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

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.

Decabromodiphenyl ether-induced PRKACA hypermethylation contributed to glycolipid metabolism disorder via regulating PKA/AMPK pathway in rat and L-02 cells.

BDE-209 is the most prevalent congener of polybrominated diphenyl ethers and has high bioaccumulation in humans and animals. BDE-209 has been reported to disrupt glycolipid metabolism, but the mechanisms are still unclear. In this study, we found that BDE-209 induced liver tissue injury and hepatotoxicity, increased the glucose and total cholesterol levels in the serum of rats, and increased glucose and triglyceride levels in L-02 cells. BDE-209 exposure changed the PKA, p-PKA, AMPK, p-AMPK, ACC, and FAS expression in rats' liver and L-02 cells. Moreover, BDE-209 induced PRKACA-1 hypermethylation in L-02 cells. AMPK activator (AICAR) inhibited the changes of p-AMPK, ACC, and FAS expression and elevation of glucose and triglyceride levels induced by BDE-209. DNA methylation inhibitor (5-Aza-CdR) reversed BDE-209 induced alters of PKA/AMPK/ACC/FAS signaling pathway. These results demonstrated that BDE-209 could disrupt the glycolipid metabolism by causing PRKACA-1 hypermethylation to regulate the PKA/AMPK signaling pathway in hepatocytes.

Decabromodiphenyl ether induces male reproductive toxicity by activating mitochondrial apoptotic pathway through glycolipid metabolism dysbiosis.

Decabromodiphenyl ether (BDE-209), an extensively used flame retardant, exists widely in the environment. Although male reproductive toxicity induced by BDE-209 has been reported, its mechanisms remain unclear. To explore the role of glycolipid metabolism in male reproductive toxicity and the potential mechanisms, forty male SD rats were divided into four groups and given gavage with BDE-209 at 0, 5, 50, and 500 mg/kg/d for 28 days. In vitro, the spermatogenic cell lines GC-2spd cells were divided into four groups: the control group, 32 µg/mL BDE-209 group, 32 µg/mL BDE-209 + 0.4 µM Fatostatin (the inhibitor of SREBP-1) group, and 0.4 µM Fatostatin group. Our results showed that BDE-209 decreased sperm quality and quantity, which was correlated with glycolipid metabolism dysbiosis of testis. The levels of glucose, triglyceride, and total cholesterol were negatively correlated with sperm concentration, and triglyceride and total cholesterol levels were negatively correlated with sperm motility, while positively correlated with the sperm malformation rate. Moreover, BDE-209 exposure activated the glycolipid metabolism pathways (PPARγ/RXRα/SCAP/SREBP-1) and mitochondrial apoptotic pathway, thereby inducing the apoptosis of spermatogenic cells. In vitro, BDE-209 caused triglyceride and total cholesterol disorder and apoptosis of GC-2spd cells, the lipid metabolism pathways inhibitor fatostain downregulated the elevation of triglyceride and total cholesterol concentrations, and suppressed apoptosis and the activation of the mitochondrial apoptotic pathway in GC-2spd cells caused by BDE-209. Our results indicated that BDE-209 induced male reproductive toxicity by causing glycolipid metabolism dysbiosis of testis resulting in activating of the mitochondrial apoptotic pathway in spermatogenic cells. The study provides new insight into the mechanisms of male reproductive toxicity caused by BDE-209.

Decabromodiphenyl ether disturbs hepatic glycolipid metabolism by regulating the PI3K/AKT/GLUT4 and mTOR/PPARγ/RXRα pathway in mice and L02 cells.

Decabromodiphenyl ether (BDE-209) is a persistent environmental pollutant that poses great risks to human health and has been associated with glucose and lipid metabolism. However, the mechanisms by which BDE-209 disturbs glycolipid metabolism in the liver remain unclear. Therefore, this study sought to confirm the effects of BDE-209 on glycolipid metabolism in mice livers and L02 cells to elucidate potential mechanisms of action. In vivo BDE-209 exposure caused histological damage and lipid accumulation, elevated glucose, low-density lipoprotein, total cholesterol, and triglyceride levels, and decreased glycogen and high-density lipoprotein levels in mice livers. Moreover, in vitro BDE-209 exposure not only induced L02 cells cytotoxicity (i.e., reduced cell viability and increased LDH leakage and ROS generation) but also increased glucose and triglyceride concentrations in L02 cells. Furthermore, IGF-1, an activator of the PI3K-AKT pathway, markedly inhibited BDE-209-induced glucose concentration increase in L02 cells and antagonized the inhibitory effect of BDE-209 on the PI3K/AKT/GLUT4 pathway by counteracting the changes in the expression levels of p-IRS, AKT, PI3K, p-AKT, and GLUT4. Moreover, GW9662, a PPARγ inhibitor, blocked lipid accumulation and the upregulation of the mTOR/PPARγ/RXRα pathway in L02 cells induced by BDE-209 by relieving the increases in p-mTOR, PPARγ, and RXRα protein expression levels. In summary, this study revealed that BDE-209 disrupted glycolipid metabolism by inhibiting the PI3K/AKT/GLUT4 pathway and activating the mTOR/PPARγ/RXRα pathway.

Silica nanoparticles induce spermatogenesis disorders via L3MBTL2-DNA damage-p53 apoptosis and RNF8-ubH2A/ubH2B pathway in mice.

Silica nanoparticles (SiNPs) can reduce both quality and quantity of sperm via inhibiting the progress of meiosis and mitosis and inducing apoptosis of spermatogenic cells, however, their specific mechanism and effects on the later stage of spermatogenesis are still unclear. To investigate the effects of SiNPs on the reproductive system, male mice were treated with SiNPs (0, 1.25, 5 and 20 mg/kg.bw) via intratracheal instillation once every 3 days and for a total of 15 days. Results revealed that exposure to SiNPs induced reduction in the rate of sperm activity, histological abnormalities in seminiferous epithelium as well as apoptosis of spermatogenic cells, which are associated with decreased level of Lethal (3) malignant brain tumor like 2 (L3MBTL2) and activation of DNA damage-p53-mitochondrial apoptosis pathways. Moreover, reduction in L3MBTL2 level caused by SiNPs also led to the lower expression of RNF8-ubH2A/ubH2B pathway, thus resulting in incomplete histone-to-protamine exchange. These results suggest that the inhibition of L3MBTL2 expression caused by SiNPs not only activates DNA damage-p53-mitochondrial apoptosis pathway leading to the apoptosis of spermatogenic cells, but also inhibits RNF8-ubH2A/ubH2B pathway resulting in incomplete histone-to-protamine exchange, thereby affected spermatogenesis. This indicates that L3MBTL2 plays an important role in reproductive toxicity of males caused by SiNPs.