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Analysis of C57Bl/6 mice at 8 and 16 months after repeated dosing of paraquat and maneb.

McIntosh-LJ; Benkovic-SA; Miller-DB; O'Callaghan-JP; Patten-R; Collier-MJ; Willoughby-C; Myers-D; Switzer-RC; Li-AA
Toxicologist 2010 Mar; 114(1):269
Combined exposure to paraquat (PQ) and maneb (MB) in C57Bl/6 mice has been hypothesized to be an animal model for Parkinson's Disease. This study examines three doses and two timepoints to assess effects of repeated PQ+MB injections on a functional observational battery (FOB) with 12 open field arena observations, motor activity, and neurohistological endpoints. Male and female mice were dosed on PND 5-19 with 0.3/1.0 mg/kg, 0.06/0.18 mg/kg, or 0.0007/0.0021 mg/kg PQ+MB respectively, and/or as adults twice weekly during weeks 27 to 31 of age with 10/30 mg/kg, 0.6/1.8 mg/kg, or 0.0007/0.0021 mg/kg PQ+MB. All animals were tested at 32 weeks, then sets dosed preweaning, as adult, or at both times were sacrificed at 33 weeks. A second set dosed at both times was held to 62 weeks and reassessed by the same FOB and motor activity tests, then sacrificed at 70 weeks. Brains of all animals were serially sectioned and every sixth section examined for cell degeneration and loss using GFAP, amino cupric silver (ACS) staining, and stereology of the substantia nigra pars compacta (SNpc). Gender effects were seen in the FOB, with high dose males showing increased incidence of tremor at 32 but not 62 weeks. High dose females showed increased horizontal activity and rearing at 62 weeks only. The high dose caused body weight loss in preweaning and adult males, and was lethal in males treated only as adults. Females did not show body weight-related effects at any dose, although brain weights were slightly reduced in high dose females. No treatment-related effects were seen across the whole brain using ACS and GFAP staining. Stereology is ongoing using StereoInvestigator v9.0 software to give a non-biased number of TH+ cells in the SNpc using the optical fractionator method.
Biological-effects; Cell-biology; Exposure-assessment; Exposure-levels; Laboratory-animals; Nervous-system-function; Neurological-reactions; Neurological-system; Neuromotor-system; Neuromotor-system-disorders Physiological-effects; Statistical-analysis; Toxic-effects; Toxic-materials; Pesticides; Pesticides-and-agricultural-chemicals; Insecticides
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NIOSH Division
Priority Area
Healthcare and Social Assistance; Transportation, Warehousing and Utilities
Source Name
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah