Regional Myelin and Axon Damage and Neuroinflammation in the Adult Mouse Brain After Long-Term Postnatal Vanadium Exposure

Abstract

Environmental exposure to vanadium occurs in areas of persistent burning of fossil fuels; this metal is known to induce oxidative stress and oligodendrocyte damage. Here, we determined whether vanadium exposure (3 mg/kg) in mice during the first 3 postnatal months leads to a sustained neuroinflammatory response. Body weight monitoring, and muscle strength and open field tests showed reduction of body weight gain and locomotor impairment in vanadium-exposed mice. Myelin histochemistry and immunohistochemistry for astrocytes, microglia, and nonphosphorylated neurofilaments revealed striking regional heterogeneity. Myelin damage involved the midline corpus callosum and fibers in cortical gray matter, hippocampus, and diencephalon that were associated with axonal damage. Astrocyte and microglial activation was identified in the same regions and in the internal capsule; however, no overt myelin and axon damage was observed in the latter. Double immunofluorescence revealed induction of high tumor necrosis factor (TNF) immunoreactivity in reactive astrocytes. Western blotting analysis showed significant induction of TNF and interleukin-1β expression. Together these findings show that chronic postnatal vanadium exposure leads to functional deficit and region-dependent myelin damage that does not spare axons. This injury is associated with glial cell activation and proinflammatory cytokine induction, which may reflect both neurotoxic and neuroprotective responses.

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

“…Previous studies (Avila-Costa et al, 2004, 2006) have reported dendritic spine loss with glaring memory alteration after vanadium inhalation. Quantitative analysis of the cell count revealed significant reduction in neuronal number both in the hippocampal regions (CA1 and CA3) and the cerebellar cortex which support our previous findings (Mustapha et al, 2014; Azeez et al, 2016; Folarin et al, 2016). This result also shows more vulnerability of CA1 region to insults than CA3; this is because high intrinsic superoxide and endogenous ROS production occur in CA1 than CA3 region (Wilde et al, 1997; Wang et al, 2005).…”

“…Few studies have reported progressive neuro-cellular and neuro-inflammatory changes induced by long term vanadium exposure. Azeez et al (2016) showed functional deficit, glial cell activation and region-dependent myelin damage in the brain of mice after 90 days of postnatal vanadium exposure. Our previous work has shown that a life time administration of vanadium in mice leads to memory deficits and progressive recovery after long period of treatment withdrawal (Folarin et al, 2016).…”

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

“…It remains to be fully understood by what specific mechanism(s) vanadium exert(s) its neuropathologies on the peripheral nervous system. However, vanadium has been reported to induce neuro‐inflammation, cause axonal damage and myelin depletion in the brain …”

“…40 It remains to be fully understood by what specific mechanism(s) vanadium exert(s) its neuropathologies on the peripheral nervous system. However, vanadium has been reported to induce neuro-inflammation, cause axonal damage 21 and myelin depletion in the brain. 8,20 Both primary demyelination and secondary demyelination because of Wallerian degeneration can result in myelinopathies; with the former more likely to be induced by neuro-inflammation and lipid peroxidation 39 while the latter is more of an aftermath of axonal damage (axonopathies) .…”

“…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. 25 These features put together, render this system highly susceptible to oxidative stress.…”