Cadmium increases ferroportin-1 gene expression in J774 macrophage cells via the production of reactive oxygen species

Park, Bo-Yeon; Chung, Jayong

doi:10.4162/nrp.2009.3.3.192

Cited by 13 publications

(10 citation statements)

References 37 publications

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“…Recently, it was shown that cadmium induction of FPN1 transcription was dependent on the generation of oxidative radicals. 29 This observation is consistent with our data and with the established role of cadmium in induction of MTF-1 responsive genes. Cadmium can directly displace zinc from metallothionein or damage metallothionein by generating oxidative radicals that would act on metallothionein and release zinc.…”

supporting

confidence: 82%

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

Troadec¹,

Ward²,

Lo³

et al. 2010

Blood

120

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IntroductionFerroportin (Fpn) is the only known mammalian iron exporter and plays an essential role in the entry of iron into plasma (for review, see Wessling-Resnick 1 and Wrighting and Andrews 2 ). Fpn is most highly expressed in cells that play a major role in iron acquisition: duodenal enterocytes, macrophages, hepatocytes and syncytial trophoblasts. Fpn, however, can be expressed on a wide variety of other cell types in response to heme 3,4 or iron. [5][6][7] Iron can regulate Fpn expression through transcriptional and translational mechanisms. Ferroportin1 (FPN1), the gene that encodes Fpn, contains a 5Ј iron-responsive element (IRE), which places its translation under the control of iron regulatory proteins. It is thought that the increased expression of Fpn by iron is a response to cellular iron load, as increased cytosolic iron would lead to increased iron export.FPN1 mRNA levels are also increased when cells are exposed to transition metals such as zinc, manganese, cadmium, copper, and other transition metals. 6 In both J774 cells and Caco cells, the increase in Fpn expression resulted in increased iron export. What is unclear, however, is the physiologic function of transition metal-induced expression of Fpn. Iron export in response to increased transition metals may protect cells from transition metal toxicity, perhaps by reducing the potential for iron-induced Fenton chemistry. Alternatively, Fpn might export other metals in addition to iron and thus increased expression of Fpn would directly protect cells from metal toxicity.In this study, we identify at least 1 mechanism by which transition metals induce Fpn expression. We show that zinc and cadmium can activate FPN1 transcription through the Metal Transcription Factor-1 (MTF-1). We also demonstrate that Fpn transports zinc and can protect cells from zinc toxicity. MethodsVector pcDNA3.1-mouse-MTF1-Flag was a gift from Dr G. K. Andrews. 8 We produced a chimera pcDNA3.1-mouse/human-MTF1-Flag by switching the mouse fragment with the human corresponding fragment between KpnI/FseI sites of mouse MTF1-Flag. To express an shRNA against mouse MTF-1, we inserted a double strand oligonucleotide targeting the gtacttcgccaccgctgta sequence of mouse MTF-1 into BamHI and EcoRI sites of pSIREN-DNR-DSRed (Clontech) according to manufacturer's instructions. The mouse/human chimera MTF-1 is resistant to shRNA against mouse MTF-1. The pGL3-control vector (Promega) was modified to perform the luciferase assay. The SV40 promoter was removed by HindIII/NheI digestion and the mouse Fpn promoter (starting at Ϫ2378, Ϫ1154, and Ϫ623 from the TATAA box) was amplified by polymerase chain reaction (PCR) and inserted using same restriction sites. The 5ЈIRE in the FPN1 promoter was deleted by BamHI/SamI digestion as described. 9 The putative metal-responsive elements (MREs) in the Fpn promoter in pGL3 were mutagenized by PCR to produce TCCAGCA*GA*AT*CT*CG and TGGAAGAA*TT*CG*AG (the consensus sequence is underlined, *mutagenized base). Fpn-green fluorescent protein (GFP) was car...

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supporting

confidence: 82%

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

Troadec¹,

Ward²,

Lo³

et al. 2010

Blood

120

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“…In macrophages, hemoglobin (Hb) is degraded and the iron released is exported into plasma through ferroportin1 on the membrane. During the process, Cd increases ferroportin1 expression in mouse macrophages (Park and Chung, 2009).…”

mentioning

confidence: 99%

Cadmium Induces Anemia through Interdependent Progress of Hemolysis, Body Iron Accumulation, and Insufficient Erythropoietin Production in Rats

Horiguchi¹,

Oguma²,

Kayama³

2011

Toxicological Sciences

113

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Cadmium is a toxic heavy metal and distributed widely in the environment. In addition to damaging the liver, kidneys, and bone, cadmium causes anemia through hemolysis, iron deficiency, and insufficient erythropoietin (EPO) production (renal anemia) along with changes in iron metabolism. Here, we investigated the role of iron in the interdependent progress of three types of anemia in cadmium-injected rats fed iron-sufficient or iron-deficient diets for 1 or 3 months. Cadmium injections for 1 month induced renal anemia without renal injury. Injections for 3 months induced hemolysis, iron deficiency, and renal anemia, accompanied by hepatic and renal damage. Iron concentrations in the liver, kidney, and spleen were increased, derived from internally released iron from hemolyzed red blood cells, increased duodenal iron absorption, insufficient erythropoiesis, and hepatic ferritin overproduced by cadmium-induced interleukin-6. Therefore, the iron deficiency anemia was actually apparent. Cadmium suppressed renal EPO production through a direct effect, accumulated iron, and destruction of EPO-producing cells. Increased duodenal iron absorption could be attributed to hypertrophy of the duodenal mucosa derived from anemia. Thus, insufficient EPO production and iron accumulation are the central factors driving anemia in cadmium toxicity.

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“…In the cell, iron is reduced to the ferric form and exported to the blood by ferroportin 1 [solute carrier family 40 (iron-regulated transporter), member 1; SLC40A1, formerly FPN1 ] at the basolateral membrane. Troadec et al (2010) reported a role for FPN1 in transition metal efflux (Cd and Zn) in mouse bone marrow macrophages, and Park and Chung (2009) found that Cd exposure increased FPN1 expression in macrophages. In blood, iron is bound to mobile transferrin ( TF ) and ferritin.…”

mentioning

confidence: 99%

Polymorphisms in Iron Homeostasis Genes and Urinary Cadmium Concentrations among Nonsmoking Women in Argentina and Bangladesh

Rentschler

Kippler

Axmon

et al. 2013

Environ Health Perspect

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Background: Cadmium (Cd) is a human toxicant and carcinogen. Genetic variation might affect long-term accumulation. Cd is absorbed via iron transporters.Objectives: We evaluated the impact of iron homeostasis genes [divalent metal transporter 1 (SLC11A2), transferrin (TF), transferrin receptors (TFR2 and TFRC), and ferroportin (SLC40A1)] on Cd accumulation.Methods: Subjects were nonsmoking women living in the Argentinean Andes [n = 172; median urinary Cd (U-Cd) = 0.24 µg/L] and Bangladesh (n = 359; U-Cd = 0.54 µg/L) with Cd exposure mainly from food. Concentrations of U-Cd and Cd in whole blood or in erythrocytes (Ery-Cd) were measured by inductively coupled plasma mass spectrometry. Fifty polymorphisms were genotyped by Sequenom. Gene expression was measured in whole blood (n = 72) with Illumina DirectHyb HumanHT-12 v4.0.Results: TFRC rs3804141 was consistently associated with U-Cd. In the Andean women, mean U-Cd concentrations were 22% (95% CI: –2, 51%), and they were 56% (95% CI: 10, 120%) higher in women with GA and AA genotypes, respectively, relative to women with the GG genotype. In the Bangladeshi women, mean U-Cd concentrations were 22% (95% CI: 1, 48%), and they were 58% (95% CI: –3, 157%) higher in women with GA and AA versus GG genotype, respectively [adjusted for age and plasma ferritin in both groups; ptrend = 0.006 (Andes) and 0.009 (Bangladesh)]. TFRC expression in blood was negatively correlated with plasma ferritin (rS = –0.33, p = 0.006), and positively correlated with Ery-Cd (significant at ferritin concentrations of < 30 µg/L only, rS = 0.40, p = 0.046). Rs3804141 did not modify these associations or predict TFRC expression. Cd was not consistently associated with any of the other polymorphisms evaluated.Conclusions: One TFRC polymorphism was associated with urine Cd concentration, a marker of Cd accumulation in the kidney, in two very different populations. The consistency of the findings supports the possibility of a causal association.

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Cadmium increases ferroportin-1 gene expression in J774 macrophage cells via the production of reactive oxygen species

Cited by 13 publications

References 37 publications

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

Cadmium Induces Anemia through Interdependent Progress of Hemolysis, Body Iron Accumulation, and Insufficient Erythropoietin Production in Rats

Polymorphisms in Iron Homeostasis Genes and Urinary Cadmium Concentrations among Nonsmoking Women in Argentina and Bangladesh

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