title: Mechanistic studies of the toxicity of zinc gluconate in the olfactory neuronal cell line Odora.
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) gel 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 molecular mechanism by which zinc exposure exerts its toxic effects on olfactory neurons. Following treatment of Odora cells with 100 and 200μM ZG for 0-24h, RNA-seq and in silico analyses revealed up-regulation of pathways associated with zinc metal response, oxidative stress, and ATP production. We observed that Odora cells recovered from zinc-induced oxidative stress, but ATP depletion persisted with longer exposure to ZG. ZG exposure increased levels of NLRP3 and IL-1β protein levels in a time-dependent manner, suggesting that zinc exposure may cause an inflammasome-mediated cell death, pyroptosis, in olfactory neurons.
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, United States.
authors.forename: Heidi
authors.initials: H
authors.lastname: Hsieh
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267-0557, United States.
authors.forename: Kavitha Subramanian
authors.initials: KS
authors.lastname: Vignesh
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267-0557, United States; Veterans Affairs Medical Center, Cincinnati, OH 45220, United States.
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, United States.
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, United States.
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, United States. Electronic address: Marybeth.genter@uc.edu.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Genter
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005942:Gluconates / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009831:Olfactory Mucosa / Q000166:cytology*; D051381:Rats
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D061945:Caspase Inhibitors; D005942:Gluconates; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D000255:Adenosine Triphosphate; C056165:acetovanillone; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D020170:Caspase 1; D005978:Glutathione; C030691:gluconic acid; D019803:Glutathione Disulfide; D019331:NG-Nitroarginine Methyl Ester; D000111:Acetylcysteine
keywords: Odora; Olfactory neurons; Pyroptosis; Toxicity; Zinc gluconate