The Mechanism of Vanadium-Mediated Developmental Hypomyelination Is Related to Destruction of Oligodendrocyte Progenitors Through a Relationship with Ferritin and Iron

Abstract

The second post-natal week in rat is the period of the most intense oligodendrocyte development and myelination. This period coincides with peak iron import by oligodendrocytes. During that time oligodendrocyte progenitors (OPCs) are sensitive to agents that may disturb normal iron homeostasis and assimilation of iron into these cells. One mechanism by which iron homeostasis can be disrupted is by environmental exposure to other metals. Vanadium is a transition metal, and exposure to vanadium during early brain development produces hypomyelination with variety of related neuro-behavioral phenotypes. In the current study, we investigated mechanisms of hypomyelination induced by vanadium exposure in developing rat brain. We demonstrate that both in vivo and in vitro, OPCs are more sensitive to vanadium exposure than astrocytes or mature oligodendrocytes. Vanadium exposure in OPCs resulted in increased ROS generation and increased annexinV labeling suggestive of apoptosis. Because ferritin is a major iron delivery protein for oligodendrocytes, we exposed the cells to recombinant ferritin and iron both of which exacerbated vanadium cytotoxicity, while the iron chelator desferroxamine (DFO) prevented cytotoxic/apoptotic effects of vanadium. To illustrate relationship between ferritin and vanadium, we demonstrate that vanadium exacerbated DNA nicking produced by iron-rich spleen ferritin, but not iron-poor apoferritin, resulting in a single and double strand breaks in a DNA relaxation assay. We propose that developmental exposure to vanadium interferes with normal iron assimilation into oligodendrocytes resulting in oxidative stress and apoptosis. Therefore, depletion of OPCs due to vanadium exposure in early post-natal period may be an important mechanism of vanadium-induced hypomyelination.

Sodium arsenite-induced cardiovascular and renal dysfunction in rat via oxidative stress and protein kinase B (Akt/PKB) signaling pathway

“…The decrease in NO bioavailability has been associated with hypertension and derangement in vascular endothelium [28,29]. From the present study, the rats did not recover from the reduced tissue NO bioavailability.…”

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

“…Vanadium-induced astrogliosis has previously been reported in the cerebellum and hippocampus of adult rats exposed to sodium metavanadate for 5 days (Garcia et al, 2005) indicating a rapid response of astrocytes to this challenge. Astrocyte activation was also observed in the hippocampus and corpus callosum after vanadium exposure in rats of 2 weeks of age (Olopade and Connor, 2011; Todorich et al, 2011) and 3-week-old mice (Mustapha et al, 2014), indicating that reactive astrogliosis is a component of vanadium neurotoxicity. In the present study astrocytic response was observed at the onset of the exposure increasing till 12 months but with increasing vanadium exposure into old age, this response decreased.…”

The impact of environmental metals in young urbanites’ brains

“…Our interest in DNA repair genes rest in the evidence that their expression is a good indicator of oxidative stress (Powel et al 2005) and metals have well known oxidative, neurotoxic, neurodevelopmental and neurobehavioral effects (Barth et al 2002; Colin-Barenque et al 2008; Afeseh-Ngwa et al 2011; Todorich et al 2011; Winneke 2011;Yen et al 2011;Martinez et al 2011). Repair enzymes recognize and remove DNA adducts, correct the DNA sequence and rejoin strand breaks.…”

“…The oxidative damage to frontal lobes in this young urbanite cohort poses a significant cause for concern in terms of developmental and cognitive effects (Barth et al 2002; Burton and Guilarte 2009; Guilarte 2010; Martinez et al 2011;Todorich et al 2011;Winneke 2011). …”