Genotoxic, cytotoxic, and cytopathological effects in rats exposed for 18 months to a mixture of 13 chemicals in doses below NOAEL levels

Tsatsakis, Aristidis; Docea, Anca Oana; Constantin, Carolina; Calina, Daniela; Zlatian, Ovidiu; Νikolouzakis, Τaxiarchis Κonstantinos; Stivaktakis, Polychronis; Kalogeraki, Alexandra; Liesivuori, Jyrki; Tzanakakis, George N.; Neagu, Monica

doi:10.1016/j.toxlet.2019.09.004

Cited by 73 publications

(39 citation statements)

References 112 publications

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“…On the other hand, the fact that even a low dose of NNK was capable of causing significant alterations in MMR and miRNA expression indicates that even a small exposure to the tobacco smoke carcinogen could have potentially harmful consequences. Taking into consideration the theory that long-term exposure to chemicals, even at low doses, could have an augmented effect [87,88], long-term studies could reveal the chronic effect of low NNK exposure to MMR genes in lung and head and neck squamous cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

Doukas

Vageli²,

Lazopoulos

et al. 2020

Cells

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Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 µM) or high (2 µM) dose of NNK induced significant upregulation of "oncomirs" miR-21 and miR-155 and downregulation of "tumor suppressor" miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.Cells 2020, 9, 1031 2 of 22 and neck squamous cell carcinoma (HNSCC), represents one of the most aggressive malignancies with a high rate of mortality. [8,9]. Tobacco smoking has been one of the most well-established risk factors for both lung and head and neck cancers [1][2][3][4][5][6][7][8]. It is known that tobacco smoke contains a mixture of thousands of compounds, including a large number of known carcinogens [2]. It is believed that exposure of cells to tobacco smoke carcinogens can lead to DNA damage, which may cause chromosomal instability and increased cell proliferation [10][11][12][13]. In particular, tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is one of the chemicals in tobacco smoke, has been linked to lung and head and neck cancer [14], and has also been shown to upregulate oncogenic pathways [15][16][17].The development and progression of lung and head and neck malignancies appear to be a complex process. Although multiple diagnostic and prognostic markers have been identified for both lung and head and neck cancers [18,19], the precise molecular mechanisms involved in the development and progression of these malignancies remain unclear.We understand that a functional DNA repair mechanism that includes the recognition and repair of mismatch DNA errors during DNA replication is essential in eliminating the harmful effect of several environmental risk factors, such as NNK, on the exposed cells [20][21][22][23]. A number of studies have shown that reduced expression of mismatch DNA repair (MMR) genes increases the incidence of microsatellite ...

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Section: Discussionmentioning

confidence: 99%

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

Doukas

Vageli²,

Lazopoulos

et al. 2020

Cells

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“…Some examples of such factors, based on existing studies, include titanium dioxide, air pollution, chlorpyrifos, aluminum sulfate, prenatal alcohol exposure, ZnO, oil fly ash, and many others (3)(4)(5)(6)(7)(8)(9). Also the real life exposure scenario in which we are exposed continuously to combination of stressors influences in the long term the immune system and the response of the organism to the viral stressors (10)(11)(12)(13)(14).…”

Section: Towards Effective Covid-19 Vaccines: Updates Perspectives Amentioning

confidence: 99%

Towards effective COVID‑19 vaccines: Updates, perspectives and challenges (Review)

et al. 2020

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In the current context of the pandemic triggered by SARS-cOV-2, the immunization of the population through vaccination is recognized as a public health priority. In the case of SARS-cOV-2, the genetic sequencing was done quickly, in one month. Since then, worldwide research has focused on obtaining a vaccine. This has a major economic impact because new technological platforms and advanced genetic engineering procedures are required to obtain a cOVId-19 vaccine. The most difficult scientific challenge for this future vaccine obtained in the laboratory is the proof of clinical safety and efficacy. The biggest challenge of manufacturing is the construction and validation of production platforms capable of making the vaccine on a large scale.

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“…It is also worth investigating if these protective effects against oxidative stress are valid in the real-life exposure scenario where the individual is exposed in a chronic manner to a combination of stimuli that can be additive, synergic or antagonist [56,57]. Several studies showed that the combined exposure at low doses can produce non-monotonic responses [58][59][60], and this is worth investigating also for Ag-NPs as the exposure to these molecules usually appearsin combination to other agents that can influence their effects on biological organisms.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Silver Nanoparticles on Antioxidant/Pro-Oxidant Balance in a Murine Model

Docea

Calina

Buga

et al. 2020

IJMS

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This study aimed to evaluate the subacute effect of two types of Ag-NPs(EG-AgNPs and PVP-EG-AgNPs) on antioxidant/pro-oxidant balance in rats. Seventy Wistar rats (35 males and 35 females) were divided in 7 groups and intraperitoneally exposed for 28 days to 0, 1, 2 and 4 mg/kg bw/day EG-Ag-NPs and 1, 2 and 4 mg/kg bw/day PVP- EG-Ag-NPs. After 28 days, the blood was collected, and the total antioxidant capacity (TAC), thiobarbituric reactive species (TBARS),protein carbonyl (PROTC) levels, reduced glutathione (GSH) levels and catalase (CAT) activity were determined. EG-Ag-NPs determined protective antioxidant effects in a dose-dependent manner. The exposure to the 4 mg/kg bw/day EG-Ag-NPs determines both in males and females a significant increase in TAC and CAT and a significant decrease in TBARS and PROTC only in females. The PVP-EG-AgNPs showed a different trend compared to EG-AgNPs. At 4 mg/kg bw/day the PVP-EG-AgNPs induce increased PROTC levels and decreased GSH (males and females) and TAC levels (males). The different mechanisms of EG-AgNPs and PVP-EG-AgNPs on antioxidant-/pro-oxidant balance can be explained by the influence of coating agent used for the preparation of the nanoparticles in the formation and composition of protein corona that influence their pathophysiology in the organism.

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Genotoxic, cytotoxic, and cytopathological effects in rats exposed for 18 months to a mixture of 13 chemicals in doses below NOAEL levels

Cited by 73 publications

References 112 publications

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

Towards effective COVID‑19 vaccines: Updates, perspectives and challenges (Review)

The Effect of Silver Nanoparticles on Antioxidant/Pro-Oxidant Balance in a Murine Model

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