Tributylphosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP) induced apoptosis and cell cycle arrest in HepG2 cells

Abstract

The purpose of this study was to investigate the cytotoxic effects of tributylphosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP) and to explore the underlying molecular mechanism focusing on oxidative stress, apoptosis, and cell cycle arrest. The results showed that TBP and TBEP could inhibit cell proliferation, induce cellular reactive oxidative stress, and suppress the mitochondrial membrane potential in HepG2 cells. TBP and TBEP could induce both mitochondrial and p53 mediated apoptosis through different mitogen-activated protein kinase (MAPK) signal pathways. TBP activated the c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinase (ERK1/2) pathways, while TBEP activated the JNK pathway. Furthermore, TBP and TBEP caused a concentration-dependent decrease of cyclin D1 expression and an increase of cyclin-dependent kinase (CDK) inhibitor proteins such as p21 and p27, resulting in significant cell cycle arrest in the G0/G1 phase. Taken together, the toxicity of TBP and TBEP on the HepG2 cells was associated with apoptosis and cell cycle arrest induced by oxidative stress.

Comparison of the Toxicity Effects of Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) with Tributyl Phosphate (TNBP) Reveals the Mechanism of the Apoptosis Pathway in Asian Freshwater Clams (Corbicula fluminea)

“…Through the mitochondrial-independent pathway, exogenous chemicals and contaminants stimulate the expression of caspase 8 , which lead to an increase in the caspase 3 levels and apoptosis. Through the mitochondrial-dependent pathway, chemical stimulation causes DNA damage, and the induced DNA damage induces mitochondria to release cytochrome c and thereby induces an increase in caspases 9 and 3 and apoptosis, which is similar to the observation that 50 μM TNBP induces mitochondrial apoptosis in HepG2 cells …”

“…33 Similarly, in our previous study, transcriptomics showed that exposure to 40 and 400 μg/L TDCIPP can induce apoptosis and genetic toxicity in Chinese rare minnows. 33 Apoptosis induction has been observed in HepG2 cells exposed to TNBP 41 and in human neuroblastoma (SH-SY5Y) cells exposed to TDCIPP. 42 Therefore, the apoptosis pathway was evaluated in this study as a potential mechanism underlying the response of C. fluminea to TDCIPP and TNBP exposure.…”

Cyto-Genotoxic and Transcriptomic Alterations in Human Liver Cells by Tris (2-Ethylhexyl) Phosphate (TEHP): A Putative Hepatocarcinogen

“…It can be surmised that the prolonged exposure of TEHP at high concentrations surpasses the cellular threshold to fix anomalies and damages, eventually triggering apoptotic cell death. Our finding is in close agreement with previous reports on OPFRs, which also exhibited similar toxic effects at high concentrations after extended exposure time periods [ 66 , 67 ].…”

Organophosphorus Compounds and MAPK Signaling Pathways

“…It was found that ( -)-ICP induces a change in the Bax/Bcl-2 ratio and hepatotoxicity by the sustained activation of JNK [53]. The addition of tributyl phosphate (TBP) and tris (2-butoxy ethyl) phosphate (TBEP) to HepG2 produced ROS overproduction and caused mitochondrial and p53-mediated apoptosis via activation of JNK and ERK1/2 pathways by TBP and activation of the JNK pathway by TBEP [54].…”