Brain Metal Distribution and Neuro-Inflammatory Profiles after Chronic Vanadium Administration and Withdrawal in Mice

Abstract

Vanadium is a potentially toxic environmental pollutant and induces oxidative damage in biological systems including the central nervous system (CNS). Its deposition in brain tissue may be involved in the pathogenesis of certain neurological disorders which after prolonged exposure can culminate into more severe pathology. Most studies on vanadium neurotoxicity have been done after acute exposure but in reality some populations are exposed for a lifetime. This work was designed to ascertain neurodegenerative consequences of chronic vanadium administration and to investigate the progressive changes in the brain after withdrawal from vanadium treatment. A total of 85 male BALB/c mice were used for the experiment and divided into three major groups of vanadium treated (intraperitoneally (i.p.) injected with 3 mg/kg body weight of sodium metavanadate and sacrificed every 3 months till 18 months); matched controls; and animals that were exposed to vanadium for 3 months and thereafter the metal was withdrawn. Brain tissues were obtained after animal sacrifice. Sagittal cut sections of paraffin embedded tissue (5 μm) were analyzed by the Laser ablation-inductively coupled plasma-mass spectrometry (LA–ICP–MS) to show the absorption and distribution of vanadium metal. Also, Haematoxylin and Eosin (H&E) staining of brain sections, and immunohistochemistry for Microglia (Iba-1), Astrocytes (GFAP), Neurons (Neu-N) and Neu-N + 4′,6-diamidine-2′-pheynylindole dihydrochloride (Dapi) Immunofluorescent labeling were observed for morphological and morphometric parameters. The LA–ICP–MS results showed progressive increase in vanadium uptake with time in different brain regions with prediction for regions like the olfactory bulb, brain stem and cerebellum. The withdrawal brains still show presence of vanadium metal in the brain slightly more than the controls. There were morphological alterations (of the layering profile, nuclear shrinkage) in the prefrontal cortex, cellular degeneration (loss of dendritic arborization) and cell death in the Hippocampal CA1 pyramidal cells and Purkinje cells of the cerebellum, including astrocytic and microglial activation in vanadium exposed brains which were all attenuated in the withdrawal group. With exposure into old age, the evident neuropathology was microgliosis, while progressive astrogliosis became more attenuated. We have shown that chronic administration of vanadium over a lifetime in mice resulted in metal accumulation which showed regional variabilities with time. The metal profile and pathological effects were not completely eliminated from the brain even after a long time withdrawal from vanadium metal.

Oxidative Stress and Vanadium

“…Neurotoxic metals as vanadium can induce oxidative damage in the brain and develop blood brain barrier disruption, neuropathology, and neuronal damage that can trigger central nervous system alterations as depression, increase in anger, fatigue, and tremors between other clinical features [71]. Also, a decrease in tyrosine hydroxylase and dopamine levels has been reported after vanadium exposure [72].…”

“…Also, a decrease in tyrosine hydroxylase and dopamine levels has been reported after vanadium exposure [72]. Chronical exposure to NaVO 3 can cause, in mice, metal accumulation in the olfactory bulb, brain stem, and cerebellum, as well as histopathological alterations like nuclear shrinkage in the prefrontal cortex and cell death of the hippocampal pyramidal cells and cerebellum Purkinje cells [71]. The accumulation of vanadium in the brain depends more on the exposure time than on the concentration of the metal.…”

Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus

“…BALB/c mice (4 weeks old) administered with 3 mg vanadium/kg/day (sodium metavanadate), thrice a week for 3, 6, 9, 12, 15, and 18 months, showed astrocytic and microglial activation after 6 months. Also, the cortical pyramidal cells showed morphological alterations including pyknosis, cell clustering, loss of layering pattern and cytoplasmic vacuolation, dendritic arborization loss of the pyramidal cells of the dorsal hippocampal CA1 region, and the Purkinje cell layer lost [54].…”

Peripheral axonopathy in sciatic nerve of adult Wistar rats following exposure to vanadium

“…Some of the vanadium‐induced pathologies reported on various organ systems include: the lungs, liver, spleen, and testes, haematological and biochemical alterations and the kidneys . In addition, vanadium has been shown to have effects on the nervous system, where it has been established to cross the blood‐brain barrier, bioaccumulate in brain tissue and exert (acute and chronic) neuropathologies and behavioural deficits …”

“…8 Some of the vanadium-induced pathologies reported on various organ systems include: the lungs, liver, spleen, and testes, 9,10 haematological and biochemical alterations 11,12 and the kidneys. 13 In addition, vanadium has been shown to have effects on the nervous system, where it has been established to cross the blood-brain barrier, [14][15][16] bioaccumulate in brain tissue 16 and exert (acute and chronic) neuropathologies and behavioural deficits. [17][18][19][20][21][22][23][24] Much like the brain, the peripheral nervous system is characterised by highly peroxidizable fatty acids tissue, low levels of antioxidants and high aerobic metabolism.…”