A fetal risk factor for Parkinson's disease.
A lack of strong evidence for genetic heritability of idiopathic Parkinson's disease (PD) has focused attention on environmental toxicants in the disease etiology, particularly agrichemicals. PD is associated with advanced age, but it is unclear whether specific neuronal damage could result from insults during development. This study hypothesized that prenatal exposure to pesticides would disrupt the development of the nigrostriatal dopamine (DA) system and enhance its vulnerability to dopaminergic neurotoxicant exposures later in life. Pregnant C57BL/6J mice were treated on gestational days 10-17 with saline or the pesticides maneb (MB, 1 mg/kg) or paraquat (PQ, 0.3 mg/kg). When offspring were evaluated in adulthood, there were no significant effects of prenatal MB or PQ exposure on locomotor activity. Subsequently, offspring were treated for 8 consecutive days with saline, MB (30 mg/kg), or PQ (5 mg/kg). One week after the last exposure, only males exposed to prenatal MB and adulthood PQ showed significant reductions in locomotor activity (95%) and changes in striatal neurochemistry. Stereological assessment of the substantia nigra pars compacta (SNpc) and ventral tegmental area correspondingly confirmed selective dopaminergic-neuron loss in SNpc. The lack of changes in other exposure groups suggests a specificity to the sequence of exposures as well as gender specificity. These results suggest that prenatal exposure to MB produces selective, permanent alterations of the nigrostriatal dopaminergic system and enhances adult susceptibility to PQ exposure. This study implicates a role for developmental neurotoxicant exposure in the induction of neurodegenerative disorders such as PD.
Barlow
Brian K
BK
Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Richfield
Eric K
EK
Cory-Slechta
Deborah A
DA
Thiruchelvam
Mona
M
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology*; D005659:Fungicides, Industrial / Q000494:pharmacology; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D008297:Male; D008344:Maneb / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010269:Paraquat / Q000494:pharmacology; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D005659:Fungicides, Industrial; D006540:Herbicides; D008344:Maneb; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat; D004298:Dopamine