Dopamine toxicity following long term exposure to low doses of 3-nitropropionic acid (3-NPA) in rats.
A toxin produced by legumes of the genus Astragalus and Arthrinium fungi, 3-NPA is a suicide inhibitor of succinate dehydrogenase and causes acute encephalopathy and late onset dystonia. It has been suggested that dopamine (DA) toxicity plays a role in 3-NPA induced brain damage. In order to simulate natural conditions of toxicant intake, adult, male, Sprague-Dawley rats were exposed to 3-NPA weekly for 24-h periods at 10 and 20 mg/40 ml in drinking water. This dosing regimen continued for 3 months with animals from both high and low dose groups sacrificed at the end of each month. Dopamine and its metabolites, 3,4-dihydroxylphenylacetic acid (DOPAC) and homovanillic acid (HVA), were assessed by HPLC-EC in the frontal cortex (FC) and caudate nucleus (CN). Increases of DA concentration were seen in both low and high dose groups in the CN after 1 and 3 months of dosing and in the FC after 2 months of exposure. An increase in DA turnover was observed in the CN of the high dose group following 2 months of dosing. Data suggest an activation of the dopaminergic system after long-term, intermittent exposure to 3-NPA. The production of radical oxygen species associated with DA metabolism may contribute to 3-NPA-induced neurotoxicity.
Johnson
J R
JR
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, USA.
Robinson
B L
BL
Ali
S F
SF
Binienda
Z
Z
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds; D018384:Oxidative Stress; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid; D004298:Dopamine