Effect of prenatal exposure to acetaminophen during critical period of brain growth spurt on exploratory and cognitive behavior: Guinea pig model

大脑快速生长关键期产前接触对乙酰氨基酚对探索和认知行为的影响：豚鼠模型

• 批准号: 9892621
• 负责人: Jacek A. Mamczarz
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892621
• 关键词: Acetaminophen; Address; Affect; Age; Aminophenols; Analgesics; Animal Model; Animals; Asthma; Attention deficit hyperactivity disorder; Behavior; Behavioral; Behavioral Assay; Birth; Brain; Brain region; Buffers; Cavia; Child; Childhood; Childhood Neurological Disorder; Cognitive; Cognitive deficits; Development; Disease; Dose; Electroencephalogram; Electroencephalography; Emotional; Event; Exposure to; Female; Fetal Growth; Fetus; Future; Growth; Hippocampus (Brain); Human; Immunohistochemistry; Impairment; Knowledge; Life; Measures; Metabolism; Modeling; Molecular; Motor Activity; Mus; Neurologic; Neurons; Operative Surgical Procedures; Oral; Placebos; Placenta; Play; Pregnancy; Pregnant Women; Puberty; Randomized; Rattus; Reporting; Risk; Role; Safety; Social Interaction; Structure; Telemetry; Testing; Third Pregnancy Trimester; Toxic effect; Tylenol; Woman; Xenobiotics; autism spectrum disorder; behavior measurement; behavior test; behavioral outcome; blind; brain electrical activity; cognitive function; critical period; density; design; developmental toxicity; dosage; emerging adult; epidemiology study; experimental study; fetal; high risk; interdisciplinary approach; male; motor impairment; neonatal period; nervous system disorder; neurobehavioral; neurotoxic; offspring; paraform; postnatal; preclinical study; pregnant; prenatal; prenatal exposure; prepuberty; reproductive development; sex; social

ABSTRACT Recommended doses of the analgesic acetaminophen (N-acetyl-p-aminophenol; Tylenol®, APAP) were presumed to be safe for pregnant women until epidemiological studies reported that children prenatally exposed to APAP are at high risk of developing a number of neurological disorders, including attention- deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). It is important to note, however, that these studies did not establish a cause-consequence relationship between prenatal APAP exposure and childhood neurological disorders. Preclinical studies, on the other hand, have shown that exposure of mice and rats to APAP during their neonatal period of brain growth spurt causes cognitive deficits among other neurobehavioral impairments in early adulthood. Unfortunately, the temporal development of the human brain does not parallel that of the mouse or the rat brain. Therefore, the question as to whether gestational exposure to APAP causes disruption of fetal brain development and, thereby, compromises neurobehavioral functions later in life remains unanswered. Here, we propose to use the guinea pig as the animal model of choice to test the central hypothesis that prenatal exposure to APAP during the period of brain growth spurt has long-term, sex-dependent effects on emotional and cognitive behavior that correlate with disruption of the electrical activity and/or structural integrity of the brain. The guinea pig is a unique animal model, because its placental structure, the temporal course of its brain development, and APAP metabolism during pregnancy closely resemble those of humans. A multidisciplinary approach involving behavioral assays, electroencephalography (EEG), and immunohistochemistry (IHC), and a placebo-controlled, randomized, blind design that minimizes experimental bias and maximizes scientific rigor will be used to address two specific aims. In Aim 1, experiments will determine whether male and female offspring born from guinea pigs orally treated with APAP (50-100 mg/kg twice a day for 10 days) during the gestational critical period of fetal brain growth spurt present impaired exploratory, social, and/or cognitive behavior. These are behavioral domains impaired in neurological disorders associated with prenatal APAP exposure of children. At the end of the behavioral test, animals will be used in the experiments designed in Aim 2 to determine whether the prenatal exposure to APAP causes significant alterations of the electrical brain activity, measured in telemetric EEG, and/or disruption of the structural integrity of the hippocampus, a brain region critical known to be structurally disrupted in ADHD and ASD. This approach will enable us to identify functional and structural correlates of the behavioral outcomes in APAP-exposed offspring. Successful completion of this study will fill in the knowledge gap regarding the safety of gestational use of APAP. It will also lay the groundwork for future studies aimed at identifying the effects of developmental effects of APAP exposure at different stages of pregnancy and the molecular mechanisms underlying these effects.

抽象的 建议的止痛乙酰氨基酚（N-乙酰基-P-氨基酚；Tylenol®，APAP）为 假定对孕妇安全，直到流行病学研究报告儿童产前 暴露于APAP的高风险是患上许多神经系统疾病，包括注意力 - 赤字/多动症（ADHD）和自闭症谱系障碍（ASD）。但是，重要的是要注意， 这些研究没有在产前APAP暴露与 儿童期神经疾病。另一方面，临床前研究表明，小鼠和 在脑生长的新生儿时期，大鼠会导致认知定义 成年初的神经行为障碍。不幸的是，人脑的临时发展 不平行小鼠或大鼠脑的平行。因此，关于妊娠暴露的问题 APAP会导致胎儿脑发育的破坏，从而损害神经行为功能 后期生活仍未得到答复。在这里，我们建议将豚鼠用作选择的动物模型 测试中心假设，即在大脑生长突变期间，产前暴露于APAP的已有 长期，性别依赖性对情绪和认知行为的影响，与中断相关 大脑的电活动和/或结构完整性。豚鼠是独特的动物模型， 因为其胎盘结构，大脑发育的临时过程以及在 怀孕非常类似于人类。涉及行为分析的多学科方法， 脑电图（EEG）和免疫组织化学（IHC）以及安慰剂对照，随机，盲目 最小化实验偏差并最大化科学严谨的设计将用于解决两个特定的特定 目标。在AIM 1中，实验将确定雄性和女性后代是否从豚鼠出生 在胎儿大脑的妊娠关键时期中，用APAP治疗（每天两次50毫克/千克） 生长突飞猛进的探索性，社会和/或认知行为受损。这些是行为领域 与儿童产前APAP暴露有关的神经系统疾病受损。在 行为测试，将在AIM 2中设计的实验中使用动物，以确定产前是否存在 暴露于APAP会导致电脑活动的重大改变，该活动在遥测脑电图中测量， 和/或破坏海马的结构完整性，海马的结构完整性是一个重要的大脑区域。 在ADHD和ASD中被破坏。这种方法将使我们能够确定功能和结构相关性 APAP暴露后代的行为结果。这项研究的成功完成将填补 关于妊娠使用APAP的安全性的知识差距。它也将为 未来的研究旨在确定不同的APAP暴露效果的影响 怀孕阶段和这些作用的分子机制。