essential metals

Abstract

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, Cd(2+), 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 (Mg(2+), Ca(2+)) and transition metal ions (e.g. Zn(2+), Cu(2+/+), Fe(3+/2+)) should be particularly sensitive to the presence of Cd(2+), 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 Cd(2+) 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 Cd(2+) 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 Cd(2+). The interference of Cd(2+) 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.

The effect of nanoparticle degradation on poly(methacrylic acid)-coated quantum dot toxicity: The importance of particle functionality assessment in toxicology

“…Interestingly, C17.2 and HUVEC cells had similar uptake levels, whereas PC12 cells had ingested lower numbers of QDots, which has been observed for various types of NPs [14,37]. This is likely due to the smaller overall size of the PC12 cells and their smaller surface area, resulting in a reduced area of interaction of NPs with the cell membrane, hereby impeding NP uptake.…”

“…As acidic conditions are known to induce acid etching of the QDot surface and hereby release Cd 2+ [37,39], the effect of pH on Cd 2+ release was evaluated using previously optimized endosomal-pH buffer systems [36] (see the Supporting Information for full experimental details). Figure 1D Figure 3A).…”

Liver and Cadmium Toxicity

“…Deregulation of the homeostasis of essential metals by Cd, and cellular Cd traffic via essential metals pathways contribute to Cd toxicity. Although many Cd-bound species can be obtained in vitro in the presence of large metal excess with pure biomolecules, demonstration of their occurrence in vivo, in mammalian cells in particular, is not an easy task [35]. The function of many metalloproteins critically depends on their interaction with a metal, usually a transition one, such as Cu, Fe, Zn, particularly the last one.…”

“…In this way, substitution of native metals by Cd is very often proposed as the leading molecular mechanism of Cd hepatotoxicity. Besides Zn involvement at the active site of enzymes, Zn has been more recently associated with an increasing number of regulatory functions [35]. MT's are involved in Zn buffering and Zn exchange between proteins.…”

New perspectives in cadmium toxicity: an introduction

“…Yet, the interference of Cd with a number of transport processes and with molecules requiring essential metals is amazing. The impact of Cd on membrane transport of metal cations and electrolytes and on intracellular processes are the topics of the second part of this special issue which is covered by Van Kerkhove et al (2010), Thévenod (2010), and Moulis (2010).…”