Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium.

Masters, Brian A.; Kelly, Edward J.; Quaife, Carol J.; Brinster, Ralph L.; Palmiter, Richard D.

doi:10.1073/pnas.91.2.584

Cited by 571 publications

(358 citation statements)

References 25 publications

Supporting

Mentioning

347

Contrasting

Unclassified

Order By: Relevance

“…Mt1 and Mt2 play a role in the oxidative stress response and their deletion in mice resulted in increased drug sensitivity of the liver and development of obesity. 34,35 Differential Mt1 and Mt2 gene expression was also detected at earlier time points (Fig. 2B).…”

Section: Resultsmentioning

confidence: 80%

See 1 more Smart Citation

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

et al. 2015

View full text Add to dashboard Cite

Several studies have described phenotypic changes in the offspring of mice exposed to a variety of environmental factors, including diet, toxins, and stress; however, the molecular pathways involved in these changes remain unclear. Using a high fat diet (HFD)-induced obesity mouse model, we examined liver gene expression in male offspring and analyzed chromatin of paternal spermatozoa. We found that the hepatic mRNA level of 7 genes (out of 20 evaluated) was significantly altered in HFD male offspring compared to control mice, suggesting that phenotypic changes in the offspring depend on parental diet. We examined 7 imprinted loci in spermatozoa DNA from HFD-treated and control fathers by bisulfite sequencing, but did not detect changes in DNA methylation associated with HFD. Using chromatin immunoprecipitation followed by high-throughput sequencing, we found differential histone H3-occupancy at genes involved in the regulation of embryogenesis and differential H3K4me1-enrichment at transcription regulatory genes in HFD fathers vs. control mice. These results suggest that dietary exposure can modulate histone composition at regulatory genes implicated in developmental processes.

show abstract

Section: Resultsmentioning

confidence: 80%

“…34,35 It should be noted that half of the analyzed genes (a total of 10) showed significant mRNA changes in the liver of HFDtreated fathers compared to LFD fathers ( Fig. 2A, Fig.…”

Section: Resultsmentioning

confidence: 99%

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Homozygous MT-I/II knock-out mice (129-Mt1 tm/Bri , Mt2 tm/Bri 129/SvPCJ background) 22 and corresponding wild-type (WT) mice were obtained from the Jackson Laboratory (Bar Harbor, ME). The homozygous mutants were mated inter se to maintain the line.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Hypersusceptibility to cisplatin carcinogenicity in metallothionein‐I/II double knockout mice: Production of hepatocellular carcinoma at clinically relevant doses

Waalkes

Liu

Kasprzak

et al. 2006

Intl Journal of Cancer

View full text Add to dashboard Cite

Metallothionein (MT) is a high-affinity metal binding protein thought to mitigate the toxicity of various metals. Cisplatin is a widely used cancer chemotherapeutic that is a rodent carcinogen and may have carcinogenic potential in humans. MT seems to reduce cisplatin toxicity by binding the metal compound but how MT deficiency might impact the carcinogenic effects of cisplatin is unknown. Thus, groups (n 5 25) of male MT-I/II double knockout (MT-null) or MT wild-type (WT) mice were exposed to a single treatment of cisplatin (5 or 10 mg/kg, i.p.), or left untreated (control) and observed over the next 104 weeks. The doses of cisplatin used equate to only a fraction of the total dose used typically in clinical settings. In cisplatin-treated MT-null mice, a dose-related increase in hepatocellular carcinoma (HCC) occurred (control, 0%; 5 mg/kg, 17%; 10 mg/kg, 36%) that was not seen in WT mice. Similarly, liver carcinoma multiplicity (HCC/liver) was increased markedly by cisplatin but only in MT-null mice, indicating the formation of multiple primaries in MT deficient mice. Harderian gland carcinoma incidence was also increased by cisplatin treatment in MT-null mice but not WT mice. Our results indicate that MT-null mice are hypersusceptible to the hepatocarcinogenic effects of cisplatin, and poor MT expression may be a predisposing factor for cisplatin-induced secondary tumors after chemotherapy. ' 2006 Wiley-Liss, Inc.Key words: cisplatin; carcinogenesis; mice; metallothionein To kill cancer cells, chemotherapeutic agents are often used at toxic levels. One long-term manifestation of these toxic effects could be secondary tumor formation. 1 As cancer survival improves because of more effective treatments, secondary, iatrogenic tumors arising from the initial therapeutic intervention will become an increasing issue 1 and knowledge of factors that predispose patients to such tumors could have important clinical applications. For instance, although cis-diamminedichloroplatinum(II) (cisplatin) is a widely used and very effective cancer chemotherapeutic, it can have limiting side effects and is considered probably carcinogenic in humans. 2,3 There are many case reports of secondary tumors developing in cancer patients that had received cisplatin for an initial malignancy, although this metallochemotherapeutic is used typically in combination with other chemical or physical treatments making etiologic linkage to any one component of the combination difficult. 2,3 Cisplatin is a complete carcinogen in rats or mice, however, inducing malignant tumors of the hematopoietic system and benign tumors of the liver. [4][5][6][7] Similarly, cisplatin will enhance the incidence or increase the multiplicity of benign lung tumors in strain A mice. [8][9][10] The platinum drug is also an effective initiator of renal and dermal cancers in rodents. 4,5,10,11 Metallothionein (MT) is a multi-functional, ubiquitously expressed, low-molecular-weight, metal-binding protein. [12][13][14][15] MT is distinctive in having numerous cysteines th...

show abstract

“…Homozygous MT-I/II knock-out mice (129-Mt1 tm/Bri , Mt2 tm/Bri 129/SvPCJ background) 30 were obtained from Jackson Laboratories (Bar Harbor, ME). The homozygous mutants were mated inter se to maintain the line.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

The Metallothionein-Null Phenotype Is Associated with Heightened Sensitivity to Lead Toxicity and an Inability to Form Inclusion Bodies

Qu¹,

Diwan²,

Liu³

et al. 2002

The American Journal of Pathology

View full text Add to dashboard Cite

Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium.

Cited by 571 publications

References 25 publications

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

Hypersusceptibility to cisplatin carcinogenicity in metallothionein‐I/II double knockout mice: Production of hepatocellular carcinoma at clinically relevant doses

The Metallothionein-Null Phenotype Is Associated with Heightened Sensitivity to Lead Toxicity and an Inability to Form Inclusion Bodies

Contact Info

Product

Resources

About