Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Program in Toxicology, 2021.
Numerous epidemiological studies have reported associations between the broad spectrum herbicide paraquat (PQ) and Parkinson’s disease (PD), with findings supported by injection and feeding studies. Despite evidence that inhalation exposure to airborne pesticides, such as PQ, is an occupational and public health concern, the ability of inhaled PQ to reproduce features of PD has not been investigated. The present study was designed to determine if inhalation exposure to PQ would lead to its disposition to the brain, dopaminergic dysregulation, and neurobehavioral outcomes consistent with the trajectory of PD. Adult male and female C57BL/6J mice were exposed to PQ aerosols (130 µg/m3) in a whole-body inhalation chamber for 4hrs/day, 5 days/week for 4 weeks. Subsets of males were sacrificed during and after exposure and PQ concentrations in various brain regions (olfactory bulb, striatum, midbrain, and cerebellum) were quantified via mass spectrometry. Alterations in motor behavior were examined using spontaneous locomotor activity, rota-rod, and grip strength. Following the conclusion of behavioral assessment 275 days after the end of exposure, mice were sacrificed and neurotransmitters were measured by mass spectrometry. PQ inhalation resulted in significant concentrations in all examined brain regions, with the highest burden observed in the olfactory bulb, consistent with nasal olfactory translocation. PQ led to significant male-specific deficits in olfactory discrimination. PQ inhalation also produced male- specific deficits in locomotor activity and grip strength, but no significant effect on motor coordination on the rota-rod apparatus. Critically, PQ inhalation exposure led to a significant male-specific reduction in midbrain dopamine, even 275 days post-exposure. Further, in the striatum, PQ significantly reduced the dopamine metabolite, homovanillic acid, glutamine, serotonin, and its metabolite 5-HIAA, relative to filtered-air controls. These data highlight the importance of inhalation as route of exposure for neurotoxic pesticides in the airborne state and lend biological plausibility to a causal relation between PQ and PD. These effects are sex-specific, and future research is needed to identify mechanisms of sex-differentiated toxicity.