N. PRAKASH)SHIVAPRASAD. G R2024-01-092024-01-092022https://krishikosh.egranth.ac.in/handle/1/5810206022Today titanium dioxide (TiO2) nanoparticles are one among the several environmental contaminants, essentially due to its widespread applications in food, medicine, cosmetic, electronic and other industries. The systemic toxicity due to titanium (Ti) following exposure to titanium dioxide nanoparticles (TiO2 NPs) is least understood. The current experimental study was undertaken to determine the impact of sub-chronic exposure to TiO2 NPs on systemic toxicity with special reference to central nervous system (CNS). Further, the antioxidant role of exogenous source of melatonin to overcome potential deleterious effects of TiO2 NPs was also examined. In the first phase toxicokinetics and tissue distribution characteristics of TiO2 NPs was studied before undertaking sub-chronic toxicological investigations. The Tmax(obs.), Cmax (obs.), elimination half-life (t1/2k10), area under the curve (AUC[0-336]) and AUC(0-∞) of TiO2 following single intraperitoneal administration of TiO2 NPs in whole blood was 0.5 h, 0.26±0.03 μg.ml-l, 486.31±39.66 h, 48.81±0.54 μg/ml*h and 128.28±7.17 μg/ml*h, respectively. The Cmax(obs.) in various tissues was in the order of liver > spleen > lung > kidney > testis > brain. The elimination half-life (t1/2k10) was in the order of spleen > kidney > liver > lung. Sub-chronic exposure to TiO2 NPs (phase 2) significantly (p<0.05) decreased both voluntary and involuntary motor activities but showed elevation in anxiety levels on Day 60 or Day 90 of the experimental study period. However, exogenous melatonin administration significantly (p<0.05) decreased the anxiety and improved voluntary and involuntary motor activities in experimental rats. Further, melatonin supplementation significantly (p<0.05/p<0.01) ameliorated TiO2 NPs induced alterations in hematology as well as serum biochemical parameters on Day 60 or Day 90 of the experimental study. Sub-chronic exposure to TiO2 NPs not only showed increased levels of ‘Ti’ in brain tissue but also induced significant (p<0.05/p<0.01) increase in some of the elements (Fe, Cu, Ca, Na) at term. However, rats receiving melatonin showed significant (p<0.05) reduction in Fe, Cu, Ca and marked reduction in Na in brain tissue. Sub-chronic exposure to TiO2 NPs induced a significant (p<0.05/p<0.01) decrease in activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) as well reduction in glutathione (GSH) levels in brain tissue (Group-II). On the contrary, rats receiving melatonin showed significant (p<0.05) restoration of these antioxidant defence mechanisms (Group-III) when examined on Day 60 or Day 90 of the experimental study. Further, melatonin administration significantly (p<0.05/p<0.01) reduced lipid peroxidation (LPO) measured in terms of thiobarbituric acid reactive substance (TBARS) 300 called (MDA) at 60 days (Group-II: 36.79+1.76 vs Group-III: 26.99+1.08nmol.g-1) or 90 days (Group-II: 41.50+2.50 vs Group-III: 28.821+1.28 nmol.g-1) of the experimental study, and the levels of MDA was comparable to control (Group-I: Day 60: 25.40+1.97 and Day 90: 26.61+1.58 nmol.g-1). Sub-chronic exposure to TiO2 NPs showed significant (p<0.05) increase in nitrite content in the brain (Group-II) on Day 60 or Day 90 of experimental study, but melatonin administration (Group-III) effectively countered its overload. Similarly, the study revealed that melatonin can prevent TiO2 NPs induced inhibition of acetylcholinesterase (AChE) activity in CNS. Sub-chronic exposure to TiO2 NPs induced significant (p<0.05/p<0.01) increase in the levels of interleukin-6 (IL-6), glial fibrillary acidic protein (GFAP) and calcium binding protein-S100B in brain or serum on Day 60 or Day 90 of the study. Melatonin administration significantly (p<0.05/p<0.01) reduced the IL-6, GFAP and S100B levels in brain as well as serum of experimental rats receiving TiO2 NPs (Group-III). Histopathological examination of sections of brain revealed that sub-chronic exposure to TiO2 NPs induced loss of purkinje layer in cerebellum, and condensation and vacuolation of neuronal cells with disruption of pyramidal cells in hippocampus and cerebral cortex. Further, swelling of endothelial cells and focal necrotic area with infiltration of glial cells was evident in sections of cerebral cortex. However, exogenous melatonin administration showed marked progressive restoration in loss of architecture induced by TiO2 NPs in experimental rats. The current experimental study explicitly demonstrates that sub-chronic exposure to TiO2 NPs can primarily cause significant alterations in redox homeostasis leading to functional and structural damage to central nervous system. Secondly, exogenous source of melatonin can play a pivotal role to overcome systemic toxicological effects including neurotoxicity. Thus, there exists a vast scope for undertaking long term studies with toxico-epidemiological relevant concentration, as well as to re-visit safety pharmacology governing TiO2 -nanoparticles exposure through various means including pharmaceuticals. Key words: Titanium dioxide (TiO2), nanoparticles, toxicokinetics, sub-chronic exposure, central nervous system (CNS), Wistar ratsEnglishThesis