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 镇痛药对乙酰氨基酚（N-乙酰基-对氨基苯酚；Tylenol®，APAP）的推荐剂量为 被认为对孕妇是安全的，直到流行病学研究报告儿童产前 接触 APAP 的人极有可能患上许多神经系统疾病，包括注意力障碍 然而，值得注意的是，缺陷/多动障碍（ADHD）和自闭症谱系障碍（ASD）。 这些研究并未建立产前 APAP 暴露与产前 APAP 之间的因果关系。 另一方面，临床前研究表明，小鼠和儿童的接触会导致儿童神经系统疾病。 大鼠在大脑生长突增的新生儿期使用 APAP 会导致认知缺陷等 不幸的是，人类大脑的时间发育会在成年早期出现神经行为障碍。 与小鼠或大鼠大脑的情况并不相似，因此，是否妊娠期暴露的问题。 APAP 会破坏胎儿大脑发育，从而损害神经行为功能 在以后的生活中仍然没有答案，在这里，我们建议使用豚鼠作为选择的动物模型。 检验中心假设，即在大脑生长突增期间产前接触 APAP 对 对情绪和认知行为的长期、性别依赖性影响与破坏相关 豚鼠的脑电活动和/或结构完整性是一种独特的动物模型， 因为它的胎盘结构、大脑发育的时间过程以及 APAP 代谢 怀孕与人类的怀孕非常相似，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、盲法 最大限度地减少实验偏差和最大限度地提高科学严谨性的设计将用于解决两个具体问题 在目标 1 中，实验将确定豚鼠是否通过口服生出雄性和雌性后代。 在妊娠关键期胎儿大脑接受 APAP（50-100 mg/kg，每天两次，持续 10 天）治疗 生长突增表现为探索、社交和/或认知行为受损。 与儿童产前 APAP 暴露相关的神经系统疾病受损。 行为测试，动物将被用于目标2中设计的实验，以确定产前是否 暴露于 APAP 会导致脑电活动发生显着改变（通过遥测脑电图测量）， 和/或海马体结构完整性的破坏，海马体是已知在结构上至关重要的大脑区域 这种方法将使我们能够识别 ADHD 和 ASD 的功能和结构相关性。 成功完成这项研究将填补 APAP 暴露后代的行为结果。 关于妊娠期使用 APAP 安全性的知识差距也将奠定基础。 未来的研究旨在确定不同环境下 APAP 暴露对发育的影响 妊娠阶段以及这些影响背后的分子机制。