Skip to main content
SpringerLink
Log in

Mild Maternal Iron Deficiency Anemia Induces Hearing Impairment Associated with Reduction of Ribbon Synapse Density and Dysregulation of VGLUT3, Myosin VIIa, and Prestin Expression in Young Guinea Pigs

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Mild maternal iron deficiency anemia (IDA) adversely affects the development of cochlear hair cells of the young offspring, but the mechanisms underlying the association are incompletely understood. The aim of this study was to evaluate whether mild maternal IDA in guinea pigs could interrupt inner hair cell (IHC) ribbon synapse density and outer hair cell motility of the offspring. Here, we established a dietary restriction model that allows us to study quantitative changes in the number of IHC ribbon synapses and hearing impairment in response to mild maternal IDA in young guinea pig. The offspring were weaned on postnatal day (PND) 9 and then were given the iron-sufficient diet. On PND 24, pups were examined the hearing function by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements. Then, the cochleae were harvested for assessment of the number of IHC ribbon synapses by immunofluorescence, the morphology of cochlear hair cells, and spiral ganglion cells (SGCs) by scanning electron microscope and hematoxylin–eosin staining, the location, and expression of vesicular glutamate transporter (VGLUT) 3, myosin VIIa, and prestin by immunofluorescence and blotting. Here, we show that mild maternal IDA in guinea pigs induced elevated ABR threshold shifts, declined DPOAE level shifts, and reduced the number of ribbon synapses, impaired the morphology of cochlear hair cells and SGCs in offsprings. In addition, downregulation of VGLUT3 and myosin VIIa, and upregulation of prestin were observed in the cochlea of offsprings from mild maternal IDA in guinea pigs. These data indicate that mild maternal IDA in guinea pigs induced hearing impairment in offsprings, and this deficit may be attributed to the reduction of ribbon synapse density and dysregulation of VGLUT3, myosin VIIa, and prestin.

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

Similar content being viewed by others

Abbreviations

ABR:

Auditory brainstem response

ANFs:

Auditory nerve fibers

CtBP2:

Carboxyterminal binding protein 2

DPOAE:

Distortion product otoacoustic emission

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GD:

Gestational day

Hb:

Hemoglobin

Hct:

Hematocrit

HE:

Staining hematoxylin–eosin staining

ID:

Iron deficiency

IDA:

Iron deficiency anemia

IHC:

Inner hair cell

OHC:

Outer hair cell

PND:

Postnatal day

SEM:

Scanning electron microscopy

SI:

Serum level of iron

SGC:

Spiral ganglion cell

SPL:

Sound pressure level

VGLUT:

Vesicular glutamate transporter

References

  • Al Ghwass MM, Halawa EF, Sabry SM, Ahmed D (2015) Iron deficiency anemia in an Egyptian pediatric population: a cross-sectional study. Ann Afr Med 14(1):25–31

    Article  PubMed  Google Scholar 

  • Amin SB, Orlando M, Eddins A, MacDonald M, Monczynski C, Wang H (2010) In utero iron status and auditory neural maturation in premature infants as evaluated by auditory brainstem response. J Pediatr 156(3):377–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amin SB, Orlando M, Wang H (2013) Latent iron deficiency in utero is associated with abnormal auditory neural myelination in ≥ 35 weeks gestational age infants. J Pediatr 163(5):1267–1271

    Article  CAS  PubMed  Google Scholar 

  • Arnold DJ, Lonsbury-Martin BL, Martin GK (1999) High-frequency hearing influences lower-frequency distortion-product otoacoustic emissions. Arch Otolaryngol Head Neck Surg 125(2):215–222

    Article  CAS  PubMed  Google Scholar 

  • Bao J, Ohlemiller KK (2010) Age-related loss of spiral ganglion neurons. Hear Res 264(1–2):93–97

    Article  PubMed  PubMed Central  Google Scholar 

  • Bharadwaj HM, Verhulst S, Shaheen L, Liberman MC, Shinn-Cunningham BG (2014) Cochlear neuropathy and the coding of supra-threshold sound. Front Syst Neurosci 8:26

    Article  PubMed  PubMed Central  Google Scholar 

  • Cho SI, Gao SS, Xia A, Wang R, Salles FT, Raphael PD, Abaya H, Wachtel J, Baek J, Jacobs D, Rasband MN, Oghalai JS (2013) Mechanisms of hearing loss after blast injury to the ear. PLoS One 8(7):e67618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choudhury V, Amin SB, Agarwal A, Srivastava LM, Soni A, Saluja S (2015) Latent iron deficiency at birth influences auditory neural maturation in late preterm and term infants. Am J Clin Nutr 102(5):1030–1034

    Article  PubMed  Google Scholar 

  • Fuchs PA, Glowatzki E, Moser T (2003) The afferent synapse of cochlear hair cells. Curr Opin Neurobiol 13(4):452–458

    Article  CAS  PubMed  Google Scholar 

  • Fujita T, Yamashita D, Katsunuma S, Hasegawa S, Tanimoto H, Nibu K (2012) Increased inner ear susceptibility to noise injury in mice with streptozotocin-induced diabetes. Diabetes 61(11):2980–2986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glowatzki E, Fuchs PA (2002) Transmitter release at the hair cell ribbon synapse. Nat Neurosci 5(2):147–154

    Article  CAS  PubMed  Google Scholar 

  • Gutema B, Adissu W, Asress Y, Gedefaw L (2014) Anemia and associated factors among school-age children in Filtu Town, Somali region, Southeast Ethiopia. BMC Hematol 14(1):13

    Article  PubMed  PubMed Central  Google Scholar 

  • Jewett DL, Romano MN, Williston JS (1970) Human auditory evoked potentials: possible brain stem components detected on the scalp. Science 167(3924):1517–1518

    Article  CAS  PubMed  Google Scholar 

  • Johnson SL, Forge A, Knipper M, Münkner S, Marcotti W (2008) Tonotopic variation in the calcium dependence of neurotransmitter release and vesicle pool replenishment at mammalian auditory ribbon synapses. J Neurosci 28(30):7670–7678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jougleux JL, Rioux FM, Church MW, Fiset S, Surette ME (2011) Mild maternal iron deficiency anemia during pregnancy and lactation in guinea pigs causes abnormal auditory function in the offspring. J Nutr 141(7):1390–1395

    Article  CAS  PubMed  Google Scholar 

  • Jougleux JL, Rioux FM, Church MW, Fiset S, Surette ME (2014) Mild iron deficiency anemia during pregnancy and lactation in guinea pigs alters amplitudes and auditory nerve velocity, but not brainstem transmission times in the offspring’s auditory brainstem response. Nutr Neurosci 17(1):37–47

    Article  CAS  PubMed  Google Scholar 

  • Kemp DT (1979) Evidence of mechanical nonlinearity and frequency selective wave amplification in the cochlea. Arch Otorhinolaryngol 224(1–2):37–45

    Article  CAS  PubMed  Google Scholar 

  • Khimich D, Nouvian R, Pujol R, Tom Dieck S, Egner A, Gundelfinger ED, Moser T (2005) Hair cell synaptic ribbons are essential for synchronous auditory signaling. Nature 434(7035):889–894

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Wang H, Shi L, Almuklass A, He T, Aiken S, Bance M, Yin S, Wang J (2012) Silent damage of noise on cochlear afferent innervation in guinea pigs and the impact on temporal processing. PLoS One 7:e49550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu K, Jiang X, Shi C, Shi L, Yang B, Shi L, Xu Y, Yang W, Yang S (2013) Cochlear inner hair cell ribbon synapse is the primary target of ototoxic aminoglycoside stimuli. Mol Neurobiol 48(3):647–654

    Article  CAS  PubMed  Google Scholar 

  • Liu K, Ji F, Xu Y, Wang X, Hou Z, Yang S (2014) Myosin VIIa and otoferlin in cochlear inner hair cells have distinct response to ototoxic exposure. Acta Otolaryngol 134(6):564–570

    Article  CAS  PubMed  Google Scholar 

  • Meyer AC, Frank T, Khimich D, Hoch G, Riedel D, Chapochnikov NM, Yarin YM, Harke B, Hell SW, Egner A, Moser T (2009) Tuning of synapse number, structure and function in the cochlea. Nat Neurosci 12(4):444–453

    Article  CAS  PubMed  Google Scholar 

  • Mihaila C, Schramm J, Strathmann FG, Lee DL, Gelein RM, Luebke AE, Mayer-Pröschel M (2011) Identifying a window of vulnerability during fetal development in a maternal iron restriction model. PLoS One 6(3):e17483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moser T, Brandt A, Lysakowski A (2006) Hair cell ribbon synapses. Cell Tissue Res 326(2):347–359

    Article  PubMed  PubMed Central  Google Scholar 

  • Pasricha SR, Drakesmith H, Black J, Hipgrave D, Biggs BA (2013) Control of iron deficiency anemia in low- and middle-income countries. Blood 121(14):2607–2617

    Article  CAS  PubMed  Google Scholar 

  • Peng Z, Wang GP, Zeng R, Guo JY, Chen CF, Gong SS (2013) Temporospatial expression and cellular localization of VGLUT3 in the rat cochlea. Brain Res 1537:100–110

    Article  CAS  PubMed  Google Scholar 

  • Safieddine S, El-Amraoui A, Petit C (2012) The auditory hair cell ribbon synapse: from assembly to function. Annu Rev Neurosci 35:509–528

    Article  CAS  PubMed  Google Scholar 

  • Schmitz F, Königstorfer A, Südhof TC (2000) RIBEYE, a component of synaptic ribbons: a protein’s journey through evolution provides insight into synaptic ribbon function. Neuron 28(3):857–872

    Article  CAS  PubMed  Google Scholar 

  • tom Dieck S, Altrock WD, Kessels MM, Qualmann B, Regus H, Brauner D, Fejtová A, Bracko O, Gundelfinger ED, Brandstätter JH (2005) Molecular dissection of the photoreceptor ribbon synapse: physical interaction of Bassoon and RIBEYE is essential for the assembly of the ribbon complex. J Cell Biol 168(5):825–836

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang H, Zhao N, Yan K, Liu X, Zhang Y, Hong Z, Wang M, Yin Q, Wu F, Lei Y, Li X, Shi L, Liu K (2015) Inner hair cell ribbon synapse plasticity might be molecular basis of temporary hearing threshold shifts in mice. Int J Clin Exp Pathol 8(7):8680–8691

    PubMed  PubMed Central  Google Scholar 

  • Werner M, VanDe Water TR, Andersson T, Arnoldsson G, Berggren D (2012) Morphological and morphometric characteristics of vestibular hair cells and support cells in long term cultures of rat utricle explants. Hear Res 283(1–2):107–116

    Article  PubMed  Google Scholar 

  • Xia A, Song Y, Wang R, Gao SS, Clifton W, Raphael P, Chao SI, Pereira FA, Groves AK, Oghalai JS (2013) Prestin regulation and function in residual outer hair cells after noise-induced hearing loss. PLoS One 8(12):e82602

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang C, Zhang W, Liu XL, Liang Y, Yuan YW, Ren C, Peng JH (2014) Localization of prestin and expression in the early period after radiation in mice. Eur Arch Otorhinolaryngol 271(12):3333–3340

    Article  PubMed  Google Scholar 

  • Yu F, Hao S, Zhao Y, Ren Y, Yang J, Sun X, Chen J (2014) Mild maternal iron deficiency anemia induces DPOAE suppression and cochlear hair cell apoptosis by caspase activation in young guinea pigs. Environ Toxicol Pharmacol 37(1):291–299

    Article  CAS  PubMed  Google Scholar 

  • Yu F, Hao S, Yang B, Zhao Y, Zhang R, Zhang W, Yang J, Chen J (2015) Insulin resistance due to dietary iron overload disrupts inner hair cell ribbon synapse plasticity in male mice. Neurosci Lett 597:183–188

    Article  CAS  PubMed  Google Scholar 

  • Zheng J, Shen W, He DZ, Long KB, Madison LD, Dallos P (2000) Prestin is the motor protein of cochlear outer hair cells. Nature 405(6783):149–155

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation Committee of China (Grant Number 81372972).

Author information

Authors and Affiliations

  1. Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China

    Fei Yu, Yue Zhao, Wenyue Zhang & Jun Yang

  2. Department of Otolaryngology, First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, China

    Shuai Hao & Bo Yang

Authors
  1. Fei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuai Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yue Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenyue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fei Yu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, F., Hao, S., Yang, B. et al. Mild Maternal Iron Deficiency Anemia Induces Hearing Impairment Associated with Reduction of Ribbon Synapse Density and Dysregulation of VGLUT3, Myosin VIIa, and Prestin Expression in Young Guinea Pigs. Neurotox Res 29, 594–604 (2016). https://doi.org/10.1007/s12640-016-9609-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-016-9609-5

Keywords

Search

Navigation