Integrating transcriptomics and metabonomics to unravel modes-of-action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in HepG2 cells

Abstract

BackgroundThe integration of different 'omics' technologies has already been shown in several in vivo studies to offer a complementary insight into cellular responses to toxic challenges. Being interested in developing in vitro cellular models as alternative to animal-based toxicity assays, we hypothesize that combining transcriptomics and metabonomics data improves the understanding of molecular mechanisms underlying the effects caused by a toxic compound also in vitro in human cells. To test this hypothesis, and with the focus on non-genotoxic carcinogenesis as an endpoint of toxicity, in the present study, the human hepatocarcinoma cell line HepG2 was exposed to the well-known environmental carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).ResultsTranscriptomics as well as metabonomics analyses demonstrated changes in TCDD-exposed HepG2 in common metabolic processes, e.g. amino acid metabolism, of which some of the changes only being confirmed if both 'omics' were integrated. In particular, this integrated analysis identified unique pathway maps involved in receptor-mediated mechanisms, such as the G-protein coupled receptor protein (GPCR) signaling pathway maps, in which the significantly up-regulated gene son of sevenless 1 (SOS1) seems to play an important role. SOS1 is an activator of several members of the RAS superfamily, a group of small GTPases known for their role in carcinogenesis.ConclusionsThe results presented here were not only comparable with other in vitro studies but also with in vivo studies. Moreover, new insights on the molecular responses caused by TCDD exposure were gained by the cross-omics analysis.

2,3,7,8‑Tetrachlorodibenzo‑p‑dioxin suppresses the growth of human liver cancer HepG2 cells in vitro: Involvement of cell signaling factors

“…TCDD has been shown to increase Ras expression in studies using transcriptomics and metabonomics to unravel modes of action of TCDD in HepG2 cells in vitro ( 45 ). In the present study, TCDD was also found to increase the levels of β-catenin, STAT3, Ras and Akt, all of which are involved in cell proliferation and differentiation ( 32 , 41 ), in HepG2 cells.…”

Development of a toxicogenomics signature for genotoxicity using a dose‐optimization and informatics strategy in human cells

“…Unfortunately, these methods often generate multiple hypotheses that are not easily testable given the promiscuity of genes. Integration of multiple omics types, including delineation of coordinately regulated transcriptomic responses, may aid in classifying the particular stress response pathways that are invoked following chemical exposure, providing insight into underlying mechanisms of action and PoT [Hartung and McBride, ; Jennen et al, ; Magkoufopoulou et al, ; Wilson et al, ].…”

The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro

“…liver enzyme induction/ inhibition and peroxisome proliferation) responsible for their toxicities (Ramirez et al 2018). The applications of transcriptomics, proteomics and metabolomics to HepG2based in vitro models also assist with the identification of key mechanisms underlying drug-induced hepatic steatosis, cholestasis, cytotoxicity and genotoxicity (Chatterjee et al 2014;Deferme et al 2015b;Rieswijk et al 2014;Smit et al 2017;Van den Hof et al 2015Van Summeren et al 2011) as well as compounds' carcinogenicity in humans (Briede et al 2018;Caiment et al 2015;Jennen et al 2011;Lizarraga et al 2012;Ruiz-Aracama et al 2011;Souza et al 2016;van Delft et al 2012).…”