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

基本信息

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
项目类别：
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

项目摘要

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-对氨基苯酚（APAP），也称为扑热息痛）广泛用于妊娠期减轻疼痛和发烧。然而，越来越多的研究表明 APAP 可能会产生负面影响影响胎儿和产后早期发育，包括多个器官系统。关于神经发育，大群体的流行病学研究表明，神经发育的风险显着增加产前儿童注意力缺陷/多动障碍 (ADHD) 和自闭症谱系障碍 (ASD) 暴露于 APAP。特别是妊娠中期和晚期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。尽管坚强对胎儿潜在不良后果的证据，APAP 影响人类胎儿的机制大脑仍未被探索。在这里，我们建议使用人类功能性大脑类器官模型来解决这个问题。大脑类器官非常适合这个项目，因为它们再现了人类胎儿的大脑正如我们和其他人所证明的那样，转录和网络活动水平的发展。我们假设 APAP 通过转录程序失调影响胎儿大脑发育参与早期神经发生和突触信号传导。我们将通过以下方式检验这一假设具体目标： (1) 识别细胞和分子途径、细胞群和共表达模块胎儿大脑发育过程中 APAP 暴露导致失调； (2) 研究突触和长期振荡网络活动表型响应 APAP 暴露，以评估其对大脑功能的影响。我们的研究将利用相关技术填补妊娠期 APAP 暴露安全性的知识空白。人脑类器官模型。此外，它将提供 APAP 可以通过的分子机制破坏胎儿大脑发育并导致神经发育疾病。