Application of the adverse outcome pathway to identify molecular changes in prenatal brain programming induced by
Britta Anna Kühne1, Elisabet Teixidó2, Miren Ettcheto3
1Grup de Recerca en Toxicologia (GRET) i INSA-UB, Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, 08028, Barcelona, Spain; BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Fetal i+D Fetal Medicine Research Center, IDIBAPS, University of Barcelona, Center for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.
Abstract:
Following a multi-disciplinary approach integrating information from several experimental models we have collected new evidence supporting, expanding and redesigning the AOP "Disrupted laminin/int-β1 interaction leading to decreased cognitive function". Investigations in vitro in rabbit and rat neurospheres and in vivo in mice exposed to EGCG (epigallocatechin-gallate) during neurodevelopment are combined with in vitro evaluations in neural progenitor cells overexpressing int-β1 and literature information from int-β1 deficiency models. We have discovered for the first time that neural progenitor cells from intrauterine growth restricted (IUGR) animals overexpress int-β1 at gene and protein level and due to this change in prenatal brain programming they respond differently than control neurospheres to the exposure of EGCG, a compound triggering neural progenitor cell migration alterations. We have also identified that EGCG developmental exposure has deleterious effects on neuronal branching and arborization in vitro and in vivo. Our results warn that a thorough developmental neurotoxicity characterization of this and other catechin-based food supplements is needed before recommending their consumption during pregnancy.
Insights
Epigallocatechin-gallate (EGCG) exposure during development alters neural progenitor cell migration and neuronal branching. This highlights potential developmental neurotoxicity risks of EGCG, particularly for pregnancies affected by intrauterine growth restriction (IUGR).
Area of Science:
- Developmental neurobiology
- Toxicology
- Molecular neuroscience
Background:
- The Adverse Outcome Pathway (AOP)
- Disrupted laminin/int-β1 interaction leading to decreased cognitive function
- requires further investigation across multiple models.
- Intrauterine growth restriction (IUGR) is associated with altered prenatal brain programming.
Purpose of the Study:
- To investigate the effects of epigallocatechin-gallate (EGCG) on neurodevelopment.
- To explore the role of int-β1 in EGCG's neurodevelopmental effects.
- To evaluate the safety of EGCG consumption during pregnancy.
Main Methods:
- In vitro studies using rabbit and rat neurospheres.
- In vivo studies in mice exposed to EGCG.
- In vitro evaluation of neural progenitor cells overexpressing int-β1.
- Analysis of literature data from int-β1 deficiency models.
Main Results:
- Neural progenitor cells from IUGR animals overexpress int-β1.
- IUGR-derived cells show altered responses to EGCG exposure.
- EGCG exposure during development impairs neuronal branching and arborization in vitro and in vivo.
Conclusions:
- EGCG developmental exposure poses potential neurotoxic risks.
- Altered int-β1 expression in IUGR influences neural progenitor cell response to EGCG.
- Further developmental neurotoxicity studies are crucial for catechin-based supplements during pregnancy.
