Effects of acetaminophen on prenatal brain development: an organoid model

对乙酰氨基酚对产前大脑发育的影响：类器官模型

• 批准号: 10510873
• 负责人: LILIA M IAKOUCHEVA
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510873
• 关键词: Acetaminophen; Acute; Address; Age; Aminophenols; Analgesic and Antipyretic; Animal Model; Apoptosis; Asia; Attention deficit hyperactivity disorder; Behavior; Behavioral; Birth; Brain; Cells; Child; Cohort Studies; Data; Development; Diagnosis; Disease; Dose; Drug usage; Electrophysiology (science); Embryonic Development; Epidemiology; Europe; Exposure to; Fetus; Fever; Flow Cytometry; Fragile X Syndrome; Frequencies; Genes; Genetic Transcription; Head; Health; Hepatotoxicity; Hour; Human; Hyperactivity; Immunohistochemistry; Injections; Intake; Knowledge; Language Development; Lead; Long-Term Effects; Measures; Modeling; Molecular; Mothers; Motor; Neuraxis; Neurodevelopmental Disorder; Neurons; Odds Ratio; Organoids; Pain; Parents; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Pregnancy; Pregnant Women; Property; Proteins; Rattus; Regression Analysis; Reporting; Rett Syndrome; Review Literature; Risk; Safety; Second Pregnancy Trimester; Signal Transduction; Slice; Study models; Symptoms; Synapses; Testing; Therapeutic; Third Pregnancy Trimester; Virus Diseases; Zebrafish; adverse outcome; autism spectrum disorder; base; body system; cognitive function; cohort; craniofacial structure; density; epidemiological model; epidemiology study; executive function; experience; fetal; human fetal brain; human stem cells; indexing; insight; multi-electrode arrays; nervous system development; neurodevelopment; neurogenesis; neurotoxicity; offspring; postnatal development; prenatal; prenatal exposure; programs; response; single-cell RNA sequencing; stem cell model; synaptogenesis; transcriptome

SUMMARY Acetaminophen (N-acetyl-p-aminophenol (APAP), also known as paracetamol) is widely used in pregnancy for pain and fever reduction. However, an increasing number of studies suggest that APAP could negatively influence fetal and early postnatal development, including multiple organs systems. Regarding neurodevelopment, epidemiological studies of large cohorts have reported a significantly increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children prenatally exposed to APAP. In particular, fetal brain development during the second and third trimesters of pregnancy appears especially vulnerable to APAP based on the epidemiological and animal model studies. Despite strong evidence for potential adverse consequences to the fetus, the mechanism by which APAP impacts human fetal brain remains unexplored. Here, we are proposing to use human functional brain organoid models to address this question. Brain organoids are a perfect fit for this project because they recapitulate human fetal brain development at the transcriptional and network activity levels, as demonstrated by us and others. We hypothesize that APAP impacts fetal brain development by dysregulating transcriptional programs involved in early neurogenesis and synaptic signaling. We will test this hypothesis through the following Specific Aims: (1) Identify cellular and molecular pathways, cell populations, and co-expression modules dysregulated by APAP exposure during fetal brain development; (2) Investigate synaptic and long-term oscillatory network activity phenotypes in response to APAP exposure to evaluate its impact on brain function. Our study will fill in the knowledge gap regarding the safety of APAP exposure in pregnancy using relevant human-derived brain organoid models. In addition, it will provide molecular mechanisms by which APAP could disrupt fetal brain development and lead to neurodevelopmental diseases.

概括 对乙酰氨基酚（N-乙酰基-P-氨基苯酚（APAP），也称为扑热息痛）在怀孕中广泛使用 减轻疼痛和发烧。但是，越来越多的研究表明APAP可能会负面 影响胎儿和早期产后发展，包括多个器官系统。关于 神经发育，大型队列的流行病学研究报告了明显增加的风险 产前儿童的注意力缺陷/多动症（ADHD）和自闭症谱系障碍（ASD） 暴露于APAP。特别是，妊娠的第二和第三种胎儿的胎儿大脑发育 根据流行病学和动物模型研究，似乎特别容易受到APAP的影响。尽管很强 对胎儿的潜在不利后果的证据，APAP影响人胎儿的机制 大脑仍然没有探索。在这里，我们提议使用人类功能性脑器官模型来解决 这个问题。脑器官非常适合该项目，因为它们概括了人类胎儿大脑 正如我们和其他人所证明的那样，在转录和网络活动水平上开发。我们 假设APAP通过转录程序失调会影响胎儿大脑的发育 参与早期神经发生和突触信号传导。我们将通过以下来检验这一假设 具体目的：（1）识别细胞和分子途径，细胞种群和共表达模块 胎儿脑发育过程中的APAP暴露失调； （2）研究突触和长期 振荡性网络活性表型响应APAP暴露以评估其对脑功能的影响。 我们的研究将填补有关使用相关的知识差距 人源性脑器官模型。此外，它将提供分子机制 破坏胎儿脑发育并导致神经发育疾病。