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Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson’s disease

Jason R. Richardson^*,,1, W. Michael Caudle^*,, Minzheng Wang^*,, E. Danielle Dean^*,, Kurt D. Pennell^*, and Gary W. Miller^*,,2

^* Center for Neurodgenerative Disease, School of Medicine and

Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; and

School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA

²Correspondence: Center for Neurodegenerative Disease, Emory University, Whitehead Biomedical Research, Bldg., Rm. 505, 615 Michael St., Atlanta, GA 30322, USA. E-mail: gary.miller{at}emory.edu

ABSTRACT

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 (2x10 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 -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, J. R., Caudle, W. M., Wang, M., Dean, E. D., Pennell, K. D., Miller, G. W. Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson’s disease.

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