Skip to main content

Advertisement

SpringerLink
Log in

Cellular localization and developmental changes of Zip8, Zip14 and transferrin receptor 1 in the inner ear of rats

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

Prior studies have demonstrated that the inner ear can accumulate a variety of essential and potentially toxic heavy metals including manganese, lead, cobalt and cadmium. Metal accumulation is regulated in part by the functionality and affinity of these metals for the different transport systems responsible for uptake across the blood-cochlea barrier and their subsequent uptake into the different cells within the inner ear. Transport of these metals across cell membranes occurs by many of the same transport systems which include DMT1, Zip8 and Zip14. All three metal transporters have been identified in the cochlea based on quantitative PCR analysis. Prior studies in our laboratory examined the localization and developmental changes of DMT1 in rat cochlea and since the two Zip proteins are also likely to contribute to the transport of essential and non-essential divalent cations, we performed immunolabeling experiments in postnatal day three rat pups and adult rats. For comparison, we also immunolabeled the specimens with antibody against transferrin receptor 1 (TfR1) which is important in DMT1-mediated transport of Fe and Mn. Results presented in this paper demonstrate that the cellular and subcellular distribution of both Zip8 and Zip14 within the different components of the inner ear are distinct from that of DMT1. Nuclear localization for both Zip transporters as well as TfR1 was observed. The findings also reveal that the selective distribution of the three proteins was altered during development presumably to meet the changing needs of the cells to maintain normal and functional levels of iron and other essential metals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Basinger MA, Jones MM, Craft WD, Walker EM Jr, Sanders MM (1987) Chelating-agent suppression of cadmium-induced hepatotoxicity. J Toxicol Environ Health 22:261–271

    Article  CAS  PubMed  Google Scholar 

  • Bertin G, Averbeck D (2006) Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review). Biochimie 88:1549–1559

    Article  CAS  PubMed  Google Scholar 

  • Chesler M (2003) Regulation and modulation of pH in the brain. Physiol Rev 83:1183–1221

    CAS  PubMed  Google Scholar 

  • De Silva DA, Yamao M (2007) Effects of the tsunami on fisheries and coastal livelihood: a case study of tsunami-ravaged southern Sri Lanka. Disasters 31:386–404

    Article  PubMed  Google Scholar 

  • Ding D, He J, Allman BL, Yu D, Jiang H, Seigel GM, Salvi RJ (2011a) Cisplatin ototoxicity in rat cochlear organotypic cultures. Hear Res 282:196–203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ding D, Roth J, Salvi R (2011b) Manganese is toxic to spiral ganglion neurons and hair cells in vitro. Neurotoxicology 32:233–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ding D, Allman BL, Salvi R (2012) Review: ototoxic characteristics of platinum antitumor drugs. Anat Rec 295:1851–1867

    Article  CAS  Google Scholar 

  • Ding D, Salvi R, Roth JA (2014) Cellular localization and developmental changes of the different isoforms of divalent metal transporter 1 (DMT1) in the inner ear of rats. Biometals 27:125–134

    Article  CAS  PubMed  Google Scholar 

  • Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95:1148–1153

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fujishiro H, Doi M, Enomoto S, Himeno S (2011) High sensitivity of RBL-2H3 cells to cadmium and manganese: an implication of the role of ZIP8. Metallomics 3:710–718

    Article  CAS  PubMed  Google Scholar 

  • Gao J, Zhao N, Knutson MD, Enns CA (2008) The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells. J Biol Chem 283:21462–21468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garrick MD (2011) Human iron transporters. Genes Nutr 6:45–54

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garrick MD, Singleton ST, Vargas F, Kuo HC, Zhao L, Knopfel M, Davidson T, Costa M, Paradkar P, Roth JA, Garrick LM (2006) DMTI: which metals does it transport? Biol Res 39:79–85

    Article  CAS  PubMed  Google Scholar 

  • Girijashanker K, He L, Soleimani M, Reed JM, Li H, Liu Z, Wang B, Dalton TP, Nebert DW (2008) Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol Pharmacol 73:1413–1423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488

    Article  CAS  PubMed  Google Scholar 

  • Gunter TE, Gerstner B, Gunter KK, Malecki J, Gelein R, Valentine WM, Aschner M, Yule DI (2013) Manganese transport via the transferrin mechanism. Neurotoxicology 34:118–127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • He L, Girijashanker K, Dalton TP, Reed J, Li H, Soleimani M, Nebert DW (2006) ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol Pharmacol 70:171–180

    CAS  PubMed  Google Scholar 

  • Herber RF (1992) The World Health Organization study on health effects of exposure to cadmium: morbidity studies. IARC Sci Publ 118:347–358

    CAS  PubMed  Google Scholar 

  • Huang CC, Lu CS, Chu NS, Hochberg F, Lilienfeld D, Olanow W, Calne DB (1993) Progress after chronic manganese exposure. Neurology 43:1479–1483

    Article  CAS  PubMed  Google Scholar 

  • Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA 99:12345–12350

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Huff J, Lunn RM, Waalkes MP, Tomatis L, Infante PF (2007) Cadmium-induced cancers in animals and in humans. Int J Occup Environ Health 13:202–212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Josephs KA, Ahlskog JE, Klos KJ, Kumar N, Fealey RD, Trenerry MR, Cowl CT (2005) Neurologic manifestations in welders with pallidal MRI T1 hyperintensity. Neurology 64:2033–2039

    Article  CAS  PubMed  Google Scholar 

  • Khalkova Z, Kostadinova G (1986) Auditory-vestibular changes in workers in ferrous metallurgy manufacture. Probl Khig 11:134–138

    PubMed  Google Scholar 

  • Korczynski RE (2000) Occupational health concerns in the welding industry. Appl Occup Environ Hyg 15:936–945

    Article  CAS  PubMed  Google Scholar 

  • Krieger D, Krieger S, Jansen O, Gass P, Theilmann L, Lichtnecker H (1995) Manganese and chronic hepatic encephalopathy. Lancet 346:270–274

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Zheng G, Wu Y, Shen X, Jing J, Yu T, Song H, Chen J, Luo W (2013) Lead exposure results in hearing loss and disruption of the cochlear blood-labyrinth barrier and the protective role of iron supplement. Neurotoxicology 39:173–181

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Ding D, Sun H, Jiang H, Wu X, Roth JA, Salvi R (2014) Cadmium-induced ototoxicity in rat cochlear organotypic cultures. Neurotox Res 26:179–189

    Article  CAS  PubMed  Google Scholar 

  • Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ (2006) Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci USA 103:13612–13617

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ma C, Schneider SN, Miller M, Nebert DW, Lind C, Roda SM, Afton SE, Caruso JA, Genter MB (2008) Manganese accumulation in the mouse ear following systemic exposure. J Biochem Mol Toxicol 22:305–310

    Article  PubMed Central  PubMed  Google Scholar 

  • Malik IA, Naz N, Sheikh N, Khan S, Moriconi F, Blaschke M, Ramadori G (2011) Comparison of changes in gene expression of transferrin receptor-1 and other iron-regulatory proteins in rat liver and brain during acute-phase response. Cell Tissue Res 344:299–312

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mazurek B, Amarjargal N, Haupt H, Fuchs J, Olze H, Machulik A, Gross J (2011) Expression of genes implicated in oxidative stress in the cochlea of newborn rats. Hear Res 277:54–60

    Article  CAS  PubMed  Google Scholar 

  • Moos T (1996) Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system. J Comp Neurol 375:675–692

    Article  CAS  PubMed  Google Scholar 

  • Moos T, Oates PS, Morgan EH (1998) Expression of the neuronal transferrin receptor is age dependent and susceptible to iron deficiency. J Comp Neurol 398:420–430

    Article  CAS  PubMed  Google Scholar 

  • Olanow CW, Good PF, Shinotoh H, Hewitt KA, Vingerhoets F, Snow BJ, Beal MF, Calne DB, Perl DP (1996) Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study. Neurology 46:492–498

    Article  CAS  PubMed  Google Scholar 

  • Pal PK, Samii A, Calne DB (1999) Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology 20:227–238

    CAS  PubMed  Google Scholar 

  • Park RM, Bowler RM, Eggerth DE, Diamond E, Spencer KJ, Smith D, Gwiazda R (2006) Issues in neurological risk assessment for occupational exposures: the Bay Bridge welders. Neurotoxicology 27:373–384

    Article  CAS  PubMed  Google Scholar 

  • Pelclova D, Sklensky M, Janicek P, Lach K (2012) Severe cobalt intoxication following hip replacement revision: clinical features and outcome. Clin Toxicol 50:262–265

    Article  CAS  Google Scholar 

  • Pinilla-Tenas JJ, Sparkman BK, Shawki A, Illing AC, Mitchell CJ, Zhao N, Liuzzi JP, Cousins RJ, Knutson MD, Mackenzie B (2011) Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol Cell Physiol 301:C862–C871

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pomier-Layrargues G, Spahr L, Butterworth RF (1995) Increased manganese concentrations in pallidum of cirrhotic patients. Lancet 345:735

    Article  CAS  PubMed  Google Scholar 

  • Roth JA, Garrick MD (2003) Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese. Biochem Pharmacol 66:1–13

    Article  CAS  PubMed  Google Scholar 

  • Roth JA, Horbinski C, Feng L, Dolan KG, Higgins D, Garrick MD (2000) Differential localization of divalent metal transporter 1 with and without iron response element in rat PC12 and sympathetic neuronal cells. J Neurosci 20:7595–7601

    CAS  PubMed  Google Scholar 

  • Wang CY, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A, Mackenzie B, Knutson MD (2012) ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem 287:34032–34043

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yang WM, Jung KJ, Lee MO, Lee YS, Lee YH, Nakagawa S, Niwa M, Cho SS, Kim DW (2011) Transient expression of iron transport proteins in the capillary of the developing rat brain. Cell Mol Neurobiol 31:93–99

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by a Grant from the National Institute for Occupational Safety and Health, R01 OH010235. We thank Dr. D. Kosman for supplying Zip8, Zip14 and TfR1 antibodies used in these studies.

Conflict of interest

There is no conflict of interest that affect objectivity in regard to publishing this paper.

Author information

Authors and Affiliations

  1. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Dalian Ding

  2. Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY, 14214, USA

    Richard Salvi

  3. Department of Pharmacology and Toxicology, University at Buffalo, 11 Cary, Hall, Buffalo, NY, 14214, USA

    Jerome A. Roth

Authors
  1. Dalian Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Salvi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerome A. Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerome A. Roth.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ding, D., Salvi, R. & Roth, J.A. Cellular localization and developmental changes of Zip8, Zip14 and transferrin receptor 1 in the inner ear of rats. Biometals 27, 731–744 (2014). https://doi.org/10.1007/s10534-014-9765-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-014-9765-0

Keywords

Search

Navigation