Effects of acetaminophen on prenatal brain development: an organoid model

点击翻译按钮获取中文摘要

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.