Transcriptomic fingerprints in human peripheral blood mononuclear cells indicative of genotoxic and non-genotoxic carcinogenic exposure

Hochstenbach, Kevin; Leeuwen, Danitsja M. van; Gottschalk, Ralph W.H.; Gmuender, Hans; Stølevik, Solvor B.; Nygaard, Unni Cecilie; Løvik, Martinus; Granum, Berit; Loveren, Henk Van; Delft, J.H.M. van

doi:10.1016/j.mrgentox.2012.01.002

Cited by 14 publications

(3 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the p53 signaling pathway was also perturbed in the forestomach, the most significantly enriched processes were associated with antigen processing and presentation, immune response, chemotaxis and keratinocyte differentiation. The results in the lung and liver are consistent with expected changes in gene expression in response to a genotoxic carcinogen, whereas the forestomach data point to additional modulating factors at work (a pro-immune, inflammatory response) (Hochstenbach et al, 2012). Please note that BPDE-DNA adducts and lacZ transgene mutant frequency were also assessed in the lung, liver, and glandular stomach tissues from the same mice (Lemieux et al, 2011, Malik et al, 2012, Labib et al, 2012) (Figure 2).…”

Section: Genomics Approaches (Ra2 and Ra3)supporting

confidence: 75%

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Moffat

Chepelev

Labib

et al. 2015

Critical Reviews in Toxicology

138

100

View full text Add to dashboard Cite

Toxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying toxicogenomics has never been done. We conducted a case study to evaluate the utility of toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in perturbed pathways with animal tissues. Quantitatively, the PODs for traditional and transcriptional approaches were similar (liver 1.2 vs. 1.0 mg/kg-bw/day; lung 0.8 vs. 3.7 mg/kg-bw/day; forestomach 0.5 vs. 7.4 mg/kg-bw/day). RA3, which applied toxicogenomics in the absence of apical toxicology data, demonstrates that this approach provides useful information in data-poor situations. Overall, our study supports the use of toxicogenomics as a relatively fast and cost-effective tool for hazard identification, preliminary evaluation of potential carcinogens, and carcinogenic potency, in addition to identifying current limitations and practical questions for future work.

show abstract

Section: Genomics Approaches (Ra2 and Ra3)supporting

confidence: 75%

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Moffat

Chepelev

Labib

et al. 2015

Critical Reviews in Toxicology

138

100

View full text Add to dashboard Cite

show abstract

“…Gene expression profiling, yielding transcript signatures, patterns, or fingerprints to distinguish genotoxic from non-genotoxic substances, has been proposed as a promising approach for almost two decades [ 28 , 41 , 42 , 43 ]. In particular, liver samples or in vitro liver cell models have been used for these approaches, referring to the liver as the main organ of xenobiotic metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, mouse liver [ 5 , 70 ] and rat liver [ 71 , 72 ] have been analyzed. In addition, blood cell models have been used [ 42 , 45 ], including TK6 cells [ 22 , 26 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Transcriptional Responses to Genotoxic and Non-Genotoxic Agents in the Blood Cell Model TK6 and the Liver Model HepaRG

Kreuzer¹,

Sprenger²,

Braeuning³

2022

IJMS

View full text Add to dashboard Cite

Transcript signatures are a promising approach to identify and classify genotoxic and non-genotoxic compounds and are of interest as biomarkers or for future regulatory application. Not much data, however, is yet available about the concordance of transcriptional responses in different cell types or tissues. Here, we analyzed transcriptomic responses to selected genotoxic food contaminants in the human p53-competent lymphoblastoid cell line TK6 using RNA sequencing. Responses to treatment with five genotoxins, as well as with four non-genotoxic liver toxicants, were compared with previously published gene expression data from the human liver cell model HepaRG. A significant overlap of the transcriptomic changes upon genotoxic stress was detectable in TK6 cells, whereas the comparison with the HepaRG model revealed considerable differences, which was confirmed by bioinformatic data mining for cellular upstream regulators or pathways. Taken together, the study presents a transcriptomic signature for genotoxin exposure in the human TK6 blood cell model. The data demonstrate that responses in different cell models have considerable variations. Detection of a transcriptomic genotoxin signature in blood cells indicates that gene expression analyses of blood samples might be a valuable approach to also estimate responses to toxic exposure in target organs such as the liver.

show abstract

Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk

Harris

Myers

McKim

et al. 2019

Environ and Mol Mutagen

View full text Add to dashboard Cite

Cancer driver mutations (CDMs) are necessary and causal for carcinogenesis and have advantages as reporters of carcinogenic risk. However, little progress has been made toward developing measurements of CDMs as biomarkers for use in cancer risk assessment. Impediments for using a CDM‐based metric to inform cancer risk include the complexity and stochastic nature of carcinogenesis, technical difficulty in quantifying low‐frequency CDMs, and lack of established relationships between cancer driver mutant fractions and tumor incidence. Through literature review and database analyses, this review identifies the most promising targets to investigate as biomarkers of cancer risk. Mutational hotspots were discerned within the 20 most mutated genes across the 10 deadliest cancers. Forty genes were identified that encompass 108 mutational hotspot codons overrepresented in the COSMIC database; 424 different mutations within these hotspot codons account for approximately 63,000 tumors and their prevalence across tumor types is described. The review summarizes literature on the prevalence of CDMs in normal tissues and suggests such mutations are direct and indirect substrates for chemical carcinogenesis, which occurs in a spatially stochastic manner. Evidence that hotspot CDMs (hCDMs) frequently occur as tumor subpopulations is presented, indicating COSMIC data may underestimate mutation prevalence. Analyses of online databases show that genes containing hCDMs are enriched in functions related to intercellular communication. In its totality, the review provides a roadmap for the development of tissue‐specific, CDM‐based biomarkers of carcinogenic potential, comprised of batteries of hCDMs and can be measured by error‐correct next‐generation sequencing. Environ. Mol. Mutagen. 61:152–175, 2020. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

show abstract

Transcriptomic fingerprints in human peripheral blood mononuclear cells indicative of genotoxic and non-genotoxic carcinogenic exposure

Cited by 14 publications

References 44 publications

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Comparative Analysis of Transcriptional Responses to Genotoxic and Non-Genotoxic Agents in the Blood Cell Model TK6 and the Liver Model HepaRG

Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk

Contact Info

Product

Resources

About