An autophagic process is activated in HepG2 cells to mediate BDE-100-induced toxicity

Pereira, Lílian Cristina; Duarte, Filipe V.; Varela, Ana; Rolo, Anabela P.; Palmeira, Carlos M.; Dorta, Daniel Junqueira

doi:10.1016/j.tox.2016.05.022

Cited by 21 publications

(6 citation statements)

References 62 publications

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“…However, the studies on the roles of autophagy in PBDEs toxicity are still lacking. Limited studies reported that both PBDE-100 and PBDE-153 treatment resulted in accumulation of autophagosomes involved in HepG2 cells injury 35, 36. In the present study, PBDE-47 triggered autophagosomes accumulation identified by the increased double-membrane autophagosome vesicles, LC3-positive puncta and levels of LC3-II both in vivo and in vitro .…”

Section: Discussionsupporting

confidence: 55%

“…More importantly, inhibition of autophagy by 3-MA also diminished PBDE-209-induced apoptosis in primary hippocampal neurons 40, supporting our findings and suggesting that targeting inhibition of autophagy may be a promising therapeutic target for the prevention and treatment of PBDEs neurotoxicity. Interestingly, some other studies also showed that apoptosis was enhanced upon inhibition of autophagy with WM in HepG2 cells following PBDE-100 or PBDE-153 treatment 35, 36, perhaps due to differences in the cell-type specificity and congener structure.…”

Section: Discussionmentioning

confidence: 97%

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Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis

Dong

et al. 2019

Theranostics

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Apoptosis is involved in 2,2',4,4'- tetrabromodiphenyl ether (PBDE-47)-induced developmental neurotoxicity. However, little is known about the role of autophagy, especially its relationship with apoptosis underlying such neurotoxic process. Methods : Using female Sprague-Dawley rats exposed to low-dose PBDE-47 (0.1, 1.0 and 10 mg/kg/day) from pre-pregnancy until weaning of offspring to mimic human exposure, we investigated the effects of PBDE-47 on autophagy and apoptosis in relation to cognitive impairment of adult offspring rats. We also evaluated relationship between autophagy and apoptosis using neuroendocrine pheochromocytoma (PC12) cells, a widely used neuron-like cell line for neuronal development. Results : In vivo , perinatal exposure to PBDE-47 induced memory deficits in adult rats. This is accompanied by hippocampal neuronal loss partly as a result of apoptosis, as evidenced by caspase-3 activation and PARP cleavage. Further study identified that PBDE-47 triggered autophagic vesicles accumulation, increased levels of microtubule-associated protein 1 light chain 3 (LC3)-II, an essential protein for autophagosomes formation, and autophagy substrate sequestosome 1 (SQSTM1/p62), but reduced levels of autophagy-related protein (ATG) 7, a key protein for autophagosomes elongation, suggestive of autophagy impairment. These findings were further demonstrated by an in vitro model of PBDE-47-treated PC12 cells. Mechanistically, autophagy alteration is more sensitive to PBDE-47 treatment than apoptosis induction. Importantly, while stimulation of autophagy by the chemical inducer rapamycin and adenovirus-mediated Atg7 overexpression aggravated PBDE-47-induced apoptosis and cell death, inhibition of autophagy by the chemical inhibitor wortmannin and siRNA knockdown of Atg7 reversed PBDE-47-produced detrimental outcomes. Interestingly, blockage of apoptosis by caspase-3 inhibitor Ac-DEVD-CHO ameliorated PBDE-47-exerted autophagy impairment and cell death, though in combination with autophagy inhibitor did not further promote cell survival. Conclusion : Our data suggest that autophagy impairment facilitates apoptosis, which, in turn, disrupts autophagy, ultimately resulting in cell death, and that autophagy may act as a promising therapeutic target for PBDE-47-induced developmental neurotoxicity.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 97%

Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis

Dong

et al. 2019

Theranostics

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“…Following BDE-100 exposure, HepG2 cells had increased staining with lysosomal dye. The study also noted that the mitochondrial DNA copy number decreased in these cells, signifying an attempt from the cell to manage mitochondrial damage by selective mitophagy [83].…”

Section: Discussionmentioning

confidence: 84%

Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism

Zhang

Kelly

et al. 2020

PLoS ONE

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Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are humanderived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpharetinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.

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“…This is consistent with a recent study using a BDE‐100, another brominated flame retardant, which also caused autophagy in HepG2 cells. [ 24 ] It is also known that rises in intracellular Ca 2+ levels, as demonstrated for HBCD in our previous studies, [ 6,14,19 ] can activate Calmodulin‐dependent protein kinase kinase‐β (CamKKβ) which is an upstream kinase for AMP‐activated protein kinase, a key activator of autophagy. [ 25 ] This Ca 2+ ‐dependent process could therefore be the mechanism by which autophagy is activated by HBCD.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of cell death induced by hexabromocyclododecane (HBCD) involves apoptosis, autophagy, and ER stress

Mohammed

Lewis

Hodges

et al. 2023

J Biochem & Molecular Tox

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Hexabromocyclododecane (HBCD), was a widely utilized brominated flame retardant, commonly found in a wide range of household products. The pervasiveness of HBCD has identified the presence of this chemical in foods and in human tissues. Therefore, HBCD has been identified as a chemical of concern. The aim was to investigate the degree of cytotoxicity of HBCD in a range of cell lines derived from different tissues, (including hematopoietic, nerve, liver, and kidney‐derived cells) with a view of determining any differential cell type effects. In addition, this study also investigated the mechanism(s) by which HBCD could cause cell death. The results showed that HCBD was considerably more toxic to leukocyte‐derived (RBL2H3) and neuronal‐derived (SHSY‐5Y) cells with LC50 values of 1.5 and 6.1 µM, respectively, compared to cells derived from liver (HepG2) and kidney (Cos‐7), which had LC50 values of 28.5 and 17.5 µM, respectively. A detailed investigation of the mechanism(s) of cell death showed that HBCD caused, at least in part, Ca2+‐dependent cell death, caspase‐activated apoptosis, and autophagy, but there was little evidence for either necrosis or necroptosis occurring. Furthermore, it was shown that HBCD can also induce the ER stress response which is a known trigger of both apoptosis and autophagy and therefore this could be one of the crucial events by which cell death is initiated. As each of these cell death mechanisms was investigated in at least two different cell lines and no differences were identified, it is likely that the mode of action is not cell‐type specific.

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An autophagic process is activated in HepG2 cells to mediate BDE-100-induced toxicity

Cited by 21 publications

References 62 publications

Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis

Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis

Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism

Mechanisms of cell death induced by hexabromocyclododecane (HBCD) involves apoptosis, autophagy, and ER stress

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