Polychlorinated Biphenyls Disturb Differentiation of Normal Human Neural Progenitor Cells: Clue for Involvement of Thyroid Hormone Receptors

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitous environmental chemicals that accumulate in adipose tissues over the food chain. Epidemiologic studies have indicated that PCBs influence brain development. Children who are exposed to PCBs during development suffer from neuropsychologic deficits such as a lower full-scale IQ (intelligence quotient), reduced visual recognition memory, and attention and motor deficits. The mechanisms leading to these effects are not fully understood. It has been speculated that PCBs may affect brain development by interfering with thyroid hormone (TH) signaling. Because most of the data are from animal studies, we established a model using primary normal human neural progenitor (NHNP) cells to determine if PCBs interfere with TH-dependent neural differentiation. NHNP cells differentiate into neurons, astrocytes, and oligodendrocytes in culture, and they express a variety of drug metabolism enzymes and nuclear receptors. Like triiodothyronine (T3), treatment with the mono-ortho-substituted PCB-118 (2,3′,4,4′,5-pentachlorobiphenyl; 0.01–1 μM) leads to a dose-dependent increase of oligodendrocyte formation. This effect was congener specific, because the coplanar PCB-126 (3,3′,4,4′,5-pentachlorobiphenyl) had no effect. Similar to the T3 response, the PCB-mediated effect on oligodendrocyte formation was blocked by retinoic acid and the thyroid hormone receptor antagonist NH-3. These results suggest that PCB-118 mimics T3 action via the TH pathway.

Actions of endocrine-disrupting chemicals on stem/progenitor cells during development and disease

“…In contrast, PBC-126 was ineffective in promoting oligodendrocyte differentiation. Thus, these observations implied that PCB-118 mimicked T 3 action via the TH pathway (Fritsche et al 2005). The activity of TH receptor (TR) can be inhibited by exposure to flame retardants (FRs).…”

“…Normal human neural progenitor (NHNP) cells were used to determine whether the polychlorinated biphenyl (PCB) compounds 2,3 0 ,4,4 0 ,5-pentachlorobiphenyl (PCB-118) and 3,3 0 ,4,4 0 ,5-pentachlorobiphenyl (PCB-126) interfered with TH-dependent neural differentiation (Fritsche et al 2005). The three-dimensional neurosphere assay was used to evaluate PCB-118, PCB-126, and tri-iodothyronine (T 3 ) activity.…”

“…The aryl hydrocarbon receptor (AhR) agonist BAP did not induce oligodendrite formation in NHNPderived neurospheres, implying that AhR signaling did not disrupt neural differentiation (Fritsche et al 2005). However, in human cord blood hematopoietic stem cells (hUCBSCs), exposure to the polycyclic aromatic hydrocarbon 3-methylcholanthrene (MC) upregulated AhR expression and signaling while downregulating the expression of the neurogenesis-related transcription factor, cAMP response element-binding protein (CREB; Fritsche et al 2005).…”

“…However, in human cord blood hematopoietic stem cells (hUCBSCs), exposure to the polycyclic aromatic hydrocarbon 3-methylcholanthrene (MC) upregulated AhR expression and signaling while downregulating the expression of the neurogenesis-related transcription factor, cAMP response element-binding protein (CREB; Fritsche et al 2005). Consequently, expression of stagespecific neuronal markers including nestin, neural cell adhesion molecule (NCAM), synaptophysin (SYP), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA), and N-methyl-D-aspartate receptor subunit 2A (NR2A) were downregulated.…”

Acrylamide alters neurotransmitter induced calcium responses in murine ESC-derived and primary neurons

“…Different cell systems are already used to investigate the differentiation and maturation of neurons, and possible factors disturbing these processes, for example neurotoxins (e.g. Fritsche et al, 2005;Gassmann et al, 2010;Huang and Schneider, 2004;Tamm et al, 2006;Tateno et al, 2004;Zimmer et al, 2011Zimmer et al, , 2012. Up to now, these cell systems have hardly been used to analyze toxic effects on fully differentiated neurons, yet (Visan et al, 2012;Zeng et al, 2006); especially not, when toxins affect neuronal function.…”