Metallothionein-Null and Wild-Type Mice Show Similar Cadmium Absorption and Tissue Distribution Following Oral Cadmium Administration

doi:10.1006/taap.2001.9244

Toxicology and Applied Pharmacology

Volume 175, Issue 3, 15 September 2001, Pages 253-259

https://doi.org/10.1006/taap.2001.9244 Get rights and content

Abstract

Cadmium (Cd) is an environmental pollutant and is toxic to many tissues. Food is the primary source of Cd exposure for the general population. Metallothionein (MT), a cysteine-rich, Cd-binding protein, plays an important role in Cd detoxication. However, the role of MT in Cd absorption and distribution is still controversial. For example, some reports assert that MT in the intestine decreases Cd absorption and increases its distribution to the kidney, relative to the liver. Therefore, to further clarify the role of MT in Cd absorption and tissue distribution, MT-I/II knockout (MT-null) mice and their parental background wild-type mice were given a single dose of ¹⁰⁹Cd (1–300 μmol/kg po or 0.1–30 μmol/kg iv). Cd content in 15 organs was determined 4 h after Cd administration by gamma scintillation spectrometry. Approximately 60% of the Cd administered iv was retained in liver, and about 5% was retained in kidney in both MT-null and wild-type mice. The distribution of iv administered Cd was independent of dose. In contrast, when administered po, approximately 0.15% of the lowest dose (1 μmol/kg) and 0.75% of the highest dose (300 μmol/kg) was detected in the liver of both MT-null and wild-type mice. Similarly in kidney, approximately 0.05% of the dose was detected after the lowest dose and about 0.15% after the higher doses in both MT-null and wild- type mice. In summary, this study demonstrates that the absorption and initial distribution of orally administered Cd is dose dependent but is not influenced by MT.

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Citation Excerpt :
Ohta and Cherian (1991) reported that though the intracellular MT does not affect the uptake of Cd from lumen, it may reduce both the release of Cd from the intestine and its deposition in liver. However, according to Liu et al. (2001), orally administrated Cd is not influenced in absorption and initial distribution by MT. The main storage sites in the body for Cd are the liver and kidneys, especially the renal cortex (Jadán-Piedra et al., 2018).
Metals are ubiquitous in the environment due to huge industrial applications in the form of different chemicals and from extensive mining activities. The frequent exposures to metals and metalloids are crucial for the human health. Trace metals are beneficial for health whereas non-essential metals are dangerous for the health and some are proven etiological factors for diseases including cancers and neurological disorders. The interactions of essential trace metals such as selenium (Se) and zinc (Zn) with non-essential metals viz. lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) in biological system are very critical and complex. A huge number of studies report the protective role of Se and Zn against metal toxicity, both in animal and cellular levels, and also explain the numerous mechanisms involved. However, it has been considered that a tiny dyshomeostasis in the metals/trace metals status in biological system could induce severe deleterious effects that can manifest to numerous diseases. Thus, in this particular review, we have demonstrated the critical protection mechanism/s of Se and Zn against Cd, Pb, As and Hg toxicity in a one by one manner to clarify the up-to-date findings and perspectives. Furthermore, biomolecular consequences are comprehensively presented in light of particular cellular/biomolecular events which are somehow linked to a subsequent disease. The analyzed reports support significant protection potential of Se and Zn, either alone or in combination with other agents, against each of the abovementioned non-essential metals. However, Se and Zn are still not being used as detoxifying agents due to some unexplained reasons. We hypothesized that Se could be a potential candidate for detoxifying As and Hg regardless of their chemical speciations, but requires intensive clinical trials. However, particularly Zn-Hg interaction warrants more investigations both in animal and cellular level.
Nrf2 activation prevents cadmium-induced acute liver injury
2012, Toxicology and Applied Pharmacology
Citation Excerpt :
After administration, Cd is distributed via the blood, where it is bound to red blood cells and plasma proteins, mainly albumin. Albumin-bound Cd is readily distributed to various organs, with the majority going to the liver, where Cd is primarily bound to MT (Liu et al., 2001). After a single injection of Cd to rats, the highest concentration of Cd is in the liver, followed by kidney, spleen, and heart (Goering and Klaassen, 1983).
Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H₂DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd.
Discovery of ZIP transporters that participate in cadmium damage to testis and kidney
2009, Toxicology and Applied Pharmacology
It has been known for decades that cadmium (Cd) must enter the cell to cause damage, but there was no mechanism to explain genetic differences in response to Cd toxicity until 2005. Starting with the mouse Cdm locus associated with differences in Cd-induced testicular necrosis between inbred strains, a 24.6-centiMorgan region on chromosome 3 was reduced ultimately to 880 kb; in this segment is the Slc39a8 gene encoding the ZIP8 Zn²⁺/HCO₃⁻ symporter. In endothelial cells of the testis vasculature, Cd-sensitive mice exhibit high ZIP8 expression, Cd-resistant mice exhibit very low expression. A 168.7-kb bacterial artificial chromosome (BAC) from a 129S6 (Cd-sensitive) BAC library containing the Slc39a8 gene was inserted into the Cd-resistant C57BL/6J genome: Cd treatment produced testicular necrosis in BAC-transgenic BTZIP8-3 mice but not in non-transgenic littermates, thereby proving that the Slc39a8 gene is indeed the Cdm locus. Cd-induced renal failure also occurred in these BTZIP8-3 mice. Immunohistochemistry showed highly expressed ZIP8 protein in the renal proximal tubular epithelial apical surface, suggesting that ZIP8 participates in Cd-induced renal failure. Slc39a14, most closely evolutionarily related to Slc39a8, encodes differentially-spliced products ZIP14A and ZIP14B that display properties similar to ZIP8. ZIP8 in alveolar cells brings environmental Cd into the organism and ZIP14 in intestinal enterocytes carries Cd into the organism and into the hepatocyte. We believe these two transporters function endogenously as Zn²⁺/HCO₃⁻ symporters important in combating inflammation and carrying out other physiological functions; Cd is able to displace the endogenous cation, enter the cell, and produce tissue damage and disease.
Metallothionein protection of cadmium toxicity
2009, Toxicology and Applied Pharmacology
The discovery of the cadmium (Cd)-binding protein from horse kidney in 1957 marked the birth of research on this low-molecular weight, cysteine-rich protein called metallothionein (MT) in Cd toxicology. MT plays minimal roles in the gastrointestinal absorption of Cd, but MT plays important roles in Cd retention in tissues and dramatically decreases biliary excretion of Cd. Cd-bound to MT is responsible for Cd accumulation in tissues and the long biological half-life of Cd in the body. Induction of MT protects against acute Cd-induced lethality, as well as acute toxicity to the liver and lung. Intracellular MT also plays important roles in ameliorating Cd toxicity following prolonged exposures, particularly chronic Cd-induced nephrotoxicity, osteotoxicity, and toxicity to the lung, liver, and immune system. There is an association between human and rodent Cd exposure and prostate cancers, especially in the portions where MT is poorly expressed. MT expression in Cd-induced tumors varies depending on the type and the stage of tumor development. For instance, high levels of MT are detected in Cd-induced sarcomas at the injection site, whereas the sarcoma metastases are devoid of MT. The use of MT-transgenic and MT-null mice has greatly helped define the role of MT in Cd toxicology, with the MT-null mice being hypersensitive and MT-transgenic mice resistant to Cd toxicity. Thus, MT is critical for protecting human health from Cd toxicity. There are large individual variations in MT expression, which might in turn predispose some people to Cd toxicity.
Strain difference of cadmium accumulation by liver slices of inbred Wistar-Imamichi and Fischer 344 rats
2008, Toxicology in Vitro
Strain difference in the accumulation of cadmium (Cd) by liver slices was examined in inbred Cd-resistant Wistar-Imamichi (WI) and Cd-sensitive Fischer 344 (F344) rats. The accumulation of Cd by liver slices of WI rats was significantly lower than that of F344 rats, suggesting strain-related differences in the transport of Cd into the liver cells of these two rat strains. In addition, a similar strain difference was observed in the accumulation of zinc (Zn) by liver slices from WI and F344 rats. Cd accumulation by F344 liver slices decreased when Zn was added to the medium in combination with Cd. Furthermore, in F344 liver slices, Zn accumulation was significantly decreased when Cd was added to the medium. These results suggest that the accumulation of Cd by the liver is probably mediated, at least in part, by Zn transport systems. However, we found no strain difference in hepatic ZnT3 or ZIP3 transcript levels between WI and F344 rats. Further work is in progress to identify the transporter that causes the strain differences in hepatic Cd accumulation seen with WI and F344 rats.
Impact of iron status on cadmium uptake in suckling piglets
2007, Toxicology
Low iron status is known to increase the uptake of dietary cadmium in both adolescents and adults and there are indications that cadmium is absorbed from the intestine by the two major iron transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1). In addition, it has been suggested that duodenal metallothionein (MT) may limit the transport of cadmium across the intestinal epithelium. The present investigation was undertaken to examine whether iron status influences cadmium absorption in newborns by applying a model of suckling piglets and the possible roles of duodenal DMT1, FPN1 and MT. An oral cadmium dose (20 μg/kg body weight) was given daily for 6 consecutive days on postnatal days (PNDs) 10–15 to iron-deficient or iron-supplemented piglets. The cadmium dose was chosen to keep the cadmium level at a realistically low but still detectable level, and without inducing any adverse health effects in the piglets. As indicators of cadmium uptake, cadmium levels in blood and kidneys were measured on PND 16 by inductively coupled plasma-mass spectrometry (ICP-MS). Cadmium levels in blood were statistically significantly correlated with cadmium levels in kidneys. The cadmium uptake was not higher in iron-deficient suckling piglets; rather, we detected a higher cadmium uptake in the iron-supplemented ones. The expression and localisation of DMT1, FPN1 and MT were not affected by iron status and could therefore not explain the findings. Our results suggest that there are developmental differences in the handling of both iron and cadmium in newborns as compared to adults.

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Toxicology and Applied Pharmacology

Abstract

References (29)

Endogenous metallothionein as determinant of intestinal cadmium absorption: A reevaluation

Toxicology

Dosage-dependent absorption of cadmium in the rat intestine measured in situ

Toxicol. Appl. Pharmacol.

On the role of metallothionein in cadmium absorption by rat jejunum in situ

Toxicology

Tissue accumulation of cadmium following oral administration to metallothionein-null mice

Toxicol. Lett.

Dosage dependent disposition of cadmium administered orally to rats

Toxicol. Appl. Pharmacol.

The involvement of metallothionein in the intestinal absorption of cadmium in mice

Toxicol. Lett.

Absorption and distribution of cadmium in metallothionein-I transgenic mice

Fundam. Appl. Toxicol.

Distribution and retention of cadmium in metallothionein I and II null mice

Toxicol. Appl. Pharmacol.

Susceptibility of MT-null mice to chronic CdCl₂-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex

Toxicol. Sci.

Role of intestinal metallothionein in absorption and distribution of orally administered cadmium

Toxicol. Appl. Pharmacol.

Effects of mucosal metallothionein in small intestine on tissue distribution of cadmium after oral administration of cadmium compounds

Toxicol. Appl. Pharmacol.

Gastrointestinal absorption of cadmium and metallothionein

Toxicol. Appl. Pharmacol.

The dose-dependent deposition of cadmium into organs of Japanese quail following oral administration

Toxicol. Appl. Pharmacol.

Tissue distribution and retention of cadmium in rats during postnatal development: Minimal role of hepatic metallothionein

Toxicol. Appl. Pharmacol.

Cited by (40)

Selenium and zinc protections against metal-(loids)-induced toxicity and disease manifestations: A review

Nrf2 activation prevents cadmium-induced acute liver injury

Discovery of ZIP transporters that participate in cadmium damage to testis and kidney

Metallothionein protection of cadmium toxicity

Strain difference of cadmium accumulation by liver slices of inbred Wistar-Imamichi and Fischer 344 rats

Impact of iron status on cadmium uptake in suckling piglets

Regular ArticleMetallothionein-Null and Wild-Type Mice Show Similar Cadmium Absorption and Tissue Distribution Following Oral Cadmium Administration

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Metallothionein-Null and Wild-Type Mice Show Similar Cadmium Absorption and Tissue Distribution Following Oral Cadmium Administration