Developmental Organochlorine Exposure and Neurodegeneration Parkinson's disease (PD) is characterized by the selective death of nigrostriatal dopamine neurons. The resultant loss of dopamine input to the striatum leads to hallmark motor symptoms of the disease. Epidemiological studies have revealed pesticide exposure as a risk factor for PD and post-mortem studies have demonstrated that organochlorine insecticides are elevated in PD brains. Our lab has previously shown that exposure of adult mice to organochlorine insecticides alters the expression and function of the dopamine transporter (DAT), a key regulator of dopamine neurotransmission and a gateway for dopaminergic toxins. We now have evidence that exposure to these compounds during development increases DAT expression in young mice. The purpose of this study is to examine the effects of organochlorine insecticides on the development of the nigrostriatal dopamine system and to determine if such exposures predispose the animals to parkinsonism.
Specific Aim 1. Gestational and lactational exposure to organochlorine insecticides disrupts the development of the nigrostriatal dopaminergic system. In this aim, we will test the hypothesis that developmental exposure to organochlorine insecticides disrupts nigrostriatal dopamine system gene expression in young and adult mice. Real-time PCR, laser capture microdissection, behavioral testing, neurochemistry, and immunochemistry will be performed to determine the effects of the insecticides on the dopamine system.
Specific Aim 2. Gestational and lactational exposure to organochlorine insecticides increases susceptibility of dopamine neurons to MPTP.
This aim will test the hypothesis that permanent alterations in the expression of key components of dopaminergic neurons by developmental exposure to organochlorines renders these animals more susceptible to the parkinsonism-inducing toxin MPTP. After developmental exposure to insecticides, adult mice will be exposed to MPTP and analyzed as in Aim 1. Completion of these specific aims will provide crucial information regarding the effects of developmental exposure of pesticides on the integrity and vulnerability of the nigrostriatal dopamine system.
