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Investigating Zinc Toxicity In Olfactory Neurons: In Silico, In Vitro, And In Vivo Studies
Author Info
Hsieh, Heidi
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447070598
Abstract Details
Year and Degree
2015, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
Abstract
Zinc is both an essential and potentially toxic metal. It is widely believed that oral zinc supplementation can reduce the effects of the common cold; however, there is strong clinical evidence that intranasal (IN) zinc gluconate (ZG) treatment for this purpose causes anosmia, or the loss of the sense of smell, in humans. Using the rat olfactory neuron cell line, Odora, we investigated the mechanism by which zinc is toxic to olfactory neurons. Following treatment of Odora cells with 100 and 200 µM ZG for 0-24 hr, we performed RNAseq and in silico analyses and found up-regulation of pathways associated with zinc metal response, oxidative stress, and ATP production. We also observed that Odora cells could recover from zinc-induced oxidative stress, but ATP depletion persisted with longer exposure to ZG. We also found that ZG exposure caused an increase in NLRP3 and Il-1ß protein levels in a time-dependent manner, suggesting that zinc causes an inflammasome-mediated cell death, pyroptosis, in olfactory neurons. The role of metallothionein (Mt), a metal response protein whose polymorphisms are associated with metal toxicity, particularly in developing nations, was also investigated. In vitro studies using shRNA knockdown of Mt1/2 demonstrated basal elevated level of markers of reactive oxygen species and depressed levels of reduced glutathione; however, the cells were still able to recover from excess zinc and showed a similar LC50 with untransfected Odora cells. In vivo studies utilizing wild-type, MT1/2 knockout mice (KO), and heterozygotes administered ZG by IN instillation showed profound loss of the olfactory mucosa in the nasal cavity. Recovery was monitored, and a lower percentage of the mice were able to smell 28 d after treatment; however, no significant difference was observed in the average thickness of the olfactory epithelium between KO and wild type mice. Both in vitro and in vivo studies showed down-regulation of actinin levels, which may be the trigger for ZG-induced olfactory mucosal damage.
Committee
Mary Beth Genter, Ph.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Sarah Pixley, Ph.D. (Committee Member)
Howard Shertzer, Ph.D. (Committee Member)
Jun Ying, Ph.D. (Committee Member)
Pages
115 p.
Subject Headings
Toxicology
Keywords
zinc
;
olfactory neuron
;
anosmia
;
metallothionein
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Citations
Hsieh, H. (2015).
Investigating Zinc Toxicity In Olfactory Neurons: In Silico, In Vitro, And In Vivo Studies
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447070598
APA Style (7th edition)
Hsieh, Heidi.
Investigating Zinc Toxicity In Olfactory Neurons: In Silico, In Vitro, And In Vivo Studies.
2015. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447070598.
MLA Style (8th edition)
Hsieh, Heidi. "Investigating Zinc Toxicity In Olfactory Neurons: In Silico, In Vitro, And In Vivo Studies." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447070598
Chicago Manual of Style (17th edition)
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Document number:
ucin1447070598
Download Count:
314
Copyright Info
© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.