2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47) activates Aryl hydrocarbon receptor (AhR) mediated ROS and NLRP3 inflammasome/p38 MAPK pathway inducing necrosis in cochlear hair cells

Tang, Jie; Hu, Bo; Zheng, Huaping; Qian, Xiaolan; Zhang, Yi; Zhu, Jia; Xu, Guangtao; Chen, Deqing; Jin, Xin; Li, Wanlu; Xu, Long

doi:10.1016/j.ecoenv.2021.112423

Cited by 21 publications

(11 citation statements)

References 47 publications

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“…29 BDE-47, a non-dioxin-like chemical, has been discovered to be an agonist of AhR and is associated with zinc regulation and calcium homeostasis in the brain. 30 In this study, treatment with Cd or BDE-47 significantly up-regulated AhR, Hsp90, ARNT, and downstream target genes of CYP1B1, while CYP1A1 was significantly down-regulated, and co-exposure enhanced 20 This suggests that BDE-47 may be an AhR activator to induce kidney toxicity. CYPs act as the downstream target genes of AhR pathway and have been reported to catalyze the metabolism of xenobiotics.…”

Section: Gsdme-dependent Pyroptosismentioning

confidence: 50%

“…The half maximal inhibitory concentration (IC 50 ) of Cd (11.40 μM) and BDE‐47 (75.02 μM) was determined based on 30% inhibition rate. The selected concentrations of Cd (5 μM) and BDE‐47 (50 μM) were below the maximum dose of Cd established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2010, 25 and BDE‐47 was within environment‐relevant levels as previously described 20 …”

Section: Methodsmentioning

confidence: 99%

“…The selected concentrations of Cd (5 μM) and BDE-47 (50 μM) were below the maximum dose of Cd established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2010, 25 and BDE-47 was within environment-relevant levels as previously described. 20…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…We have previously discovered that BDE‐47 induces ROS, leading to necrosis in auditory epithelial cells 20 . Recent studies have shown that increased ROS production is involved not only in apoptosis or necrosis but also pyroptosis, an emerging programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously discovered that BDE-47 induces ROS, leading to necrosis in auditory epithelial cells. 20 Recent studies have shown that increased ROS production is involved not only in apoptosis or necrosis but also pyroptosis, an emerging programmed cell death. Pyroptosis is defined as a gasdermin-dependent pathway that is activated by caspase-1-mediated inflammasome in response to certain bacterial insults.…”

mentioning

confidence: 99%

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2,2′,4,4′‐Tetrabromodiphenyl ether and cadmium co‐exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME‐dependent pyroptosis in renal tubular epithelial cells

Sheng,

Zhang,

Cai

et al. 2023

Environmental Toxicology

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We have previously found that a mixture exposure of 2,2′,4,4′‐tetrabromodiphenyl ether (BDE‐47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand–receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE‐47 (50 μM) or Cd (5 μM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co‐treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N‐acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved‐caspase‐3 and gasdermin E N‐terminal (GSDME‐NT), while caspase‐8, caspase‐3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE‐47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME‐dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.

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Section: Gsdme-dependent Pyroptosismentioning

confidence: 50%

Section: Methodsmentioning

confidence: 99%

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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2,2′,4,4′‐Tetrabromodiphenyl ether and cadmium co‐exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME‐dependent pyroptosis in renal tubular epithelial cells

Sheng,

Zhang,

Cai

et al. 2023

Environmental Toxicology

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Miniaturized method for the quantification of persistent organic pollutants and their metabolites in HepG2 cells: assessment of their biotransformation

Oro‐Carretero

Sanz‐Landaluze

2023

Anal Bioanal Chem

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Biotransformation can greatly influence the accumulation and, subsequently, toxicity of substances in living beings. Although traditionally these studies to quantify metabolization of a compound have been carried out with in vivo species, currently, in vitro test methods with very different cell lines are being developed for their evaluation. However, this is still a very limited field due to multiple variables of a very diverse nature. So, an increasing number of analytical chemists are working with cells or other similar biological samples of very small size. This makes it necessary to address the development of analytical methods that allow determining their concentration both inside the cells and in their exposure medium. The aim of this study is to develop a set of analytical methodologies for the quantification of polycyclic aromatic hydrocarbons, PAHs (phenanthrene, PHE), and polybrominated diphenyl ethers, PBDEs (2,2′,4,4′-tetrabromodiphenyl ether, BDE-47), and their major metabolites in cells and their exposure medium. Analytical methodologies, based on miniaturized ultrasound probe-assisted extraction, gas chromatography–mass spectrometry–microelectron capture detector (GC–MS-µECD), and liquid chromatography–fluorescence detector (LC-FL) determination techniques, have been optimized and then applied to a biotransformation study in HepG2 at 48 h of exposure. Significant concentrations of the major metabolites of PHE (1-OH, 2-OH, 3-OH, 4-OH-, and 9-OH-PHE) and BDE-47 (5-MeO-, 5-OH-, and 3-OH-BDE-47) were detected and quantified inside the cells and in the exposure medium. These results provide a new method for determination and improve information on the metabolization ratios for a better knowledge of the metabolic pathways and their toxicity. Graphical abstract

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Aryl hydrocarbon receptor: From pathogenesis to therapeutic targets in aging-related tissue fibrosis

Yang

Wang²,

Hua³

et al. 2022

Ageing Research Reviews

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2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47) activates Aryl hydrocarbon receptor (AhR) mediated ROS and NLRP3 inflammasome/p38 MAPK pathway inducing necrosis in cochlear hair cells

Cited by 21 publications

References 47 publications

2,2′,4,4′‐Tetrabromodiphenyl ether and cadmium co‐exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME‐dependent pyroptosis in renal tubular epithelial cells

2,2′,4,4′‐Tetrabromodiphenyl ether and cadmium co‐exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME‐dependent pyroptosis in renal tubular epithelial cells

Miniaturized method for the quantification of persistent organic pollutants and their metabolites in HepG2 cells: assessment of their biotransformation

Aryl hydrocarbon receptor: From pathogenesis to therapeutic targets in aging-related tissue fibrosis

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