Mercury is unique among the heavy metals in that it can exist in several physical and chemical forms, including elemental mercury, which is a liquid at room temperature. All forms of mercury have toxic effects in a number of organs, especially in the kidneys. Within the kidney, the pars recta of the proximal tubule is the most vulnerable segment of the nephron to the toxic effects of mercury. The biological and toxicological activity of mercurous and mercuric ions in the kidney can be defined largely by the molecular interactions that occur at critical nucleophilic sites in and around target cells. Because of the high bonding affinity between mercury and sulfur, there is particular interest in the interactions that occur between mercuric ions and the thiol group(s) of proteins, peptides and amino acids. Molecular interactions with sulfhydryl groups in molecules of albumin, metallothionein, glutathione, and cysteine have been implicated in mechanisms involved in the proximal tubular uptake, accumulation, transport, and toxicity of mercuric ions. In addition, the susceptibility of target cells in the kidneys to the injurious effects of mercury is modified by a number of intracellular and extracellular factors relating to several thiol-containing molecules. These very factors are the theoretical basis for most of the currently employed therapeutic strategies. This review provides an update on the current body of knowledge regarding the molecular interactions that occur between mercury and various thiol-containing molecules with respect to the mechanisms involved in the renal cellular uptake, accumulation, elimination, and toxicity of mercury.

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Molecular Interactions with Mercury in the Kidney

Lanthanide doped nanoparticles (Ln:NPs) hold promise as novel luminescent probes for numerous applications in nanobiophotonics. Despite excellent photostability, narrowband photoluminescence, efficient anti-Stokes emission and long luminescence lifetimes, which are needed to meet the requirements of multiplexed and background free detection at prolonged observation times, concern about their toxicity is still an issue for both in vivo and in vitro applications. Similar to other chemicals or pharmaceuticals, the very same properties that are desirable and potentially useful from a biomedical perspective can also give rise to unexpected and hazardous toxicities. In engineered bionanomaterials, the potentially harmful effects may originate not only from their chemical composition but also from their small size. The latter property enables the nanoparticles to bypass the biological barriers, thus allowing deep tissue penetration and the accumulation of the nanoparticles in a number of organs. In addition, nanoparticles are known to possess high surface chemical reactivity as well as a large surface-to-volume ratio, which may seriously affect their biocompatibility. Herein we survey the underlying mechanisms of nanotoxicity and provide an overview on the nanotoxicity of lanthanides and of upconverting nanoparticles.

Upconverting nanoparticles: assessing the toxicity

For the past three decades, most attention in heavy metal toxicology has been paid to cadmium, mercury, lead, chromium, nickel, vanadium, and tin because these metals widely polluted the environment. However, with the development of new materials in the last decade, the need for toxicological studies on those new materials has been increasing. A group of rare earths (RE) is a good example. Although some RE have been used for superconductors, plastic magnets, and ceramics, few toxicological data are available compared to other heavy metals described above. Because chemical properties of RE are very similar, it is plausible that their binding affinities to biomolecules, metabolism, and toxicity in the living system are also very similar. In this report, we present an overview of the metabolism and health hazards of RE and related compounds, including our recent studies.

Exposure, metabolism, and toxicity of rare earths and related compounds.

Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium

Lanthanides, also called rare-earth elements, are an interesting group of 15 chemically active, mainly trivalent, f-electronic, silvery-white metals. In fact, lanthanides are not as rare as the name implies, except for promethium, a radioactive artificial element not found in nature. The mean concentrations of lanthanides in the earth's crust are comparable to those of life-important elements like iodine, cobalt and selenium. Many lanthanide compounds show particular magnetic, catalytic and optic properties, and that is why their technical applications are so extensive. Numerous industrial sources enable lanthanides to penetrate into the human body and therefore detailed toxicological studies of these metals are necessary. In the liver, gadolinium selectively inhibits secretion by Kupffer cells and it decreases cytochrome P450 activity in hepatocytes, thereby protecting liver cells against toxic products of xenobiotic biotransformation. Praseodymium ion (Pr3+) produces the same protective effect in liver tissue cultures. Cytophysiological effects of lanthanides appear to result from the similarity of their cationic radii to the size of Ca2+ ions. Trivalent lanthanide ions, especially La3+ and Gd3+, block different calcium channels in human and animal cells. Lanthanides can affect numerous enzymes: Dy3+ and La3+ block Ca2+-ATPase and Mg2+-ATPase, while Eu3+ and Tb3+ inhibit calcineurin. In neurons, lanthanide ions regulate the transport and release of synaptic transmitters and block some membrane receptors, e.g. GABA and glutamate receptors. It is likely that lanthanides significantly and uniquely affect biochemical pathways, thus altering physiological processes in the tissues of humans and animals.

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Toxicological and cytophysiological aspects of lanthanides action.

Neurotoxicity of lanthanum chloride in newborn chicks

The effects of lanthanum chloride administration in newborn chicks on glutamate uptake and release by brain synaptosomes.

Administration of HgCl2 at a dose of 5 mg/kg body weight/day for 15 days to male albino rats brought about a marked depression of the scavenging enzymes viz. glutathione peroxidase and glutathione S-transferase, in kidney. There was an adaptive rise in the levels of catalase and no increased lipid peroxidation was observed. The levels of both glutathione and glutathione reductase were decreased, whereas total thiol increased. In the intoxicated rats, Vitamin-E was effective in bringing back glutathione levels to normal. The adaptation in this group of animals is reflected by increased superoxide dismutase activities. Feeding of Vitamin-E alone could cause a depression of the scavenging enzymes like glutathione peroxidase and glutathione S-transferase along with a slight lowering of glutathione levels.

Effects of mercuric chloride on several scavenging enzymes in rat kidney and influence of vitamin E supplementation.

Both nitrofurantoin-sensitive and nitrofurantoin-resistant strains ofVibrio el tor were found to lyze in the presence of Tris-EDTA at alkaline pH. The rate of lysis was appreciably enhanced by lysozyme. The amounts of intracellular components,viz. proteins and carbohydrates, released from the nitrofurantoin-sensitive strain by Tris-EDTA treatment, were significantly lower than those from the nitrofurantoin-resistant strain. Differences in periplasmic proteins released from Tris-EDTA treated cells of nitrofurantoin-resistant and -sensitive strains were revealed by gel electrophoresis.

A. Basu

Papers

Neurotoxicity of lanthanum chloride in newborn chicks

The effects of lanthanum chloride administration in newborn chicks on glutamate uptake and release by brain synaptosomes.

Effects of mercuric chloride on several scavenging enzymes in rat kidney and influence of vitamin E supplementation.

Lysis of nitrofurantoin-resistant strain of Vibrio el tor.