Evaluation of C57B1/6 mice for motor abnormalities and Parkinson-patterned neuropathology after Paraquat and Maneb exposure at human-relevant doses.
McIntosh LJ; O'Callaghan JP; Benkovic A; Miller DB; Patten R; Collier M; Switzer R; Li AA
Toxicol Lett 2009 Sep; 189(Suppl 1):S217
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 marked clinical reaction in naïve adult males after three injections, leading to termination for welfare reasons. 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 preweaning, 0.6/1.8 mg/kg PQ/MB adult) and a low dose (0.0007/0.002 mg/kg PQ/MB preweaning and adult) representing exposure levels relevant to humans. Animals dosed preweaning only, as adults only, or both, were tested for motor activity and arena behaviour at 32 weeks, and then evaluated for neuropathology at 33 weeks. One additional group dosed preweaning and as adults was retested at 62 weeks and sacrificed at 70 weeks of age. There was an increased incidence of tremors in the high dose males at 32 weeks of age, but not at 62 weeks of age, inconsistent with a progressive disease state. In the 1 h motor activity testing, there was an increase in ambulatory activity and rearing in high dose females at 62 weeks of age only. Staining with GFAP and silver 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 quantitation of TH+ neurons in the substantia nigra is ongoing.
Age-factors; Cell-biology; Exposure-assessment; Exposure-levels; Exposure-methods; Laboratory-animals; Laboratory-testing; Neurological-reactions; Neuromotor-system; Neuromotor-system-disorders; Neuromuscular-function; Quantitative-analysis
Laura J. McIntosh, Exponent, Inc., Toxicology and Mechanistic Biology, Menlo Park, CA
Abstract; Conference/Symposia Proceedings
Agriculture, Forestry and Fishing
Toxicology Letters. Abstracts of the 46th Congress of the European Societies of Toxicology