Zhang Wenping, Tian Fengjie, Zheng Jinping, Li Senlin, Qiang Mei
Department of Neurotoxicology, School of Public Health, Shanxi Medical University, Shanxi, Taiyuan, 030001, China.
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America.
PLoS One. 2016 Feb 22;11(2):e0149574. doi: 10.1371/journal.pone.0149574. eCollection 2016.
Recently, an increasing number of human and animal studies have reported that exposure to benzo(a)pyrene (BaP) induces neurological abnormalities and is also associated with adverse effects, such as tumor formation, immunosuppression, teratogenicity, and hormonal disorders. However, the exact mechanisms underlying BaP-induced impairment of neurological function remain unclear. The aim of this study was to examine the regulating mechanisms underlying the impact of chronic BaP exposure on neurobehavioral performance.
C57BL mice received either BaP in different doses (1.0, 2.5, 6.25 mg/kg) or olive oil twice a week for 90 days. Memory and emotional behaviors were evaluated using Y-maze and open-field tests, respectively. Furthermore, levels of mRNA expression were measured by using qPCR, and DNA methylation of NMDA receptor 2B subunit (NR2B) was examined using bisulfate pyrosequencing in the prefrontal cortex and hippocampus.
Compared to controls, mice that received BaP (2.5, 6.25 mg/kg) showed deficits in short-term memory and an anxiety-like behavior. These behavioral alterations were associated with a down-regulation of the NR2B gene and a concomitant increase in the level of DNA methylation in the NR2B promoter in the two brain regions.
Chronic BaP exposure induces an increase in DNA methylation in the NR2B gene promoter and down-regulates NR2B expression, which may contribute to its neurotoxic effects on behavioral performance. The results suggest that NR2B vulnerability represents a target for environmental toxicants in the brain.
最近，越来越多的人类和动物研究报告称，接触苯并(a)芘（BaP）会诱发神经异常，还与诸如肿瘤形成、免疫抑制、致畸性和激素紊乱等不良反应有关。然而，BaP诱发神经功能损伤的确切机制仍不清楚。本研究的目的是探讨慢性BaP暴露对神经行为表现影响的调节机制。
C57BL小鼠每周两次接受不同剂量（1.0、2.5、6.25mg/kg）的BaP或橄榄油，持续90天。分别使用Y迷宫和旷场试验评估记忆和情绪行为。此外，采用qPCR测量mRNA表达水平，并使用亚硫酸氢盐焦磷酸测序法检测前额叶皮质和海马中N-甲基-D-天冬氨酸受体2B亚基（NR2B）的DNA甲基化情况。
与对照组相比，接受BaP（2.5、6.25mg/kg）的小鼠表现出短期记忆缺陷和类似焦虑的行为。这些行为改变与两个脑区中NR2B基因的下调以及NR2B启动子中DNA甲基化水平的相应增加有关。
慢性BaP暴露导致NR2B基因启动子中的DNA甲基化增加并下调NR2B表达，这可能导致其对行为表现产生神经毒性作用。结果表明，NR2B的易损性是大脑中环境毒物的一个靶点。
