The mechanism of vanadium-mediated developmental hypomyelination is related to destruction of oligodendrocyte progenitors through a relationship with ferritin and iron.
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.
Department of Neurosurgery, Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033-0850, USA.
Bozho
B
Todorich
James O
JO
Olopade
Nodar
N
Surguladze
Xuesheng
X
Zhang
Elizabeth
E
Neely
James R
JR
Connor
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005293:Ferritins / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014639:Vanadium / Q000633:toxicity*
D014639:Vanadium; D005293:Ferritins; D007501:Iron