Investigating the Neurotoxic Effects of Agrochemicals (Dieldrin and Lindane) in Huntington's Disease Neuropathology

Science Center, Bent Corridor

Huntington’s disease (HD) is a genetic neurodegenerative disease that results in movement, cognition, personality and mood impairments. Indeed, the striatum that is necessary for normal motor function is mostly affected in HD. Current evidence suggests that environmental factors including pesticides may modify HD neuropathology by worsening symptomology, age of onset, and progression. In this study, we investigated the effects of two potentially exposed pesticides, dieldrin and lindane in HD neuropathology. Dieldrin and lindane are organochloride pesticides reported to accumulate in Parkinson’s disease (PD) postmortem brain tissues and cause dopaminergic cell loss. Recognizing the similarities in pathophysiological mechanisms between PD, HD and pesticide neurotoxicity, we hypothesized that exposure to lindane and dieldrin may potentiate the neurotoxic properties of mutant HD protein to cause enhanced striatal neurodegeneration. We examined the effects of lindane and dieldrin independently and cooperatively in an established mouse striatal cell model of HD expressing 7 (wild-type) or 111 (mutant) polyglutamine repeats. Following exposures of wild type and mutant HD striatal cells to varying concentrations of dieldrin or lindane at different time points, we observed that mutant HD striatal cells exhibited a time-dependent toxic gain of function and decreased mitochondrial-dependent cell viability compared to wild type. However, we report no genotypic and time-dependent differences in survival upon lindane exposure. Interestingly, our preliminary results suggest that dieldrin and lindane cooperatively potentiate striatal HD neurotoxicity. In summary, we have uncovered a novel disease-toxicant interaction between mutant HD and dieldrin. Ongoing experiments are to examine the effects of dieldrin induced oxidative stress and protein kinase C delta mediated cell death pathway. The overall implication of this research is to uncover and understand gene-environment interaction that may modify HD neuropathology.