Investigating neurodevelopmental toxicity of perfluoroalkyl acids and their derivatives in human brain organoids models

研究全氟烷基酸及其衍生物在人脑类器官模型中的神经发育毒性

基本信息

批准号：
10563204
负责人：
LILIA M IAKOUCHEVA
金额：
$ 60.57万
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：
2022-02-07 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563204
关键词：
3-Dimensional ATAC-seq Acids Affect Animals Astrocytes Attention deficit hyperactivity disorder Biological Blood - brain barrier anatomy Blood specimen Brain CRISPR interference Carbon Carboxylic Acids Carpet Cell Cycle Cell Differentiation Induction Cell Proliferation Cell Survival Cells Chemicals Chromatin Clothing Complex Detection Development Developmental Delay Disorders Disease Dose Environment Environmental Risk Factor Experimental Models Family Fetal Development Fluorine Food Genes Genetic Genetic Screening Genetic Transcription Glutamates Growth Half-Life Head circumference High Prevalence Human Human Development Hyperactivity Industrialization Knowledge Libraries Literature Low Birth Weight Infant Machine Learning Microcephaly Modeling Molecular Morphology Mothers Mus Neurodevelopmental Disorder Neuroglia Neurons Organoids Paper Pathway interactions Phenotype Placenta Play Poly-fluoroalkyl substances Population Prevalence Problem behavior Proliferating Rattus Reporting Role Schizophrenia Serum Sulfonic Acids Testing Time Toxic effect Umbilical Cord Blood Zebrafish autism spectrum disorder behavioral phenotyping developmental toxicity differential expression early pregnancy loss excitatory neuron exome exposed human population gene discovery genetic risk factor genome sequencing genome wide association study genome-wide human stem cells in vitro Model induced pluripotent stem cell insight lentivirally transduced man multi-electrode arrays nerve stem cell neural network neurodevelopment offspring postnatal progenitor programs rare variant single-cell RNA sequencing stem cell model transcriptome sequencing transcriptomics variant detection whole genome

项目摘要

SUMMARY Per- and polyfluoroalkyl substances and their derivatives (PFAS) are industrial chemicals that are wide- spread in the environment, including blood serum of wildlife and humans. Their pervasiveness and long half-life raises the questions about their toxicity, especially with regards to the effect on the developing fetus. Several studies have demonstrated that these compounds cross the placenta, are found in the umbilical cord blood, and can cause neurodevelopmental abnormalities in the offspring of the exposed mothers, including early pregnancy loss, low birth weight, hyperactivity, decreased head circumference and behavior problems. However, the molecular mechanisms following PFAS exposure, such as dysregulated genes and pathways, especially in the context of human brain development, remain unexplored. Here, we are proposing to use human induced pluripotent stem cell (iPSC) derived models such as neural progenitor cells (NPCs), spheroids and brain cortical organoids, to fill in this knowledge gap. We hypothesize that PFAS impact early brain development by dysregulating transcriptional programs of NPCs that are involved in proliferation, cell cycle and survival. We also hypothesize that these early alterations will have significant impact on the formation of cortical networks. We are proposing the following Specific Aims to test these hypotheses: (1) Investigate dose- dependent impact of PFAS on neural progenitor cell cycle, cell viability and proliferation; (2) Perform genome- wide pooled genetic screens with CRISPRi/a sgRNA libraries to identify modifier genes and pathways upon PFAS treatment; (3) Validate the impact of PFAS on long-term neurodevelopment in cortical organoids models and identify cell populations impacted by PFAS. Our study will identify genes, molecular and cellular pathways dysregulated by PFAS exposure across various stages of brain development, modeled in vitro. It has a potential to uncover new mechanisms behind PFAS exposure, and to predict the impact of PFAS on developing human brain network function.

概括全氟烷基和多氟烷基物质及其衍生物 (PFAS) 是用途广泛的工业化学品。在环境中传播，包括野生动物和人类的血清。它们的普遍性和长半衰期提出了有关其毒性的问题，特别是对发育中胎儿的影响。一些研究表明，这些化合物可以穿过胎盘，存在于脐带血中，并且可能会导致接触过的母亲的后代出现神经发育异常，包括早孕损失、低出生体重、多动症、头围减小和行为问题。然而， PFAS 暴露后的分子机制，例如失调的基因和通路，尤其是在人类大脑发育的背景仍未被探索。在这里，我们建议使用人类诱导多能干细胞 (iPSC) 衍生模型，例如神经祖细胞 (NPC)、球体和脑皮质类器官，以填补这一知识空白。我们假设 PFAS 通过以下方式影响早期大脑发育：与增殖、细胞周期和存活相关的 NPC 转录程序失调。我们还假设这些早期的改变将对皮质的形成产生重大影响。网络。我们提出以下具体目标来检验这些假设：（1）研究剂量- PFAS 对神经祖细胞周期、细胞活力和增殖的依赖性影响； (2) 进行基因组- 使用 CRISPRi/a sgRNA 文库进行广泛的遗传筛选，以识别修饰基因和通路 PFAS处理； (3) 在皮质类器官模型中验证PFAS对长期神经发育的影响并确定受 PFAS 影响的细胞群。我们的研究将确定基因、分子和细胞途径在体外模型中，大脑发育各个阶段的 PFAS 暴露导致失调。它有潜力揭示 PFAS 暴露背后的新机制，并预测 PFAS 对人类发育的影响脑网络功能。