Toxicological effects of volatile organic compounds are mediated by aggravated oxidative stress and neuroinflammatory processes in piglets

Anthropogenic and natural sources of volatile organic compounds (VOCs) have been associated with hematological, cardiovascular, and respiratory diseases. VOCs can also track directly from the nose to the olfactory bulb (OB). This study investigated whether inhaled VOC-induced toxicity increases free radical generation and oxidative stress biomarker levels along the olfactory neural pathway from the nasal mucosa to brain regions implicated in Alzheimer's disease. In this study, twenty male six-week-old Landrace piglets were randomly divided into three groups and daily exposed to VOCs for eight weeks: Group A (unexposed piglets; n = 6), Group B (2 h exposure; n = 7), and Group C (3 h exposure; n = 7). The VOC mixture consisted of 5% formaldehyde, 5% benzene, 10% toluene, 10% xylene, and 70% water, and released at a steady-state Total VOC (TVOC) level of 1.0 mg/m3 range (0.6 - 1.8 mg/m3) in the test room. Biomarkers of oxidative stress, antioxidant status, and pro-inflammatory cytokines were assessed in the nasal mucosa, olfactory bulb, pyriform cortex, entorhinal cortex, and hippocampus. Exposure of piglets to VOCs significantly elevated malondialdehyde, hydrogen peroxide (H₂O₂) generation, nitric oxide, and acetylcholinesterase (AChE) activity along the contiguous olfactory neural structures, from the olfactory mucosa in the nose to the olfactory cortex and adjoining hippocampus. There was also a time-dependent significant reduction in glutathione content, superoxide dismutase levels, and glutathione S-transferase activities in the olfactory regions of VOCs-exposed piglets. Olfactory neuroinflammation was evidenced by significant elevations of IL-6, IL-8, IFNγ, and TNF-α. In summary, exposure of piglets to volatile organic compounds resulted in a significant elevation of biomarkers of oxidative stress and pro-inflammatory cytokines, and in depletion of the neuronal and systemic antioxidant defense systems. Furthermore, the observed olfactory neurotoxicity and neuroinflammation were more pronounced and prolonged after three hours of exposure to volatile organic compounds. Parallel patterns of neurotoxicity in the nasal-olfactory mucosa and the olfactory cortex suggest that the nose could serve as a window into pathophysiologic events underlying neurodegenerative diseases.