Transcriptional profiling of male F344 rats suggests the involvement of calcium signaling in the mode of action of acrylamide-induced thyroid cancer

Chepelev, Nikolai L.; Gagné, Rémi; Maynor, Timothy; Kuo, Byron; Hobbs, Cheryl A.; Recio, Leslie; Yauk, Carole L.

doi:10.1016/j.fct.2017.06.019

Cited by 17 publications

(18 citation statements)

References 60 publications

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“…Likewise, novel toxicogenomic evidence obtained from studies in F344 rats given AA at dosages up to 12.0 mg/kg bw/day for different subchronic time periods does not convincingly support a genotoxic or hormonal MOA. Instead, pronounced effects on calcium signalling and on cytoskeletal functions were observed in the thyroid, a tumour target organ in the male rat (Chepelev et al 2017). Under the same experimental conditions, evidence for a similar MOA being operative in rat testes has been reported (Recio et al 2017).…”

Section: Acrylamidementioning

confidence: 77%

“…Several toxicogenomic studies on rats and mice exposed to AA in a time-and dose-dependent manner were conducted (Chepelev et al 2017(Chepelev et al , 2018Recio et al 2017). The group performed mRNA gene expression profiling to develop a MOA and to calculate transcriptional BMDLs for the most sensitive pathways, comparing these with data derived from traditional (apical) cancer studies.…”

Section: Impact Of Aa On Transcription and Gene Expression Profilesmentioning

confidence: 99%

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Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

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The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as “omics” approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.

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Section: Acrylamidementioning

confidence: 77%

Section: Impact Of Aa On Transcription and Gene Expression Profilesmentioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

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“…It is hypothesized that disruption in calcium signaling also could lead to cancer development via hormonal actions. However, lack of empirical proof warrants his hypothesis to be further investigated ( 55 ).…”

Section: Calcium Signaling—cytoskeletal Mode Of Mechanismmentioning

confidence: 99%

“…The idea of cytoskeletal proteins mediating the genotoxic effects of AA were implicitly corroborated using various study models ( 55 , 56 ). Cytoskeletal proteins are tasked with multitude of functions that integral for cell survival such as movement of vesicles and cell compartments, regulation of cell division ( 57 ), and cell mechanics ( 58 ).…”

Section: Cytoskeletal—aa—genotoxic Effectsmentioning

confidence: 99%

Dietary Acrylamide and the Risks of Developing Cancer: Facts to Ponder

2018

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Acrylamide (AA) is a water soluble white crystalline solid commonly used in industries. It was listed as an industrial chemical with potential carcinogenic properties. However to date, AA was used to produce polyacrylamide polymer, which was widely used as a coagulant in water treatment; additives during papermaking; grouting material for dams, tunnels, and other underground building constructions. AA in food could be formed during high-temperature cooking via several mechanisms, i.e., formation via acrylic acid which may be derived from the degradation of lipid, carbohydrates, or free amino acids; formation via the dehydration/decarboxylation of organic acids (malic acid, lactic acid, and citric acid); and direct formation from amino acids. The big debate is whether this compound is toxic to human beings or not. In the present review, we discuss the formation of AA in food products, its consumption, and possible link to the development of any cancers. We discuss the body enzymatic influence on AA and mechanism of action of AA on hormone, calcium signaling pathways, and cytoskeletal filaments. We also highlight the deleterious effects of AA on nervous system, reproductive system, immune system, and the liver. The present and future mitigation strategies are also discussed. The present review on AA may be beneficial for researchers, food industry, and also medical personnel.

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“…Differently expressed genes in both tissues provided at best marginal support for hormonal and genotoxic MOAs. Instead, pronounced effects on calcium signalling/cytoskeletal genes were seen in the thyroid target organ, suggesting perturbation of calcium signalling as a novel MOA for AA mediated thyroid carcinogenicity in the male rat (Chepelev et al 2017 ). A similar MOA has also been evidenced as probably causative for tumour induction in another target organ of AA, the rat testes, under the same experimental conditions (Recio et al 2017 ).…”

Section: State Of the Artmentioning

confidence: 99%

Exposure assessment of process-related contaminants in food by biomarker monitoring

et al. 2018

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Exposure assessment is a fundamental part of the risk assessment paradigm, but can often present a number of challenges and uncertainties. This is especially the case for process contaminants formed during the processing, e.g. heating of food, since they are in part highly reactive and/or volatile, thus making exposure assessment by analysing contents in food unreliable. New approaches are therefore required to accurately assess consumer exposure and thus better inform the risk assessment. Such novel approaches may include the use of biomarkers, physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry, and/or duplicate diet studies. This review focuses on the state of the art with respect to the use of biomarkers of exposure for the process contaminants acrylamide, 3-MCPD esters, glycidyl esters, furan and acrolein. From the overview presented, it becomes clear that the field of assessing human exposure to process-related contaminants in food by biomarker monitoring is promising and strongly developing. The current state of the art as well as the existing data gaps and challenges for the future were defined. They include (1) using PBK modelling and duplicate diet studies to establish, preferably in humans, correlations between external exposure and biomarkers; (2) elucidation of the possible endogenous formation of the process-related contaminants and the resulting biomarker levels; (3) the influence of inter-individual variations and how to include that in the biomarker-based exposure predictions; (4) the correction for confounding factors; (5) the value of the different biomarkers in relation to exposure scenario’s and risk assessment, and (6) the possibilities of novel methodologies. In spite of these challenges it can be concluded that biomarker-based exposure assessment provides a unique opportunity to more accurately assess consumer exposure to process-related contaminants in food and thus to better inform risk assessment.

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Transcriptional profiling of male F344 rats suggests the involvement of calcium signaling in the mode of action of acrylamide-induced thyroid cancer

Cited by 17 publications

References 60 publications

Mode of action-based risk assessment of genotoxic carcinogens

Mode of action-based risk assessment of genotoxic carcinogens

Dietary Acrylamide and the Risks of Developing Cancer: Facts to Ponder

Exposure assessment of process-related contaminants in food by biomarker monitoring

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