Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States..
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.
Neurotoxicol Teratol. 2021 Sep-Oct;87:107010. doi: 10.1016/j.ntt.2021.107010. Epub 2021 Jul 1.
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.
对氧磷酶 2（PON2）是一种细胞内抗氧化酶，已被证明在减轻大脑氧化应激方面发挥着重要作用。氧化应激是神经毒物毒性的常见机制，并且越来越多地与多种神经疾病的病因有关。虽然 PON2 缺乏会增加体外大脑中的氧化应激，但对于 PON2 缺乏对体内行为的影响以及 PON2 缺乏会导致哪些全局转录变化知之甚少。我们试图描述 PON2 缺乏对小鼠行为的影响，重点是运动，并通过 RNA-Seq 评估转录变化。行为终点包括笼内行为（Noldus PhenoTyper）、运动协调（转棒）和各种步态指标（Noldus CatWalk）。笼内行为分析表明，PON2 缺乏的小鼠与野生型对照相比，夜间活动增加，并且更多地呆在笼子中央，表现出可能的抗焦虑表型。PON2 缺乏的小鼠在转棒上测试时，跌倒潜伏期明显缩短，表明运动协调受损。观察到最小的步态改变，与 PON2 缺乏相关的唯一显著变化是腰带支撑姿势减少。本研究未发现除一个笼内行为指标外，在性别方面存在显著的行为差异。最后，一部分样本用于 RNA-Seq 分析，研究了三个不同的大脑区域：大脑皮层、纹状体和小脑。与野生型小鼠相比，PON2 缺乏和野生型小鼠的大脑区域和性别特异性的 RNA 表达发生了高度变化，表明 PON2 可能以性别特异性的方式在大脑中发挥不同的区域作用。综上所述，这些发现表明 PON2 缺乏会显著改变大脑的生化和表型水平，对运动功能有特定影响。这些数据对未来的基因-环境毒理学研究具有重要意义，并需要进一步研究 PON2 在大脑中的作用。
