The cytological effects of HBCDs on human hepatocyte L02 and the potential molecular mechanism

An, Jing; Zou, Wen; Chen, Cen; Zhong, Fang; Yu, Qiang; Wang, Qi J.

doi:10.1080/10934529.2013.781875

Cited by 12 publications

(14 citation statements)

References 30 publications

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“…Furthermore, in the immortalised human hepatocyte L02 cell line, the EC 50 for a 24-hour exposure to HBCD was reported as ca. 60 μM (An et al 2013). Hence, the EC 50 value for this hepatic cell line treated with HBCD is consistent with previously published values, for the case of exposures conducted in the presence of serum which more closely reflects the in vivo situation.…”

Section: Discussionsupporting

confidence: 91%

“…In several in vitro studies, induction of cell apoptosis by exposure to high concentrations of HBCD in HepG2 cells (Hu et al 2009;An et al 2014) and human L02 hepatocytes (An et al 2013) has been suggested to result from increased production of reactive oxygen species (ROS). However, a slight increase in ROS has also been observed after low concentration (10 −7 −10 −1 μM) exposures in human L02 hepatocytes, while there was no acute toxic effect reported (An et al 2013;Zou et al 2013). More studies are necessary to better understand whether any molecular changes result from concentrations that are realistic for human exposure.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

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Transcriptomic and metabolomic approaches to investigate the molecular responses of human cell lines exposed to the flame retardant hexabromocyclododecane (HBCD)

Zhang

Williams

Abdallah

et al. 2015

Toxicology in Vitro

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The potential for human exposure to the brominated flame retardant, hexabromocyclododecane (HBCD) has given rise to health concerns, yet there is relatively limited knowledge about its possible toxic effects and the underlying molecular mechanisms that may mediate any impacts on health. In this study, unbiased transcriptomic and metabolomic approaches were employed to investigate the potential molecular changes that could lead to the toxicity of HBCD under concentrations relevant to human exposure conditions using in vitro models. A concentration-dependent cytotoxic effect of HBCD to A549 and HepG2/C3A cells was observed based on MTT assays or CCK-8 assays with EC50 values of 27.4 μM and 63.0 μM, respectively. Microarray-based transcriptomics and mass spectrometry-based metabolomics revealed few molecular changes in A549 cells or HepG2/C3A cells following a 24-hour exposure to several sub-lethal concentrations (2 to 4000 nM) of HBCD. Quantification of the level of HBCD in the HepG2/C3A exposed cells suggested that the flame retardant was present at concentrations several orders of magnitude higher than those reported to occur in human tissues. We conclude that at the concentrations known to be achievable following exposure in humans, HBCD exhibits no detectable acute toxicity in A549 cells, representative of the lung, or in HepG2/C3A cells, that are hepatocytes with some xenobiotic metabolic capacity.

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Section: Discussionsupporting

confidence: 91%

Section: Accepted M Manuscriptmentioning

confidence: 99%

Transcriptomic and metabolomic approaches to investigate the molecular responses of human cell lines exposed to the flame retardant hexabromocyclododecane (HBCD)

Zhang

Williams

Abdallah

et al. 2015

Toxicology in Vitro

View full text Add to dashboard Cite

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“…The ROS level in HBCDD treated cells was elevated in a time‐dependent manner. It was also shown that the ROS level induced by low concentrations of HBCDDs was comparatively lower than that induced by high concentrations of HBCDDs (An et al., 2013).…”

Section: Assessmentmentioning

confidence: 99%

“…In vitro steroidogenic effects of mixtures of persistent organic pollutants (POPs) extracted from burbot (Lota lota) caught in two Norwegian lakes.HBCDDs were not tested alone but in chemical mixture.An et al. (2013). The cytological effects of HBCDs on human hepatocyte L02 and the potential molecular mechanism.High concentration of HBCDDs (> 20 μM) decreased survival of L02 hepatocytes, lower dose of HBCDDs (10 −13 –10 −7 M) stimulated cell proliferation and up‐regulation of PCNA protein expression level.An et al.…”

Section: Appendix D – Mode Of Action Studiesmentioning

confidence: 99%

Update of the risk assessment of hexabromocyclododecanes (HBCDDs) in food

Schrenk

Bignami

Bodin³

et al. 2021

EFS2

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The European Commission asked EFSA to update its 2011 risk assessment on hexabromocyclododecanes ( HBCDD s) in food. HBCDD s, predominantly mixtures of the stereoisomers α‐, β‐ and γ‐ HBCDD , were widely used additive flame retardants. Concern has been raised because of the occurrence of HBCDD s in the environment, food and in humans. Main targets for toxicity are neurodevelopment, the liver, thyroid hormone homeostasis and the reproductive and immune systems. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour in mice can be considered the critical effects. Based on effects on spontaneous behaviour in mice, the Panel identified a lowest observed adverse effect level ( LOAEL ) of 0.9 mg/kg body weight (bw) as the Reference Point, corresponding to a body burden of 0.75 mg/kg bw. The chronic intake that would lead to the same body burden in humans was calculated to be 2.35 μg/kg bw per day. The derivation of a health‐based guidance value ( HBGV ) was not considered appropriate. Instead, the margin of exposure ( MOE ) approach was applied to assess possible health concerns. Over 6,000 analytical results for HBCDD s in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary LB exposure to HBCDD s were fish meat, eggs, livestock meat and poultry. The CONTAM Panel concluded that the resulting MOE values support the conclusion that current dietary exposure to HBCDD s across European countries does not raise a health concern. An exception is breastfed infants with high milk consumption, for which the lowest MOE values may raise a health concern.

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“…Comet assay DNA single-strand breaks (SSB) were evaluated with the alkaline single-cell gel electrophoresis [22]. Briefly, normal melting point agarose (NMA, 1 %) was prepared on the frosted microscope slides.…”

Section: Cell Viabilitymentioning

confidence: 99%

DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

et al. 2014

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The aim of the present study was to investigate the effects of DNA-PKcs deficiency on the chemosensitivity of human hepatoma HepG2 cells to cisplatin (CDDP) and 5-fluorouracil (5-Fu), and to explore the underlying molecular mechanism. After transfection with DNA-PKcs siRNA or control siRNA, HepG2 cells were exposed to combination treatment of CDDP and 5-Fu. The cell viability, DNA damage, cell apoptosis, intracellular reactive oxygen species and glutathione (GSH) level, expression of apoptosis related proteins, activity of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and nuclear factor-κB (NF-κB) pathways were assessed. The combination of CDDP and 5-Fu had a synergistic cytotoxic effect in HepG2 cells in terms of the cell viability, DNA damage, apoptosis, and oxidative stress level. DNA-PKcs siRNA could sensitize the HepG2 cells to the combined treatment. DNA-PKcs suppression further reduced the Akt phosphorylation level and Bcl-2 expression in HepG2 cells exposed to CDDP and 5-Fu, but enhanced the expression of pro-apoptotic proteins p53 and caspase-3. Moreover, CDDP could inhibit the transcriptional activity of NF-κB through degradation of IkB-α, while 5-Fu alone seemed in some extent increases the NF-κB activity. The combined treatment with CDDP and 5-Fu resulted in significantly decrease of the transcriptional activity of NF-κB, which was further aggravated by DNA-PKcs siRNA treatment. In conclusion, DNA-PKcs suppression had complementary effects in combination with CDDP and 5-Fu treatment in HepG2 cells, which was associated with suppression of NF-κB signaling pathway cascade, activation of caspase-3 and p53, as well as down-regulation of Bcl-2 and GSH.

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The cytological effects of HBCDs on human hepatocyte L02 and the potential molecular mechanism

Cited by 12 publications

References 30 publications

Transcriptomic and metabolomic approaches to investigate the molecular responses of human cell lines exposed to the flame retardant hexabromocyclododecane (HBCD)

Transcriptomic and metabolomic approaches to investigate the molecular responses of human cell lines exposed to the flame retardant hexabromocyclododecane (HBCD)

Update of the risk assessment of hexabromocyclododecanes (HBCDDs) in food

DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

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