Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: experimental dopamine depletion prevents reductions in GABA

Neurotoxicology. 2008 Mar;29(2):301-8. doi: 10.1016/j.neuro.2007.12.002. Epub 2007 Dec 28.

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been demonstrated to be toxic to the dopamine (DA) systems of the central nervous system. One proposed mechanism for PCB-induced DA neurotoxicity is inhibition of the vesicular monoamine transporter (VMAT); such inhibition results in increased levels of unsequestered DA and DA metabolism leading to oxidative stress. We have used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to determine whether alterations in the vesicular storage of DA, resulting from PCB exposure and consequent induction of oxidative stress, leads to GABA and DA neuronal dysfunction. Twenty-four-hour exposure to an environmentally relevant mixture of PCBs reduced tissue DA and GABA concentrations, increased medium levels of DA and measures of oxidative stress in both the striatum and VM. Alterations in neurochemistry and increases in measures of oxidative stress were blocked in the presence of n-acetylcysteine (NAC). Although NAC treatment did not alter PCB-induced changes in DA neurochemistry, it did protect against reductions in GABA concentration. To determine whether alterations in the vesicular storage of DA were responsible for PCB-induced oxidative stress and consequent reductions in GABA levels, we depleted DA from the co-cultures using alpha-methyl-p-tyrosine (AMPT). AMPT reduced striatal and VM DA levels by 90% and 70%, respectively. PCB exposure, following DA depletion, neither increased levels of oxidative stress nor resulted in GABA depletion. These results suggest that PCB-induced alterations in the vesicular storage of DA, resulting in increased levels of unsequestered DA, leads to increased oxidative stress, depletion of tissue glutathione, and consequent reductions in tissue GABA concentrations.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Antioxidants / pharmacology
  • Basal Ganglia / drug effects*
  • Basal Ganglia / embryology
  • Basal Ganglia / enzymology
  • Basal Ganglia / metabolism
  • Coculture Techniques
  • Dopamine / metabolism*
  • Down-Regulation
  • Environmental Pollutants / toxicity*
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Dyes
  • Glutathione / metabolism
  • Mesencephalon / drug effects*
  • Mesencephalon / embryology
  • Mesencephalon / enzymology
  • Mesencephalon / metabolism
  • Microscopy, Fluorescence / methods
  • Organ Culture Techniques
  • Oxidative Stress / drug effects*
  • Polychlorinated Biphenyls / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Rhodamine 123
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / metabolism
  • Tyrosine 3-Monooxygenase / antagonists & inhibitors
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Methyltyrosine / pharmacology
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Antioxidants
  • Environmental Pollutants
  • Enzyme Inhibitors
  • Fluorescent Dyes
  • Rhodamine 123
  • gamma-Aminobutyric Acid
  • alpha-Methyltyrosine
  • Polychlorinated Biphenyls
  • Tyrosine 3-Monooxygenase
  • Glutathione
  • Dopamine
  • Acetylcysteine