BDE-99 deregulates BDNF, Bcl-2 and the mRNA expression of thyroid receptor isoforms in rat cerebellar granular neurons.
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.
Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira i Virgili, Sant Llorens 21, 43201 Reus, Spain.
Jordi
J
Blanco
Miquel
M
Mulero
Marta
M
López
José L
JL
Domingo
Domènec J
DJ
Sánchez
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006980:Hyperthyroidism / Q000139:chemically induced / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000187:drug effects / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014284:Triiodothyronine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C477694:2,2',4,4',5-brominated diphenyl ether; D019208:Brain-Derived Neurotrophic Factor; D055768:Halogenated Diphenyl Ethers; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine