Figure 3. Schematic illustrating the hypothesized mechanism by which developmental dieldrin exposure alters the dopamine system and causes enhanced neurotoxicity of MPTP. Dieldrin’s primary mechanism of toxicity is through blockade of chloride flux through GABA_A receptors. Inhibition of chloride flux in the dopamine neurons of the substantia nigra pars compacta causes increased neuronal activity and burst firing of dopamine neurons. Increased neuronal activity can then activate Nurr1 transcription, which can target downstream genes such as the DAT and VMAT2, resulting in increased transcription and translation. These alterations of DAT and VMAT2 produce a state in which the ratio of DAT:VMAT2 is increased, thereby increasing the neurotoxicity of MPTP.