RGD Reference Report - Fat mass and obesity-associated gene (FTO) hypermethylation induced by decabromodiphenyl ethane causing cardiac dysfunction via glucolipid metabolism disorder. - Rat Genome Database

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Fat mass and obesity-associated gene (FTO) hypermethylation induced by decabromodiphenyl ethane causing cardiac dysfunction via glucolipid metabolism disorder.

Authors: Gao, Leqiang  Zhang, Yue  Liu, Jianhui  Li, Xiangyang  Sang, Yujian  Zhou, Guiqing  Xue, Jinglong  Jing, Li  Shi, Zhixiong  Wei, Jialiu  Lu, Xiangfeng  Zhou, Xianqing 
Citation: Gao L, etal., Ecotoxicol Environ Saf. 2022 Jun 1;237:113534. doi: 10.1016/j.ecoenv.2022.113534. Epub 2022 Apr 21.
RGD ID: 329951017
Pubmed: PMID:35462195   (View Abstract at PubMed)
DOI: DOI:10.1016/j.ecoenv.2022.113534   (Journal Full-text)

Decabromodiphenyl ethane (DBDPE) is a major alternative to BDE-209 owing to its lower toxicity. However, the mass production and increased consumption of DBDPE in recent years have raised concerns related to its adverse health effects. However, the effect and mechanism of DBDPE on cardiotoxicity have rarely been studied. In the present study, we investigated the impacts of DBDPE on the cardiovascular system in male SD rats and then explored the underlying mechanisms to explain the cardiotoxicity of DBDPE using AC16 cells. Under in vivo conditions, male rats were administered with an oral dosage of DBDPE at 0, 5, 50, and 500 mg/kg/day for 28 days, respectively. Histopathological analysis demonstrated that DBDPE induced cardiomyocyte injury and fibrosis, and ultrastructural observation revealed that DBDPE could induce mitochondria damage and dissolution. DBDPE could thus decrease the level of MYH6 and increase the level of SERCA2, which are the two key proteins involved in the maintenance of homeostasis during myocardial contractile and diastolic processes. Furthermore, DBDPE could increase the serum levels of glucose and low-density lipoprotein but decrease the content of high-density lipoprotein. In addition, DBDPE could activate the PI3K/AKT/GLUT2 and PPARγ/RXRα signaling pathways in AC16 cells. In addition, DBDPE decreased the UCP2 level and ATP synthesis in mitochondria both under in vitro and in vivo conditions, consequently leading to apoptosis via the Cytochrome C/Caspase-9/Caspase-3 pathway. Bisulfite sequencing PCR (BSP) identified the hypermethylation status of fat mass and obesity-associated gene (FTO). 5-aza exerted the opposite effects on the PI3K/AKT/GLUT2, PPARγ/RXRα, and Cytochrome C/Caspase-9/Caspase-3 signaling pathways induced by DBDPE in AC16 cells. In addition, the DBDPE-treated altered levels of UCP2, ATP, and apoptosis were also found to be significantly reversed by 5-aza in AC16 cells. These results suggested that FTO hypermethylation played a regulative role in the pathological process of DBDPE-induced glycolipid metabolism disorder, thereby contributing to the dysfunction of myocardial contraction and relaxation through cardiomyocytes fibrosis and apoptosis via the mitochondrial-mediated apoptotic pathway resulting from mitochondrial dysfunction.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FTOHumanCardiotoxicity  ISOFto (Rattus norvegicus)DNA:hypermethylation:promoterRGD 
FtoRatCardiotoxicity  IDA DNA:hypermethylation:promoterRGD 
FtoMouseCardiotoxicity  ISOFto (Rattus norvegicus)DNA:hypermethylation:promoterRGD 

Objects Annotated

Genes (Rattus norvegicus)
Fto  (FTO, alpha-ketoglutarate dependent dioxygenase)

Genes (Mus musculus)
Fto  (FTO alpha-ketoglutarate dependent dioxygenase)

Genes (Homo sapiens)
FTO  (FTO alpha-ketoglutarate dependent dioxygenase)


Additional Information