Olfactory Receptor Dysfunction Induced by Fenton and Fenton-Like Reactions: Linking Molecular Damage to Behavior

When inhaled, environmental toxins enter not only the respiratory system but also the olfactory system. Metallic compounds in the environment form various free radicals through Fenton reactions and Fenton-like reactions. These free radicals damage the olfactory system in various ways. Reactive oxygen species generated during Fenton and Fenton-like reactions damage olfactory G protein-coupled receptors, disrupting the receptor's coupling to GOₗf and cAMP- and IP3/Ca2+-dependent signaling. The cascade of reactions involves ion channels, mitochondria, enzymes, lipids, proteins, DNA, and antioxidant defense mechanisms, including Nrf2-dependent transcriptional programs, glutathione, and others. Essentially, Fenton and Fenton-like reactions both generate free radicals; however, the reactive hydroxyl radical (•OH) generated in the classical Fenton reaction rapidly and locally damages neuronal cell and receptor structural molecules, whereas Fenton-like reactions, through surface-mediated, prolonged ROS production, cause progressive, chronic damage that differentially alters GPCR-GOₗf signaling and neuronal function; the study of these mechanisms is essential for assessing oxidative neurotoxicity of the olfactory system. This review discusses damage to olfactory receptor structures by radicals generated during Fenton and Fenton-like reactions, the characteristics of these chemical reactions, and the corresponding behavioral clinical changes.