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other·preclinical research, biomedical research, neurology, research methods·PMC10472293

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 · 9 authors, 8 centres

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It found that BPA reduced spheroid size and altered key proteins involved in proliferation and signaling, without changing cell viability or differentiation markers.

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However, it significantly reduced spheroid size at day 21, indicating inhibited proliferation. Proteomic analysis revealed decreased levels of proteins critical for neural stem cell proliferation and development, including Wnt-8b, GAP43, TPPP3, and GPC4, across all treatment groups. The study concludes that BPA exerts inhibitory effects on neural stem cell proliferation through molecular perturbations, such as disruption of the Wnt signaling pathway, without affecting initial differentiation.

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preclinical research

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ORIGINAL PAPER

PMC10472293

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

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ABSTRACT

Abstract 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. Keywords: bisphenol A, neural stem cells, human induced pluripotent stem cells, DOHaD, new approach methodology

CITATION EXPORT

Alex Horánszky, Bachuki Shashikadze, Radwa Elkhateib et al.. 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. (2023). https://doi.org/10.3389/fcell.2023.1236243

AUTHORS

9 · 8 CENTRES

Alex Horánszky, Bachuki Shashikadze, Radwa Elkhateib, Salvo Danilo Lombardo, Federica Lamberto, Melinda Zana, Jörg Menche, Thomas Fröhlich, András Dinnyés

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