Polybrominated Diphenyl Ethers Induce Developmental Neurotoxicity in a Human in Vitro Model: Evidence for Endocrine Disruption

Abstract

BackgroundPolybrominated diphenyl ethers (PBDEs) are persistent and bioaccumulative flame retardants, which are found in rising concentrations in human tissues. They are of concern for human health because animal studies have shown that they possess the potential to be developmentally neurotoxic.ObjectiveBecause there is little knowledge of the effects of PBDEs on human brain cells, we investigated their toxic potential for human neural development in vitro. Moreover, we studied the involvement of thyroid hormone (TH) disruption in the effects caused by PBDEs.MethodsWe used the two PBDE congeners BDE-47 and BDE-99 (0.1–10 μM), which are most prominent in human tissues. As a model of neural development, we employed primary fetal human neural progenitor cells (hNPCs), which are cultured as neurospheres and mimic basic processes of brain development in vitro: proliferation, migration, and differentiation.ResultsPBDEs do not disturb hNPC proliferation but decrease migration distance of hNPCs. Moreover, they cause a reduction of differentiation into neurons and oligodendrocytes. Simultaneous exposure with the TH receptor (THR) agonist triiodothyronine rescues these effects on migration and differentiation, whereas the THR antagonist NH-3 does not exert an additive effect.ConclusionPBDEs disturb development of hNPCs in vitro via endocrine disruption of cellular TH signaling at concentrations that might be of relevance for human exposure.

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

“…Cytotoxicity as measured by MTT reduction was detected in the neuroblastoma cell line SK-N-MC (Tagliaferri et al, 2010) and the human astrocytoma cell line (132-1N1) (Madia et al, 2004). In addition, alterations in neural migration/differentiation of human neural progenitor cells (Schreiber et al, 2010) and modulations of calcium uptake determined in rat mitochondria (Coburn et al, 2008) have been reported. Large-scale proteomic analyses with non-toxic and cytotoxic concentrations showed that BDE-99 alters the expression of cytoskeletal proteins already at low concentrations in cerebellar cortical cells isolated from rat fetuses on GD21 (Sprague-Dawley rats).…”

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology

“…they may then, e.g., be used for electrophysiological studies or to follow differentiation during radial migration on a laminin-coated surface (Moors et al, 2007(Moors et al, , 2009van Vliet et al, 2007). It is noteworthy that despite differentiation onto a surface, this manner of differentiation differs from simple 2D single cell plating because there is glial cell guidance with neuronal growth on top in a processorganized manner out of an organoid cell system (Ahlenius and Kokaia, 2010;Bal-Price et al, 2012;liu and Sun, 2011;Schreiber et al, 2010). this phenomenon can be seen in the organized process of cell migration, which can also be quantified in such a system (Moors et al, 2007(Moors et al, , 2009.…”

Advancing the science of developmental neurotoxicity (DNT): testing for better safety evaluation

“…Mouse neural progenitor cells (mNPCs) can be prepared from embryonic or postnatal mouse pup brains of different ages. Such progenitors grow as neurospheres, develop in vitro, and are especially valuable as a source of genetically manipulated primary cells (Gassmann et al, 2010). Human cell systems are recommended as the most relevant in the context of the 21 st century approach in toxicity testing: getting a better prediction of human toxicity by using human in vitro models (NRC 2007).…”