PMID- 18262273 OWN - NLM STAT- MEDLINE DCOM- 20080605 LR - 20211020 IS - 0161-813X (Print) IS - 0161-813X (Linking) VI - 29 IP - 2 DP - 2008 Mar TI - Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: experimental dopamine depletion prevents reductions in GABA. PG - 301-8 LID - 10.1016/j.neuro.2007.12.002 [doi] AB - 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. FAU - Lyng, Gregory D AU - Lyng GD AD - School of Public Health, University at Albany, Albany, NY 12201, USA. FAU - Seegal, Richard F AU - Seegal RF LA - eng GR - P01 ES011263/ES/NIEHS NIH HHS/United States GR - P01 ES011263-050003/ES/NIEHS NIH HHS/United States GR - ES829390/ES/NIEHS NIH HHS/United States GR - ES11263/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20071228 PL - Netherlands TA - Neurotoxicology JT - Neurotoxicology JID - 7905589 RN - 0 (Antioxidants) RN - 0 (Environmental Pollutants) RN - 0 (Enzyme Inhibitors) RN - 0 (Fluorescent Dyes) RN - 1N3CZ14C5O (Rhodamine 123) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 658-48-0 (alpha-Methyltyrosine) RN - DFC2HB4I0K (Polychlorinated Biphenyls) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - GAN16C9B8O (Glutathione) RN - VTD58H1Z2X (Dopamine) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/pharmacology MH - Animals MH - Antioxidants/pharmacology MH - Basal Ganglia/*drug effects/embryology/enzymology/metabolism MH - Coculture Techniques MH - Dopamine/*metabolism MH - Down-Regulation MH - Environmental Pollutants/*toxicity MH - Enzyme Inhibitors/pharmacology MH - Fluorescent Dyes MH - Glutathione/metabolism MH - Mesencephalon/*drug effects/embryology/enzymology/metabolism MH - Microscopy, Fluorescence/methods MH - Organ Culture Techniques MH - Oxidative Stress/*drug effects MH - Polychlorinated Biphenyls/*toxicity MH - Rats MH - Rats, Sprague-Dawley MH - Rhodamine 123 MH - Synaptic Vesicles/drug effects/metabolism MH - Tyrosine 3-Monooxygenase/antagonists & inhibitors/metabolism MH - alpha-Methyltyrosine/pharmacology MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC2291544 MID - NIHMS43372 EDAT- 2008/02/12 09:00 MHDA- 2008/06/06 09:00 PMCR- 2009/03/01 CRDT- 2008/02/12 09:00 PHST- 2007/08/10 00:00 [received] PHST- 2007/12/13 00:00 [revised] PHST- 2007/12/17 00:00 [accepted] PHST- 2008/02/12 09:00 [pubmed] PHST- 2008/06/06 09:00 [medline] PHST- 2008/02/12 09:00 [entrez] PHST- 2009/03/01 00:00 [pmc-release] AID - S0161-813X(07)00273-2 [pii] AID - 10.1016/j.neuro.2007.12.002 [doi] PST - ppublish SO - Neurotoxicology. 2008 Mar;29(2):301-8. doi: 10.1016/j.neuro.2007.12.002. Epub 2007 Dec 28.