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，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的常见毒性机制，并且越来越多地涉及多种神经系统疾病的病因。虽然 PON2 缺乏会增加大脑的体外氧化应激，但人们对其对体内行为的影响以及 PON2 缺乏导致的全局转录本变化知之甚少。我们试图表征 PON2 缺陷对小鼠行为的影响，重点是运动，并通过 RNA-Seq 评估转录变化。行为终点包括家笼行为 (Noldus PhenoTyper)、运动协调 (Rotarod) 和各种步态指标 (Noldus CatWalk)。家笼行为分析显示，与野生型对照相比，PON2 缺陷小鼠夜间活动增加，并且在笼子中央呆的时间更长，表现出可能的抗焦虑表型。在转棒上进行测试时，PON2 缺陷小鼠的跌倒潜伏期明显缩短，表明运动协调能力受损。观察到最小的步态改变，腰带支撑姿势的减少被认为是 PON2 缺陷时步态的唯一显着变化。除了一项家庭笼养指标外，这项研究中没有发现显着的基于性别的行为差异。最后，一部分样本被用于 RNA 测序分析，观察三个独立的大脑区域：大脑皮层、纹状体和小脑。在比较 PON2 缺陷小鼠和野生型小鼠时，发现了 RNA 表达的高度区域和性别特异性变化，这表明 PON2 可能以性别特异性方式在大脑中发挥不同的区域作用。总而言之，这些发现表明 PON2 缺陷会在生化和表型水平上显着改变大脑，并对运动功能产生特定影响。这些数据对未来的基因环境毒理学研究具有重要意义，并有必要进一步研究 PON2 在大脑中的作用。