ToxSci Advance Access originally published online on April 27, 2007
Toxicological Sciences 2007 98(1):198-205; doi:10.1093/toxsci/kfm095
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Manganese Induces Oxidative Impairment in Cultured Rat Astrocytes
,1
* Departments of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
Murray State University, Breathitt Veterinary Center, Toxicology Department, Hopkinsville, Kentucky 42241
Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, 02-792 Warsaw, Poland
Pharmacology, and the Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
1 To whom correspondence should be addressed at Department of Pediatrics, B-3307 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232-2495. Fax: (615) 322-6541. E-mail: Michael.Aschner{at}vanderbilt.edu.
Received February 21, 2007; accepted April 18, 2007
 |
Abstract |
|---|
Excessive free radical formation has been implicated as a causative factor in neurotoxic damage associated with exposures to a variety of metals, including manganese (Mn). It is well established that Mn accumulates in astrocytes, affecting their ability to indirectly induce and/or exacerbate neuronal dysfunction. The present study examined the effects of Mn treatment on the following endpoints in primary astrocyte cultures: (1) oxidative injury, (2) alterations in high-energy phosphate (adenosine 5'-triphosphate, ATP) levels, (3) mitochondrial inner membrane potential, and (4) glutamine uptake and the expression of glutamine transporters. We quantified astrocyte cerebral oxidative damage by measuring F2-isoprostanes (F2-IsoPs) using stable isotope dilution methods followed by gas chromatography–mass spectrometry with selective ion monitoring. Our data showed a significant (p < 0.01) elevation in F2-IsoPs levels at 2 h following exposure to Mn (100µM, 500µM, or 1mM). Consistent with this observation, Mn induced a concentration-dependent reduction in ATP and the inner mitochondrial membrane potential (
m), measured by the high pressure liquid chromatography method and the potentiometric dye, tetramethyl rhodamine ethyl ester, respectively. Moreover, 30 min of pretreatment with Mn (100µM, 500µM, or 1mM) inhibited the net uptake of glutamine (GLN) (3H-glutamine) measured at 1 and 5 min. Expression of the messenger RNA coding the GLN transporters, SNAT3/SN1 and SNAT1, was inhibited after 100 and 500µM Mn treatment for 24 h. Our results demonstrate that induction of oxidative stress, associated mitochondrial dysfunction, and alterations in GLN/glutamate cycling in astrocytes represent key mechanisms by which Mn exerts its neurotoxicity.
Key Words: astrocyte; manganese; F2-isoprostanes; mitochondria; ATP; m; glutamine.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E.-S. Y. Lee, Z. Yin, D. Milatovic, H. Jiang, and M. Aschner Estrogen and Tamoxifen Protect against Mn-Induced Toxicity in Rat Cortical Primary Cultures of Neurons and Astrocytes Toxicol. Sci., July 1, 2009; 110(1): 156 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tamm, F. Sabri, and S. Ceccatelli Mitochondrial-Mediated Apoptosis in Neural Stem Cells Exposed to Manganese Toxicol. Sci., February 1, 2008; 101(2): 310 - 320. [Abstract] [Full Text] [PDF]
|
|