RESUMEN

Decabromodiphenyl ether (BDE209), the homologue with the highest number of brominates in polybrominated diphenyl ethers (PBDEs), is one of the most widespread environmental persistent organic pollutants (POPs) due to its mass production and extensive application in recent decades. BDE209 is neurotoxic, possibly related to its interference with the thyroid hormone (TH) system. However, the underlying molecular mechanisms of BDE209-induced TH interference and neurobehavioral disorders remains unknown. Here, we explored how BDE209 manipulated the major enzyme, human type II iodothyronine deiodinase (Dio2), that is most important in regulating local cerebral TH equilibrium by neuroglial cells, using an in vitro model of human glioma H4 cells. Clonogenic cell survival assay and LC/MS/MS analysis showed that BDE209 could induce chronic neurotoxicity by inducing TH interference. Co-IP assay, RT-qPCR and confocal assay identified that BDE209 destroyed the stability of Dio2 without affecting its expression, and promoted its binding to p62, thereby enhancing its autophagic degradation, thus causing TH metabolism disorder and neurotoxicity. Furthermore, molecular docking studies predicted that BDE209 could effectively suppress Dio2 activity by competing with tetraiodothyronine (T4). Collectively, our study demonstrates that BDE209-induced Dio2 degradation and loss of its enzymatic activity in neuroglial cells are the fundamental pathogenic basis for BDE209-mediated cerebral TH disequilibrium and neurotoxicity, providing a target of interest for further investigation using glial/neuronal cell co-culture system and in vivo models.

Asunto(s)

Glioma , Hipotiroidismo , Humanos , Yoduro Peroxidasa/genética , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , Hormonas Tiroideas , Autofagia , Éteres Difenilos Halogenados/química

RESUMEN

BDE47 (2,2,4,4-tetrabromodiphenyl ether) is a member of the most important congeners of polybrominated diphenyl ethers (PBDEs) and has been identified as a developmental, reproductive and nervous system toxicant and endocrine system disruptor due to its frequent detection in human tissue and environmental samples. Our preliminary work suggested that high- and low-level of bromodiphenyl ethers have different effects on neuronal cells with differential targets of actions on neural tissues. In this study, we presented the underlying mechanism of BDE47 neurotoxicity from the perspective of thyroid hormone (TH) metabolism using in vitro model of human SK-N-AS neuronal cells. BDE47 could induce local TH metabolism disorder in neuronal cells by inhibiting the expression of the main enzyme, human type III iodothyronine deiodinase (Dio3). Further elucidation revealed that BDE47 effectively up-regulating miR-24-3p, which binds to the 3'-UTR of Dio3 and inhibits its expression. In addition, BDE47 could also inhibit the deiodinase activity of Dio3. Collectively, our study demonstrates the molecular mechanism of BDE47 regulating Dio3-induced TH metabolism disorder through inducing miR-24-3p, providing new clues for the role of miRNAs in neurodevelopmental toxicity mediated by environmental pollutants.

Asunto(s)

Contaminantes Ambientales , MicroARNs , Humanos , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Hormonas Tiroideas , MicroARNs/genética , MicroARNs/metabolismo , Contaminantes Ambientales/toxicidad , Neuronas/metabolismo , Éteres Difenilos Halogenados/toxicidad , Éteres Difenilos Halogenados/metabolismo

RESUMEN

Smilax china L. (SCL) is extensively used in the treatment of pelvic inflammatory disease (PID). This study aimed to clarify the potential active ingredients of SCL and mechanisms on PID. SCL was widely distributed in Japan, South Korea, and China, which was traditionally considered heat-clearing, detoxicating, and dampness-eliminating medicine. Systems pharmacology revealed that 32 compounds in SCL may interact with 19 targets for immunoenhancement, antiapoptosis, anti-inflammation, and antioxidant activity of the PID model. Molecular docking revealed that isorhamnetin, moracin M, rutin, and oxyresveratrol may have higher binding potential with prostaglandin-endoperoxide synthase 2 (PTGS2), mitogen-activated protein kinase 1 (MAPK1), siderocalin (LCN2), tumor necrosis factor (TNF), and matrix metalloprotein-9 (MMP9), respectively. Molecular dynamics simulation showed that the binding modes of moracin M-MAPK1, rutin-TNF, and oxyresveratrol-MMP9 complexes were more stable, evidenced by relatively smaller fluctuations in root mean square deviation values. Conclusively, SCL may treat PID by inhibiting inflammatory factors, antitissue fibrosis, and microbial growth.