| Title: |
Gene-Environment Interactions in Developmental Neurotoxicity : a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres |
| Authors: |
Modafferi, Sergio; Zhong, Xiali; Kleensang, Andre; Murata, Yohei; Fagiani, Francesca; Pamies, David; Hogberg, Helena T.; Calabrese, Vittorio; Hartung, Thomas; Smirnova, Lena |
| Source: |
Environmental Health Perspectives. National Institute of Environmental Health Sciences. 2021, 129(7), 077001. ISSN 0091-6765. eISSN 1552-9924. Available under: doi:10.1289/EHP8580 |
| Publication Year: |
2021 |
| Collection: |
University of Konstanz: Konstanz Online Publication Server (KOPS) |
| Subject Terms: |
ddc:570 |
| Description: |
Background: Autism spectrum disorder (ASD) is a major public health concern caused by complex genetic and environmental components. Mechanisms of gene–environment (G×E ) interactions and reliable biomarkers associated with ASD are mostly unknown or controversial. Induced pluripotent stem cells (iPSCs) from patients or with clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9)-introduced mutations in candidate ASD genes provide an opportunity to study (G×E) interactions. Objectives: In this study, we aimed to identify a potential synergy between mutation in the high-risk autism gene encoding chromodomain helicase DNA binding protein 8 (CHD8) and environmental exposure to an organophosphate pesticide (chlorpyrifos; CPF) in an iPSC-derived human three-dimensional (3D) brain model. Methods: This study employed human iPSC-derived 3D brain organoids (BrainSpheres) carrying a heterozygote CRISPR/Cas9-introduced inactivating mutation in CHD8 and exposed to CPF or its oxon-metabolite (CPO). Neural differentiation, viability, oxidative stress, and neurite outgrowth were assessed, and levels of main neurotransmitters and selected metabolites were validated against human data on ASD metabolic derangements. Results: Expression of CHD8 protein was significantly lower in CHD8 heterozygous knockout (CHD8 +/− ) BrainSpheres compared with CHD8 +/+ ones. Exposure to CPF/CPO treatment further reduced CHD8 protein levels, showing the potential (G×E) interaction synergy. A novel approach for validation of the model was chosen: from the literature, we identified a panel of metabolic biomarkers in patients and assessed them by targeted metabolomics in vitro. A synergistic effect was observed on the cholinergic system, S-adenosylmethionine, S-adenosylhomocysteine, lactic acid, tryptophan, kynurenic acid, and α-hydroxyglutaric acid levels. Neurite outgrowth was perturbed by CPF/CPO exposure. Heterozygous knockout of CHD8 in BrainSpheres led to an imbalance of excitatory/inhibitory ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISBN: |
978-1-76300-133-6; 1-76300-133-4 |
| Relation: |
http://dx.doi.org/10.1289/EHP8580 |
| DOI: |
10.1289/EHP8580 |
| Availability: |
http://nbn-resolving.de/urn:nbn:de:bsz:352-2-pg44r1obew6k9; https://doi.org/10.1289/EHP8580 |
| Rights: |
https://rightsstatements.org/page/InC/1.0/ |
| Accession Number: |
edsbas.2C809AD |
| Database: |
BASE |