BDE-99 impairs differentiation of human and mouse NPCs into the oligodendroglial lineage by species-specific modes of action

Abstract

Polybrominated diphenyl ethers (PBDEs) are bioaccumulating flame retardants causing developmental neurotoxicity (DNT) in humans and rodents. Their DNT effects are suspected to involve thyroid hormone (TH) signaling disruption. Here, we tested the hypothesis whether disturbance of neural progenitor cell (NPC) differentiation into the oligodendrocyte lineage (O4+ cells) by BDE-99 involves disruption of TH action in human and mouse (h,m)NPCs. Therefore, we quantified differentiation of NPCs into O4+ cells and measured their maturation via expression of myelin-associated genes (hMBP, mMog) in presence and absence of TH and/or BDE-99. T3 promoted O4+ cell differentiation in mouse, but not hNPCs, and induced hMBP/mMog gene expression in both species. BDE-99 reduced generation of human and mouse O4+ cells, but there is no indication for BDE-99 interfering with cellular TH signaling during O4+ cell formation. BDE-99 reduced hMBP expression due to oligodendrocyte reduction, but concentrations that did not affect the number of mouse O4+ cells inhibited TH-induced mMog transcription by a yet unknown mechanism. In addition, ascorbic acid antagonized only the BDE-99-dependent loss of human, not mouse, O4+ cells by a mechanism probably independent of reactive oxygen species. These data point to species-specific modes of action of BDE-99 on h/mNPC development into the oligodendrocyte lineage.

Establishment of an a priori protocol for the implementation and interpretation of an in‐vitro testing battery for the assessment of developmental neurotoxicity

“…These test methods are human cell-based and encompass four different cell systems, i.e. primary human neural progenitor cells (hNPC), neural crest cells (NCC), gene expression analyses indicate a drastic transcriptome change reflecting a multitude of neurodevelopmental processes including cell differentiation (Masjosthusmann et al, 2018) that are underpinned by their phenotypic descriptions: GFAP+ and/or nestin+ radial glia differentiation (and their migration; (Moors et al, 2007(Moors et al, , 2009(Moors et al, , 2012Baumann et al, 2015;Schmuck et al, 2017), neuronal ( (Moors et al, 2009(Moors et al, , 2012Baumann et al, 2015;Schmuck et al, 2017) and oligodendrocyte differentiation ( (Fritsche et al, 2005;Moors et al, 2009;Baumann et al, 2015;Dach et al, 2017). Here, specific gene expression products for radial glia, neurons, astrocytes and oligodendrocytes increase in expression during the early differentiation process (Masjosthusmann et al, 2018).…”

“…Oligodendrocytes differentiate in co-culture with astrocytes and neurons in secondary 3D structures from hNPC within 5 DIV (Dach et al, 2017;Alépée et al, 2014;Moors et al, 2009;Schreiber et al, 2010;Schmuck et al, 2017) into a mixed culture of pre-oligodendrocytes, immature, and non-myelinating, mature oligodendrocytes ( Figure 5). The hNPC oligodendrocyte differentiation and maturation was recently put into an assay format (NPC5; (Dach et al, 2017;Nimtz et al, 2019). DAPI-stained nuclei that co-localize for the epitope O4 after 5 DIV are identified.…”

The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity

“…In humans, maternal hypothyroidism during pregnancy is associated with decreased IQ and diminished performance on tests of fine motor skills, vocabulary, and speech in their children [29]. TH has been shown to affect oligodendrocyte commitment and maturation [30,31], and neuronal commitment [32] during mouse neurogenesis, as well as oligodendrocyte maturation in primary human neuronal precursor cells (NPCs) [31].…”

Thyroid-disrupting chemicals and brain development: an update

“…Using a reporter gene assay, PBDE congeners, including hydroxylated compounds, inhibited TR-mediated transcription at varying concentrations ( 355 , 356 , 357 , 358 , 359 ). The antagonist action of PBDEs on TR is further evident through its effect on purkinje cell dendrite arborisation and neural progenitor cell differentiation into the oligodendrocyte lineage ( 360 , 361 ). In contrast, several hydroxylated PBDEs have been reported to act as agonists on TH-dependent transcription ( 355 ).…”