The incidence of
Parkinson's disease (PD) correlates with environmental exposure to pesticides, such as the organochlorine
insecticide,
dieldrin. Previous studies found an increased concentration of the
pesticide in the striatal region of the brains of PD patients and also that
dieldrin adversely affects cellular processes associated with PD. These processes include mitochondrial function and
reactive oxygen species production. However, the mechanism and specific cellular targets responsible for
dieldrin-mediated cellular dysfunction and the structural components of
dieldrin contributing to its toxicity (toxicophore) have not been fully defined. In order to identify the toxicophore of
dieldrin, a structure-activity approach was used, with the toxicity profiles of numerous analogues of
dieldrin (including
aldrin,
endrin, and cis-
aldrin diol) assessed in PC6-3 cells. The MTT and
lactate dehydrogenase (LDH) assays were used to monitor cell viability and membrane permeability
after treatment with each compound. Cellular assays monitoring ROS production and extracellular
dopamine metabolite levels were also used. Structure and stereochemistry for
dieldrin were found to be very important for toxicity and other end points measured. Small changes in structure for
dieldrin (e.g., comparison to the stereoisomer
endrin) yielded significant differences in toxicity. Interestingly, the cis-diol metabolite of
dieldrin was found to be significantly more toxic than the parent compound. Disruption of
dopamine catabolism yielded elevated levels of the
neurotoxin,
3,4-dihydroxyphenylacetaldehyde, for many organochlorines. Comparisons of the toxicity profiles for each
dieldrin analogue indicated a structure-specific effect important for elucidating the mechanisms of
dieldrin neurotoxicity.