Proteomics and disease network associations evaluation of environmentally relevant Bisphenol A concentrations in a human 3D neural stem cell model

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Melinda Zana¹  Alex Horánszky²  Federica Lamberto²  András Dinnyés³  Bachuki Shashikadze⁴  Thomas Fröhlich⁴  Radwa Elkhateib⁴  Salvo Danilo Lombardo⁵  Jörg Menche⁶ 

[1] BioTalentum Ltd., Gödöllő, Hungary;BioTalentum Ltd., Gödöllő, Hungary;Department of Physiology and Animal Health, Institute of Physiology and Animal Nutrition, Hungarian University of Agriculture and Life Sciences, Gödöllő, Hungary;BioTalentum Ltd., Gödöllő, Hungary;Department of Physiology and Animal Health, Institute of Physiology and Animal Nutrition, Hungarian University of Agriculture and Life Sciences, Gödöllő, Hungary;Department of Cell Biology and Molecular Medicine, University of Szeged, Szeged, Hungary;Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Munich, Germany;Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria;Department of Structural and Computational Biology, Center for Molecular Biology, University of Vienna, Vienna, Austria;CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria;Department of Structural and Computational Biology, Center for Molecular Biology, University of Vienna, Vienna, Austria;CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;Faculty of Mathematics, University of Vienna, Vienna, Austria;

关键词: bisphenol A;    neural stem cells;    human induced pluripotent stem cells;    DOHaD;    new approach methodology;   

DOI  :  10.3389/fcell.2023.1236243

 received in 2023-06-07, accepted in 2023-07-31,  发布年份 2023

来源: Frontiers

【 摘 要 】

Bisphenol A (BPA) exposure is associated with a plethora of neurodevelopmental abnormalities and brain disorders. Previous studies have demonstrated BPA-induced perturbations to critical neural stem cell (NSC) characteristics, such as proliferation and differentiation, although the underlying molecular mechanisms remain under debate. The present study evaluated the effects of a repeated-dose exposure of environmentally relevant BPA concentrations during the in vitro 3D neural induction of human induced pluripotent stem cells (hiPSCs), emulating a chronic exposure scenario. Firstly, we demonstrated that our model is suitable for NSC differentiation during the early stages of embryonic brain development. Our morphological image analysis showed that BPA exposure at 0.01, 0.1 and 1 µM decreased the average spheroid size by day 21 (D21) of the neural induction, while no effect on cell viability was detected. No alteration to the rate of the neural induction was observed based on the expression of key neural lineage and neuroectodermal transcripts. Quantitative proteomics at D21 revealed several differentially abundant proteins across all BPA-treated groups with important functions in NSC proliferation and maintenance (e.g., FABP7, GPC4, GAP43, Wnt-8B, TPPP3). Additionally, a network analysis demonstrated alterations to the glycolytic pathway, potentially implicating BPA-induced changes to glycolytic signalling in NSC proliferation impairments, as well as the pathophysiology of brain disorders including intellectual disability, autism spectrum disorders, and amyotrophic lateral sclerosis (ALS). This study enhances the current understanding of BPA-related NSC aberrations based mostly on acute, often high dose exposures of rodent in vivo and in vitro models and human GWAS data in a novel human 3D cell-based model with real-life scenario relevant prolonged and low-level exposures, offering further mechanistic insights into the ramifications of BPA exposure on the developing human brain and consequently, later life neurological disorders.

【 授权许可】

Unknown   
Copyright © 2023 Horánszky, Shashikadze, Elkhateib, Lombardo, Lamberto, Zana, Menche, Fröhlich and Dinnyés.