Paraoxonase 2 deficiency in mice alters motor behavior and causes region-specific transcript changes in the brain.

Autor: Garrick JM; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States.. Electronic address: jacqueg@uw.edu., Cole TB; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States.; Center on Human Development and Disabilities, University of Washington, United States., Bammler TK; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States., MacDonald JW; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States., Marsillach J; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States., Furlong CE; Depts. of Medicine (Div. Medical Genetics) and of Genome Sciences, University of Washington, United States., Costa LG; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States.; Dept. of Medicine and Surgery, University of Parma, Italy.
Jazyk: angličtina
Zdroj: Neurotoxicology and teratology [Neurotoxicol Teratol] 2021 Sep-Oct; Vol. 87, pp. 107010. Date of Electronic Publication: 2021 Jul 01.
DOI: 10.1016/j.ntt.2021.107010
Abstrakt: Paraoxonase 2 (PON2) is an intracellular antioxidant enzyme shown to play an important role in mitigating oxidative stress in the brain. Oxidative stress is a common mechanism of toxicity for neurotoxicants and is increasingly implicated in the etiology of multiple neurological diseases. While PON2 deficiency increases oxidative stress in the brain in-vitro, little is known about its effects on behavior in-vivo and what global transcript changes occur from PON2 deficiency. We sought to characterize the effects of PON2 deficiency on behavior in mice, with an emphasis on locomotion, and evaluate transcriptional changes with RNA-Seq. Behavioral endpoints included home-cage behavior (Noldus PhenoTyper), motor coordination (Rotarod) and various gait metrics (Noldus CatWalk). Home-cage behavior analysis showed PON2 deficient mice had increased activity at night compared to wildtype controls and spent more time in the center of the cage, displaying a possible anxiolytic phenotype. PON2 deficient mice had significantly shorter latency to fall when tested on the rotarod, suggesting impaired motor coordination. Minimal gait alterations were observed, with decreased girdle support posture noted as the only significant change in gait with PON2 deficiency. Beyond one home-cage metric, no significant sex-based behavioral differences were found in this study. Finally, A subset of samples were utilized for RNA-Seq analysis, looking at three discrete brain regions: cerebral cortex, striatum, and cerebellum. Highly regional- and sex-specific changes in RNA expression were found when comparing PON2 deficient and wildtype mice, suggesting PON2 may play distinct regional roles in the brain in a sex-specific manner. Taken together, these findings demonstrates that PON2 deficiency significantly alters the brain on both a biochemical and phenotypic level, with a specific impact on motor function. These data have implications for future gene-environment toxicological studies and warrants further investigation of the role of PON2 in the brain.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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