Tris (2-chloroethyl) phosphate induces senescence-like phenotype of hepatocytes via the p21Waf1/Cip1-Rb pathway in a p53-independent manner

Zhang, Wenjuan; Zhang, Youjian; Hou, Jian; Tian, Xiaowei; Yin, Wang; Xiong, Wei; Lu, Wenyu; Zheng, Hongyan; Yuan, Jing

doi:10.1016/j.etap.2017.08.028

Cited by 20 publications

(6 citation statements)

References 38 publications

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“…In this study, we used the hepatoblastoma cell line (HepG2) and L02 cell lines as representative of primary human hepatocytes, since the isolation and culture of primary human hepatocytes are particularly difficult. Besides, HepG2 cells [24,25] and L02 cells [26,27] have been shown to be highly relevant and suitable for senescence studies in vitro model.…”

Section: In Vitro Studiesmentioning

confidence: 99%

The p66shc-mediated Regulation of Hepatocyte Senescence Influences Hepatic Steatosis in Nonalcoholic Fatty Liver Disease

Zhang

Wang

et al. 2020

Med Sci Monit

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Background: Recent studies have suggested that hepatocyte senescence could contribute to hepatic steatosis and its progression in nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism causing hepatocyte senescence in this pathological condition is still unclear. A thorough understanding of the mechanism could provide a new target for therapeutic intervention. The purpose of this study was to investigate the role of p66shc in hepatocyte senescence and hepatocyte damage in NAFLD progression. Material/Methods: We examined the expression levels of hepatic p66shc and senescence markers in rats and humans with NAFLD, and we assessed the effect of p66shc knockdown or overexpression on senescence and steatosis in human liver cells. Results: In this study, we showed that increased hepatic p66shc expression was consistent with upregulated expression of the following senescence markers in NAFLD rats: heterochromatin protein-1-beta (HP1b), p16, p21, and p53. Furthermore, senescence and steatosis could be induced in hepatoblastoma cell line (HepG2) cells when cells were stimulated with a low concentration of H 2 O 2 , and this effect was significantly alleviated by knockdown of p66shc. However, overexpression of p66shc could promote senescence and steatosis in L02 cells. Finally, increased hepatic p66shc protein levels correlated with enhanced expression of the senescence marker p21 and mirrored the degree of disease severity in NAFLD patients. Conclusions: Our findings indicated that the increase in hepatocyte senescence and steatosis in NAFLD may be caused by the upregulation of p66shc expression, implying that strategies for p66shc-mediated regulation of hepatocyte senescence may provide new therapeutic tools for NAFLD.

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Section: In Vitro Studiesmentioning

confidence: 99%

The p66shc-mediated Regulation of Hepatocyte Senescence Influences Hepatic Steatosis in Nonalcoholic Fatty Liver Disease

Zhang

Wang

et al. 2020

Med Sci Monit

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“…We have encountered very few reports on the hepatotoxicity of TCEP. For example, human hepatoma (Hep3B) cells exposed to TCEP under in vitro conditions demonstrated reduced cell survival and senescence like growth arrest via the p21 Waf1/Cip1 -Rb pathway [16]. Along the same line, the TCEP-exposed rat hepatic (H4IIE) cell line showed decreased cell survival at higher concentrations (50-100 µM).…”

Section: Introductionmentioning

confidence: 94%

Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

Alsalem

Saquib

Siddiqui

et al. 2020

Toxics

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Tris(2-chloroethyl) phosphate (TCEP) is one of the organophosphorus flame retardants (OPFRs) used in consumer commodities and have been detected in human body fluids. Research on TCEP-induced transcriptomic alterations and toxicological consequences in liver cells is still lacking. Herein, human hepatocellular (HepG2) cells were treated with 100, 200, and 400 μM TCEP for 3 days to quantify hepatotoxicity by MTT, NRU, and comet assays. Apoptosis, mitochondrial membrane potential (ΔΨm), oxidative stress, and Ca2+ influx were measured by flow cytometry. A qPCR array was employed for transcriptomic analysis. MTT and NRU data showed 70.92% and 75.57% reduction in cell survival at 400 μM. In addition, 20-fold greater DNA damage was recorded at 400 μM. Cell cycle data showed 65.96% subG1 apoptotic peak in 400 μM treated cells. An elevated level of oxidative stress, esterase, Ca2+ influx, and ΔΨm dysfunction were recorded in TCEP-treated cells. Out of 84 genes, the qPCR array showed upregulation of 17 genes and downregulation of 10 key genes belonging to human cancer pathways. Our study endorses the fact that TCEP possesses hepatotoxic potential at higher concentrations and prolonged exposure. Hence, TCEP may act as a cancer-inducing entity by provoking the gene network of human cancer pathways.

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“…The same group demonstrated that TCEP induced senescence-like growth arrest via the p21 Waf1/Cip1 -Rb pathway in a p53-independent manner in hepatocytes. 28 We suggest that DNA damage which we observed may be due to the ability of TCEP and TCPP to generate free radicals that can damage biomolecules and affect gene expression.…”

Section: Discussionmentioning

confidence: 73%

DNA damage and methylation induced by organophosphate flame retardants: Tris(2-chloroethyl) phosphate and tris(1-chloro-2-propyl) phosphate in human peripheral blood mononuclear cells

et al. 2019

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Phosphorus flame retardants are a group of chemicals that are used to slow or prevent the spread of fire. These compounds have been detected in different environments including human organism. In the present study, we have investigated DNA-damaging potential and effect on DNA methylation of tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) phosphate (TCPP) in human peripheral blood mononuclear cells (PBMCs). In order to determine DNA damage and repair, the alkaline and neutral versions of the comet assay were used. The level of DNA methylation was determined with specific antibodies against methylated DNA. PBMCs were exposed to TCEP and TCPP at the concentrations in the range of 1–1000 µM for 24 h. We have observed that TCEP and TCPP induced DNA damage—DNA breaks and alkali-labile sites. All DNA damages were effectively repaired during 120-min repair incubation. The results have also shown that TCEP and TCPP decreased the level of DNA methylation in PBMCs. In the case of TCEP, this effect was observed at a very low concentration of 1 µM.

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Tris (2-chloroethyl) phosphate induces senescence-like phenotype of hepatocytes via the p21Waf1/Cip1-Rb pathway in a p53-independent manner

Cited by 20 publications

References 38 publications

The p66shc-mediated Regulation of Hepatocyte Senescence Influences Hepatic Steatosis in Nonalcoholic Fatty Liver Disease

The p66shc-mediated Regulation of Hepatocyte Senescence Influences Hepatic Steatosis in Nonalcoholic Fatty Liver Disease

Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

DNA damage and methylation induced by organophosphate flame retardants: Tris(2-chloroethyl) phosphate and tris(1-chloro-2-propyl) phosphate in human peripheral blood mononuclear cells

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