Developmental heptachlor exposure increases susceptibility of dopamine neurons to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)in a gender-specific manner.
Parkinson's disease (PD) is primarily thought of as a disease of aging. However, recent evidence points to the potential for exposure to xenobiotics during development to increase risk of PD. Here, we report that developmental exposure to the organochlorine pesticide heptachlor alters the dopamine system and increases neurotoxicity in an animal model of PD. Exposure of pregnant mice to heptachlor led to increased levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) levels at both the protein and mRNA level in their offspring. Increased DAT and VMAT2 levels were accompanied by alterations of mRNA levels of nuclear transcription factors that control dopamine neuron development and regulate DAT and VMAT2 levels in adulthood. At 12 weeks of age, control and heptachlor-exposed offspring were administered a moderate dose (2 x 10mg/kg) of the parkinsonism-inducing agent MPTP. Greater neurotoxicity as evidenced by a greater loss of striatal dopamine and potentiation of increased levels of glial fibrillary acidic protein and alpha-synuclein was observed in heptachlor-exposed offspring. The neurotoxicity observed was greater in the male offspring than the female offspring, suggesting that males are more susceptible to the long-term effects of developmental heptachlor exposure. These data suggest that developmental heptachlor exposure causes long-term alterations of the dopamine system thereby rendering it more susceptible to dopaminergic damage in adulthood.
Richardson
Jason R
JR
Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322, United States. jricha3@eohsi.rutgers.edu
Caudle
W Michael
WM
Wang
Min Zheng
MZ
Dean
E Danielle
ED
Pennell
Kurt D
KD
Miller
Gary W
GW
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006533:Heptachlor / Q000378:metabolism / Q000633:toxicity*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018398:Homeodomain Proteins; C493453:Slc18a2 protein, mouse; D014157:Transcription Factors; D050493:Vesicular Monoamine Transport Proteins; C433629:homeobox protein PITX3; D006533:Heptachlor; D004298:Dopamine