Dose-response evaluation of C57Bl/6 mice for motor abnormalities and Parkinson-patterned neuropathology after paraquat and maneb exposure.
McIntosh-LJ; O'Callaghan-JP; Benkovic-SA; Miller-DB; Patten-R; Collier-MJ; Switzer-RC; Warren-S; Li-AA
Toxicologist 2009 Mar; 108(1):441
The combination of paraquat and maneb (PQ/MB) has been proposed to be a risk factor for Parkinson's Disease. C57Bl/6 mice were dosed daily from PND 5-19 (0.3/1.0 mg/kg PQ/MB) and/or twice weekly from week 28-31 of age (10/30 mg/kg PQ/MB), the levels reported in the literature to cause loss of substantia nigra cells. This high dose was reduced to 5/15 mg/kg PQ/MB following lethality in na´ve males after the fourth of seven injections as adults. Additionally, two other doses were derived from human PQ exposure models and were administered as a middle dose (0.06/0.18 mg/kg PQ/MB juvenile, 0.6/1.8 mg/kg PQ/MB adult) and a low dose (0.0007/0.002 mg/kg PQ/MB juvenile and adult) to represent exposure levels more relevant to humans. Animals dosed as juveniles only, as adults only, or both, were tested for motor activity and arena behavior at 32 weeks, and then perfusion fixed for evaluation of neuropathology at 33 weeks. One additional group dosed as juveniles and adults was tested again at 62 weeks and sacrificed at 70 weeks of age. At 32 weeks of age, there were no effects of treatment on behavioral endpoints. At 62 weeks of age, treated animals were similar to controls in the arena and activity cage, except in high dose females where ambulatory and rearing activity was increased. Staining with anti-GFAP and deOlmos' amino cupric silver method did not detect any degenerative response related to treatment across the entire brain at either 33 or 70 weeks of age in either gender. Stereological analysis and quantification of dopaminergic neurons in the substantia nigra is ongoing.
Biological-effects; Biological-factors; Cellular-reactions; Cell-biology; Cell-damage; Cancer; Chemical-hypersensitivity; Chemical-reactions; Chemical-warfare-agents; Cytology; Exposure-assessment; Exposure-levels; Exposure-methods; Irritants; Laboratory-animals; Neurological-reactions; Risk-factors; Toxic-effects
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland