南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (8): 1237-1243.doi: 10.12122/j.issn.1673-4254.2022.08.17

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邻苯二甲酸二乙基己酯可能通过损伤血脑屏障诱导小鼠焦虑样行为和学习记忆障碍

李 帆，朱艳艳，孙晓明，胡慧娟，周苗苗，白怡雪，胡 浩   

  1. 西安交通大学医学部基础医学实验教学中心，第二附属医院皮肤科，医学部药理学系，宗濂书院2018级临床医学专业，陕西 西安 710061
  • 出版日期:2022-08-20 发布日期:2022-09-05

Diethylhexyl phthalate induces anxiety-like behavior and learning and memory impairment in mice probably by damaging blood-brain barrier

LI Fan, ZHU Yanyan, SUN Xiaoming, HU Huijuan, ZHOU Miaomaio, BAI Yixue, HU Hao   

  1. Basic Medicine Experimental Teaching Center, Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Department of Dermatology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Grade 2018 Clinical Medicine, Zonglian College, Xi'an Jiaotong University, Xi'an 710061, China
  • Online:2022-08-20 Published:2022-09-05

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摘要： 目的 探讨邻苯二甲酸二乙基己酯（DEHP）对小鼠焦虑样行为和学习记忆能力的影响及机制。方法 将40只雄性ICR小鼠随机分为对照组（0 mg/kg）和DEHP暴露组（10、50、100 mg/kg）。通过灌胃暴露DEHP 4周，再进行开场实验、高架十字迷宫实验和Morris水迷宫实验。取小鼠海马组织检测丙二醛（MDA）含量，取大脑进行HE切片观察海马组织形态学变化，检测海马组织紧密连接蛋白ZO-1、Occludin的分子表达。结果 与对照组相比，4周DEHP暴露对各组小鼠体质量未造成明显的影响（P>0.05）。行为学实验表明，DEHP暴露组小鼠在开场中心区域的运动距离（P<0.05）和停留时间（P<0.05）少于对照组；在高架十字迷宫开臂区的运动距离和停留时间少于对照组（P<0.05）。在Morris水迷宫实验中，和对照组小鼠相比，DEHP暴露组小鼠找到平台的潜伏期明显延长（P<0.05），且穿越平台位置的次数减少（P<0.05）。HE染色可以观察到海马CA1至CA3区出现明显的椎体细胞坏死，海马组织中MDA含量增加（P<0.05），且与血脑屏障完整性相关的ZO-1和Occludin在基因（P<0.01）、蛋白（P<0.05）水平的表达也显著降低。此外，多元线性回归分析显示，DEHP诱导的小鼠焦虑样行为与学习记忆能力之间有密切的关联性。结论 DEHP暴露可能通过破坏血脑屏障，损伤海马椎体神经细胞，进而诱导小鼠焦虑样行为和学习记忆能力下降。

关键词: 邻苯二甲酸二乙基己酯；焦虑；学习记忆；血脑屏障

Abstract: Objective To investigate the effects of diethylhexyl phthalate (DEHP) exposure on anxiety-like behaviors and learning and memory ability in mice and explore the underlying mechanism. Methods Forty male ICR mice were randomized equally into control group (0 mg/kg) and 10, 50 and 100 mg/kg DEHP exposure groups, in which the mice were exposed to DEHP at the indicated doses by gavage for 4 weeks. After the treatments, the mice were assessed for behavioral changes using open filed test, elevated plus-maze and Morris water maze test. Brain tissues were collected from the mice for determination of malondialdehyde (MDA) content, pathologies and expressions of ZO-1 and occludin in the hippocampus. Results Compared with the control group, the mice with DEHP exposure for 4 weeks exhibited no significant body weight change (P>0.05) but presented with obvious behavioral changes, manifested by reduced movement distance (P<0.05) and time spent in the center of the open field (P<0.05), reduced movement distance (P<0.05) and time spent in the open arm of the elevated maze (P<0.05), significantly increased latency of searching for the platform (P<0.05), and decreased frequency of crossing the platform (P< 0.05). HE staining showed obvious vertebral cell death in the hippocampal CA1 to CA3 regions of the mice with DEHP exposure. The exposed mice showed significantly increased MDA content and decreased expressions of ZO-1 and occludin at both the mRNA and protein levels in the hippocampus (P<0.05 or 0.01). Multivariate linear regression analysis suggested a close correlation between anxiety-like behaviors and learning and memory abilities in DEHP-exposed mice. Conclusion DEHP exposure may cause damages of the blood-brain barrier and the pyramidal cells in the hippocampus of mice, thereby inducing anxiety-like behaviors and learning and memory impairment.

Key words: diethylhexyl phthalate; anxiety; learning and memory; blood-brain barrier