TBBPA targets converging key events of human oligodendrocyte development resulting in two novel AOPs
ALTEX
; 38(2): 215-234, 2021.
Article
em En
| MEDLINE
| ID: mdl-33099281
Myelinating oligodendrocytes (OLs) establish saltatory nerve conduction during white matter development. Thus, interference with oligodendrogenesis leads to an adverse outcome on brain performance in the child due to aberrant myelination. An intertwined network of hormonal, transcriptional and biosynthetic processes regulates OL development, thereby simultaneously creating various routes of interference for environmental toxicants. The flame retardant tetrabromobisphenol A (TBBPA) is debated as an endocrine disruptor, especially of the thyroid hormone (TH) system. We identified how TBBPA interferes with the establishment of a population of maturing OLs by two independent modes-of-action (MoA), dependent and independent of TH signaling. Combining the previously published oligodendrocyte maturation assay (NPC6) with large-scale transcriptomics, we describe TBBPA as a TH disruptor, impairing human OL maturation in vitro by dysregulation of oligodendrogenesis-associated genes (i.e., MBP, KLF9 and EGR1). Furthermore, TBBPA disrupts a gene expression network regulating cholesterol homeostasis, reducing OL numbers independently of TH signaling. These two MoA converge in a novel putative adverse outcome pathway (AOP) network on the key event (KE) hypomyelination. Comparative analyses of human and rat neural progenitor cells (NPCs) revealed that human oligodendrogenesis is more sensitive to endocrine disruption by TBBPA. Therefore, ethical, cost-efficient and species-overarching in vitro assays are needed for developmental neurotoxicity hazard assessment. By incorporation of large-scale transcriptomic analyses, we brought the NPC6 assay to a higher readiness level for future applications in a regulatory context. The combination of phenotypic and transcriptomic analyses helps to study MoA to eventually build AOPs for a better understanding of neurodevelopmental toxicity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bifenil Polibromatos
/
Retardadores de Chama
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ALTEX
Assunto da revista:
MEDICINA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Alemanha