151 | Dysregulation of the lung-brain axis induced by CMIT/MIT: oxidative stress and junctional protein impairment lead to α-synuclein accumulation and dopaminergic neurotoxicity

Nicla Tranchida¹, Rosanna Di Paola², Marika Cordaro³ | ¹Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy; ²Department of Veterinary Sciences, University of Messina, Italy; ³Department of Biomedical, Dental and Morphological and Functional Imaging University of Messina, Italy.

Chronic exposure to environmental pollutants can profoundly dysregulate the physiological role of the lung, shifting it from a homeostatic organ to an active driver of systemic pathology. In this study, we examined how prolonged inhalation of the biocidal mixture chlorine/methylisothiazolinone (CMIT/MIT) disrupts the lung–brain axis by exposing CD1 mice to the compound for 28 days and evaluating pulmonary structural remodeling using the Ashcroft score, alveolar–capillary barrier integrity through BALF analysis, and systemic redox status via assessment of the Nrf2/HO-1 pathway and ROS/RNS levels. Neuroinflammation, blood–brain barrier integrity—assessed by Occludin and ZO-1 expression—and dopaminergic neurotoxicity, including α-synuclein accumulation and loss of TH-positive neurons, were analyzed in parallel with motor and cognitive behavioral performance. Chronic exposure initiated a pronounced pathological cascade, beginning with severe pulmonary fibrosis and a marked cytokine storm in the BALF characterized by elevated IL-1β, TNF-α, and IL-6; this localized injury propagated systemically, leading to a collapse of antioxidant defenses with depletion of SOD, catalase, and GSH and activation of the NLRP3 inflammasome. Concurrent systemic vascular activation, evidenced by increased ICAM-1 and VCAM-1 expression, was associated with blood–brain barrier disruption, as demonstrated by the loss of tight junction proteins. Within the central nervous system, we observed intense reactive gliosis, oxidative stress, and a significant loss of dopaminergic neurons in the hippocampus accompanied by α-synuclein accumulation, changes that translated functionally into severe motor deficits in the Pole and Rotarod tests as well as cognitive impairment and anxiety-like behaviors. Overall, these findings demonstrate that the lung–brain axis represents a critical conduit for environmentally induced neurotoxicity, as CMIT/MIT exposure promotes a state of sterile inflammation and systemic redox failure in which the lung acts as a primary signaling hub, priming the brain for neurodegenerative processes and underscoring the need for a systemic approach to environmental risk assessment that recognizes pulmonary health as a fundamental prerequisite for neurological integrity.