Qi Miao, Zhu Peixin, Wang Honglai, He Qi, Huo Chunyue
Capital Medical University, Yanjing Medical College, Beijing 101300, China.
Beijing Miyun Mental Health Hospital, Beijing 101500, China.
Pharmacol Biochem Behav. 2024 Dec;245:173888. doi: 10.1016/j.pbb.2024.173888. Epub 2024 Oct 9.
Neurodevelopmental disorders, notably schizophrenia, present ongoing challenges in mental health. Methylazoxymethanol (MAM), a potent neurodevelopmental disruptor, is implicated in inducing schizophrenia-like structural and functional alterations in rodent models. This study conducts a systematic review and meta-analysis to assess comprehensively the behavioral consequences of embryonic MAM exposure in rodents, focusing on diverse paradigms reflective of schizophrenia-related phenotypes.
Employing a meticulous search strategy across PubMed, Embase, Cochrane Library, Sino Med, CNKI, Weip Database, Wan Fang, and Web of Science, this study adheres to PRISMA guidelines. The analysis includes studies examining the impact of embryonic MAM exposure on behavioral outcomes, such as Prepulse Inhibition (PPI), social interaction (SI), novel object recognition (NOR), elevated plus maze (EPM) performance, and open field test (OFT) results. The study protocol is registered with PROSPERO, number 42024521442 CRD.
Involving 19 studies, the meta-analysis reveals nuanced behavioral alterations. MAM-exposed male rats in the EPM group exhibit a Mean Difference of -0.27 (95 % CI: [-1.02, 0.49]) during puberty, with a broader Mean Difference of -0.50 (95 % CI: [-1.97, 0.96]) in adulthood. Combining both stages yields an overall Mean Difference of -0.31 (95 % CI: [-1.01, 0.38]), indicating potential EPM performance differences. Subgroup analysis by MAM dosage levels reveals a Mean Difference of -0.90 (95 % CI: [-1.86, 0.05]) for moderate-dose MAM and 0.65 (95 % CI: [0.29, 1.02]) for high-dose MAM. In the OFT group, adulthood shows a Mean Difference of -1.22 (95 % CI: [-2.14, -0.29]), emphasizing altered exploratory behavior. The NOR group indicates significant Mean Differences of -6.18 (95 % CI: [-8.41, -3.94]) in adulthood, signifying recognition memory deficits. SI assessments show consistent negative Mean Differences during puberty and adulthood for male rats (-1.88 and - 1.87, respectively) and female rats in preestrus and estrus (-1.09).
This systematic review and meta-analysis offer a comprehensive overview of behavioral consequences linked to embryonic MAM exposure in rodents. Findings underscore intricate relationships between MAM and various behavioral domains relevant to schizophrenia. Dose-dependent effects, developmental stage considerations, and potential sex-specific influences contribute to the complexity of MAM-induced alterations, advancing our understanding of neurodevelopmental disruptions and suggesting avenues for future research and therapeutic interventions targeting the developmental origins of psychiatric disorders.
神经发育障碍，尤其是精神分裂症，给心理健康带来了持续挑战。甲基偶氮甲醇（MAM）是一种强效的神经发育干扰物，与在啮齿动物模型中诱导类似精神分裂症的结构和功能改变有关。本研究进行了一项系统综述和荟萃分析，以全面评估胚胎期暴露于MAM对啮齿动物行为的影响，重点关注反映精神分裂症相关表型的各种范式。
本研究采用精心设计的检索策略，检索了PubMed、Embase、Cochrane图书馆、中国生物医学文献数据库、中国知网、维普数据库、万方数据库和Web of Science，并遵循PRISMA指南。分析包括研究胚胎期暴露于MAM对行为结果的影响，如前脉冲抑制（PPI）、社交互动（SI）、新物体识别（NOR）、高架十字迷宫（EPM）表现和旷场试验（OFT）结果。该研究方案已在PROSPERO注册，注册号为42024521442 CRD。
荟萃分析纳入了19项研究，揭示了细微的行为改变。EPM组中，暴露于MAM的雄性大鼠在青春期的平均差异为-0.27（95%CI：[-1.02, 0.49]），成年期的平均差异更广泛，为-0.50（95%CI：[-1.97, 0.96]）。两个阶段合并后的总体平均差异为-0.31（95%CI：[-1.01, 0.38]），表明EPM表现可能存在差异。按MAM剂量水平进行的亚组分析显示，中剂量MAM的平均差异为-0.90（95%CI：[-1.86, 0.05]），高剂量MAM的平均差异为0.65（95%CI：[0.29, 1.02]）。在OFT组中，成年期的平均差异为-1.22（95%CI：[-2.14, -0.29]），强调探索行为发生改变。NOR组表明成年期的平均差异显著为-6.18（95%CI：[-8.41, -3.94]），表明存在识别记忆缺陷。SI评估显示，青春期和成年期雄性大鼠（分别为-1.88和-1.87）以及处于发情前期和发情期的雌性大鼠（-1.09）的平均差异始终为负。
这项系统综述和荟萃分析全面概述了与胚胎期暴露于MAM相关的啮齿动物行为后果。研究结果强调了MAM与各种与精神分裂症相关的行为领域之间的复杂关系。剂量依赖性效应、发育阶段考虑因素以及潜在的性别特异性影响导致了MAM诱导改变的复杂性，增进了我们对神经发育干扰的理解，并为未来针对精神疾病发育起源的研究和治疗干预提供了途径。
