Mechanistic studies of the toxicity of zinc gluconate in the olfactory neuronal cell line Odora

•The olfactory neuron cell line Odora was used to study zinc gluconate (ZG) toxicity.•ZG induces oxidative stress, ATP depletion, and cytoskeletal changes in Odora cells.•Metallothionein upregulation was a key response in ZG-treated Odora cells.•ZG-treated Odora cells appear to die via pyroptosis, rather than apoptosis.

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 200 μM ZG for 0-24 h, 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.