Transcriptional profiling of male CD-1 mouse lungs and Harderian glands supports the involvement of calcium signaling in acrylamide-induced tumors

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

doi:10.1016/j.yrtph.2018.02.005

Cited by 17 publications

(14 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…(3) evidence is accumulating from toxicogenomic studies arguing for MOAs other than genotoxicity. This applies especially to the target organs of AA in rodent carcinogenicity studies, such as the thyroid, the testes, and the Harderian gland, where pronounced effects on calcium signalling and on cytoskeletal functions have been observed, but no compelling support for a genotoxic or hormonal MOA was found (Chepelev et al 2017(Chepelev et al , 2018Recio et al 2017).…”

Section: Impact Of Aa On Transcription and Gene Expression Profilesmentioning

confidence: 99%

See 1 more Smart Citation

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Impact Of Aa On Transcription and Gene Expression Profilesmentioning

confidence: 99%

Section: Impact Of Aa On Transcription and Gene Expression Profilesmentioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Our previous study also displayed that AA could induce the toxicity through the oxidant damage in brain of rats (Zhao, Wang, Hu, Chen, & Chan, 2017). Various oxidant‐stress‐related signaling pathways, such as MAPK, NF‐κB, and Nrf2, have been found to play a key role in AA toxicity (Bo, Yilin, Chaoyue, Lu, & Yuan, 2020; Pan et al., 2017), and the chemical and biochemical mechanisms of AA have been extensively studied, accompanied by the performed transcriptome and proteomics profiles in cell and animal models (Chepelev et al., 2018; Zhao et al., 2019). However, the details of AA toxicity were obscure, therefore, it is very important that new means have been found out and used to explore the mechanism of AA toxicity.…”

Section: Introductionmentioning

confidence: 99%

Acrylamide alters the miRNA profiles and miR‐27a‐5p plays the key role in multiple tissues of rats

Zhang

Yang

et al. 2020

Food Frontiers

View full text Add to dashboard Cite

Acrylamide (AA) is the potential carcinogen, which can induce multiple toxic effects in laboratory animals and humans. So far, increasing attention have been paid to toxical mechanism and intervention measures of AA, however, these details and methods are still obscure. MicroRNAs (miRNAs) have been demonstrated to be involved in toxical functional mechanisms induced by chemicals in vivo or vitro. To explore novel target and mechanism of AA toxicity, a more detailed miRNA expression profiling study is needed. In this study, we established the short‐term high‐dose model of rats with the treatment of 35 mg/kg·b.w./day AA for 17 days, analyzed the miRNAs expression profiling in AA and control groups, and discovered the altered miRNA profiles in 11 tissues with AA treatment. Interestingly enough, the expression of miR‐27a‐5p were significantly up‐regulated in AA group, especially in bladder and hepar. Furthermore, we found miR‐27a‐5p increased in 11 tissues of long‐term low‐dose AA‐treated rats (3.5 mg/kg·b.w./day for 68 days). Therefore, these results revealed that AA changed miRNAs profiles in multiple tissues of SD rats for the first time and suggested that miR‐27a‐5p could be used as the target biomarker for the detection and interference of AA toxicity.

show abstract

“…Several toxicogenomic studies in rodents exposed up to relatively high doses of AA were conducted and gene expression profiling was performed to approach elucidation of key MOA(s) (Chepelev et al 2017 , 2018 ; Recio et al 2017 ). They are of interest because they address potential MOAs in the main rodent target tissues of AA-induced neoplastic changes, the thyroid, the testes, and the Harderian gland.…”

Section: Introductionmentioning

confidence: 99%

“…In animals exposed to dosages of 1.5–24.0 mg/kg bw AA in drinking water for up to 31 days, pronounced effects on genes involved in calcium signalling and cellular transport were observed, concomitant with cytoskeletal processes in target tissues. However, no evidence supporting a genotoxic MOA became apparent, even at the rather high dosages applied (Chepelev et al 2017 , 2018 ; Recio et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

Eisenbrand

2020

Arch Toxicol

View full text Add to dashboard Cite

The weight of evidence pro/contra classifying the process-related food contaminant (PRC) acrylamide (AA) as a genotoxic carcinogen is reviewed. Current dietary AA exposure estimates reflect margins of exposure (MOEs) < 500. Several arguments support the view that AA may not act as a genotoxic carcinogen, especially not at consumer-relevant exposure levels: Biotransformation of AA into genotoxic glycidamide (GA) in primary rat hepatocytes is markedly slower than detoxifying coupling to glutathione (GS). Repeated feeding of rats with AA containing foods, bringing about uptake of 100 µg/kg/day of AA, resulted in dose x time-related buildup of AA-hemoglobin (Hb) adducts, whereas GA-Hb adducts remained within the background. Since hepatic oxidative biotransformation of AA into GA was proven by simultaneous urinary mercapturic acid monitoring it can be concluded that at this nutritional intake level any GA formed in the liver from AA is quantitatively coupled to GS to be excreted as mercapturic acid in urine. In an oral single dose–response study in rats, AA induced DNA N7-GA-Gua adducts dose-dependently in the high dose range (> 100 µg/kg b w). At variance, in the dose range below 100 µg/kg b.w. down to levels of average consumers exposure, DNA N7 -Gua lesions were found only sporadically, without dose dependence, and at levels close to the lower bound of similar human background DNA N7-Gua lesions. No DNA damage was detected by the comet assay within this low dose range. GA is a very weak mutagen, known to predominantly induce DNA N7-GA-Gua adducts, especially in the lower dose range. There is consensus that DNA N7-GA-Gua adducts exhibit rather low mutagenic potency. The low mutagenic potential of GA has further been evidenced by comparison to preactivated forms of other process-related contaminants, such as N-Nitroso compounds or polycyclic aromatic hydrocarbons, potent food borne mutagens/carcinogens. Toxicogenomic studies provide no evidence supporting a genotoxic mode of action (MOA), rather indicate effects on calcium signalling and cytoskeletal functions in rodent target organs. Rodent carcinogenicity studies show induction of strain- and species-specific neoplasms, with MOAs not considered likely predictive for human cancer risk. In summary, the overall evidence clearly argues for a nongenotoxic/nonmutagenic MOA underlying the neoplastic effects of AA in rodents. In consequence, a tolerable intake level (TDI) may be defined, guided by mechanistic elucidation of key adverse effects and supported by biomarker-based dosimetry in experimental systems and humans.

show abstract

Transcriptional profiling of male CD-1 mouse lungs and Harderian glands supports the involvement of calcium signaling in acrylamide-induced tumors

Cited by 17 publications

References 70 publications

Mode of action-based risk assessment of genotoxic carcinogens

Mode of action-based risk assessment of genotoxic carcinogens

Acrylamide alters the miRNA profiles and miR‐27a‐5p plays the key role in multiple tissues of rats

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

Contact Info

Product

Resources

About