Effects of acetaminophen on prenatal brain development: an organoid model

总结 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， 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。 影响胎儿和出生后早期发育，包括多器官系统。关于 神经发育，大队列的流行病学研究报告说， 注意力缺陷多动障碍（ADHD）和自闭症谱系障碍（ASD）的产前儿童 暴露于APAP。特别是，在怀孕的第二和第三个三个月期间， 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。尽管遭到强烈 对胎儿潜在不良后果的证据，APAP影响人类胎儿的机制 大脑尚未被探索。在这里，我们建议使用人类功能性脑类器官模型来解决 这个问题脑类器官非常适合这个项目，因为它们重现了人类胎儿的大脑 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的发展。我们 假设APAP通过转录程序失调影响胎儿脑发育 参与早期神经发生和突触信号传导。我们将通过以下方式来验证这一假设 具体目的：（1）识别细胞和分子途径、细胞群体和共表达模块 胎儿脑发育期间APAP暴露失调;（2）研究突触和长期 振荡网络活动表型响应APAP暴露，以评估其对脑功能的影响。 我们的研究将填补知识空白，关于APAP暴露在怀孕期间的安全性，使用相关的 人类脑类器官模型。此外，它将提供APAP可以发挥作用的分子机制 破坏胎儿大脑发育并导致神经发育疾病。

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.