Zinc gluconate toxicity in wild-type vs. MT1/2-deficient mice

Abstract

Previous studies have suggested that oral zinc supplementation can help reduce the duration of the common cold; however, the use of intranasal (IN) zinc is strongly associated with anosmia, or the loss of the sense of smell, in humans. Prior studies from this lab showed that upregulation of metallothioneins (MT) is a rapid and robust response to zinc gluconate (ZG). Therefore, we assessed the role of MT in the recovery of nasal epithelial damage resulting from IN zinc administration. The main studies in this investigation used a high dose of ZG (170 mM) to ensure ablation of the olfactory mucosa, so that the progression of histological and functional recovery could be assessed. In vivo studies using wild-type, MT1/2 knockout mice (MT 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 MT KO mice were able to smell 28 d after treatment; however, no significant difference was observed in the rate of cell proliferation in the basal layer of the olfactory epithelium between MT KO and wild-type mice. A lower concentration of ZG (33 mM), equivalent to that found in homeopathic IN ZG preparations, also caused olfactory epithelial toxicity in mice. These studies suggest that the use of zinc in drug formulations intended for IN administration in humans must be carefully evaluated for their potential to cause olfactory functional deficits.

International consensus statement on allergy and rhinology: Olfaction

“…Such studies have utilized a variety of outcome metrics, including the UPSIT R , Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test, SS, and measurement of event-related potentials (ERPs) to assess odor threshold, discrimination, and identification (TDI), suggesting that RT-induced OD is both qualitative and quantitative. [415][416][417][418][419][420][421] Various mechanisms have been proposed regarding the pathophysiology of these observed changes, although there is limited evidence in their validation. Proposed mechanisms include direct cytotoxic damage to the OE, OB, or its supporting cells; impaired neurogenesis; treatmentinduced obstruction of the OC; and decreased vascular perfusion to the OC.…”

Blocking olfactory input alters aggression in male and female California mice (Peromyscus californicus)

“…Treatment with zinc gluconate eliminates electrical activity in olfactory sensory neurons and damages the subepithelial structures in addition to the easily repaired epithelial layer (Lim et al, 2009). Zinc gluconate also produces a complete detachment of the epithelial layer in the main olfactory system while leaving the accessory olfactory system intact (Hsieh et al, 2017). Our findings indicate that zinc gluconate's actions are sufficient to impair the detection of food items and salient social odors.…”

“…However, interpretation of the effects of bulbectomy on aggression is complicated because non‐volatile chemical signals such as urine and secretions from the preputial gland alter aggression (Thompson et al, 2007) and can be detected through a secondary olfactory pathway involving the vomeronasal organ (Wysocki et al, 1980) which may also be destroyed during olfactory bulbectomy. Intranasal administration of zinc‐containing compounds, in contrast, blocks the olfactory epithelium less invasively while leaving the vomeronasal organ intact (Duncan‐Lewis et al, 2011; Hsieh et al, 2017). Therefore, zinc gluconate can be used to identify the specific role of olfactory epithelium in social signaling.…”

Correlation Between Nasal Epithelial Injury and In Vitro Cytotoxicity Using a Series of Small Molecule Protein Tyrosine Phosphatase 1B Inhibitors Investigated for Reversal of Leptin Resistance in Obesity

“…Similarly, IN administration of zinc oxide nanoparticles in rats or zinc gluconate in mice resulted in olfactory epithelial injury and impaired olfaction. 20,21 Injury to olfactory epithelium occurred as early as 2 hours following IN administration of zinc gluconate in mice, with detachment of the epithelium from the basement membrane by 4 hours. 21 These data provide further support that injury to olfactory epithelium can occur rapidly upon IN administration of a toxicant.…”

“…20,21 Injury to olfactory epithelium occurred as early as 2 hours following IN administration of zinc gluconate in mice, with detachment of the epithelium from the basement membrane by 4 hours. 21 These data provide further support that injury to olfactory epithelium can occur rapidly upon IN administration of a toxicant. Degeneration resulting in atrophy or complete necrosis of the olfactory epithelium is a common change after administration of an olfactory toxin.…”