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Updated: May 28, 2026
A Versatile, Behavioral Method to Investigate Thyroid Hormone Effects on Cerebellar Function
Published on: October 6, 2023
BDE-99 deregulates BDNF, Bcl-2 and the mRNA expression of thyroid receptor isoforms in rat cerebellar granular
Jordi Blanco1, Miquel Mulero, Marta López
1Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira i Virgili, Sant Llorens 21, 43201 Reus, Spain.
Abstract:
Although the disruption of thyroid hormone (TH) signaling can largely explain the neurotoxic effects of polybrominated diphenyl ethers (PBDEs), there are still many unknowns about how this interference occurs. In this study, we expose a primary culture of rat cerebellar granule neurons (CGNs) to a 25μM concentration of one of the most prevalent PBDE congeners in humans, 2,2',4,4',5-pentaBDE (BDE-99). The main goal was to investigate the time course of BDE-99 toxicity in relation to the disruption of thyroid receptor (TR) function over 24h. In a first stage, we found that BDE-99 directly down-regulated the transcription of the isoforms TR-alpha1 and TR-alpha2, which may be a consequence of a hypothetical state that mimics hyperthyroidism. In a later stage, BDE-99 disrupted the expression of triiodothyronine (T3)-responsive genes, possibly as an effect of its metabolism. A down-regulation of the expression of the T3-mediated neurotrophin brain-derived neurotrophic factor (BDNF) and the anti-apoptotic Bcl-2 protein was also observed. Down-regulation of these two proteins was correlated with an increase in the production of reactive oxygen species (ROS). It was also found that expression of the TR-beta1 isoform, which is normally transcriptionally repressed by T3 in CGNs, was up-regulated. This up-regulation could compensate the down-regulation of the TR-alpha1 isoform, and thus slow down cell death. The dually disruptive action of BDE-99 might provide a better understanding of the potentially neurotoxic mechanism of PBDEs.
Insights
Polybrominated diphenyl ethers (PBDEs) like BDE-99 disrupt thyroid hormone (TH) signaling, down-regulating key proteins and increasing oxidative stress in neurons. This dual action may explain PBDE neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Endocrinology
Background:
- Polybrominated diphenyl ethers (PBDEs) are flame retardants with known neurotoxic effects, largely attributed to thyroid hormone (TH) signaling disruption.
- The precise mechanisms by which PBDEs interfere with TH signaling and cause neuronal damage remain incompletely understood.
Purpose of the Study:
- To investigate the time-dependent effects of BDE-99, a prevalent PBDE congener, on thyroid receptor (TR) function and neuronal health in primary rat cerebellar granule neurons (CGNs).
- To elucidate the molecular pathways involved in BDE-99-induced neurotoxicity over a 24-hour exposure period.
Main Methods:
- Primary cultures of rat CGNs were exposed to 25μM BDE-99.
- Transcriptional changes of TR isoforms (TR-alpha1, TR-alpha2, TR-beta1) and T3-responsive genes, including brain-derived neurotrophic factor (BDNF) and Bcl-2, were analyzed.
- Reactive oxygen species (ROS) production was measured to assess oxidative stress.
Main Results:
- BDE-99 exposure led to the down-regulation of TR-alpha1 and TR-alpha2 isoforms, potentially mimicking a hyperthyroid state.
- Later, BDE-99 disrupted the expression of T3-responsive genes, including decreased levels of neurotrophin BDNF and anti-apoptotic Bcl-2.
- Increased ROS production correlated with the down-regulation of BDNF and Bcl-2.
- Expression of the TR-beta1 isoform, typically repressed by T3, was upregulated, possibly as a compensatory mechanism.
Conclusions:
- BDE-99 exerts a dual disruptive action on thyroid hormone signaling pathways in neurons.
- The observed down-regulation of TR-alpha isoforms and T3-responsive genes, coupled with increased oxidative stress, provides insight into PBDE neurotoxicity.
- Upregulation of TR-beta1 may represent a cellular defense mechanism against BDE-99-induced neurotoxicity.
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