Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson's disease.
Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.
Richardson
Jason R
JR
Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322, USA. jricha3@eohsi.rutgers.edu
Caudle
W Michael
WM
Wang
Minzheng
M
Dean
E Danielle
ED
Pennell
Kurt D
KD
Miller
Gary W
GW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004026:Dieldrin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D007774:Lactation; D008297:Male; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000209:etiology; D010575:Pesticides / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D050493:Vesicular Monoamine Transport Proteins / Q000032:analysis / Q000235:genetics
D050483:Dopamine Plasma Membrane Transport Proteins; D010575:Pesticides; D012333:RNA, Messenger; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004026:Dieldrin; D004298:Dopamine