Cobalt-induced oxidative stress contributes to alveolar/bronchiolar carcinogenesis in B6C3F1/N mice
| Autor: | Mark J. Hoenerhoff, Keith R. Shockley, Ramesh C Kovi, Ronald Herbert, Raveena M Chhabria, Mamta Behl, Kevin Gerrish, Robert C. Sills, Arun R. Pandiri, Thai-Vu Ton, Teja N Peddada, Norris D Flagler |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Lung Neoplasms Carcinogenesis Health Toxicology and Mutagenesis Context (language use) Toxicology medicine.disease_cause Article Cell Line Pathogenesis Mice ErbB medicine Animals Humans Protein kinase B PI3K/AKT/mTOR pathway Dose-Response Relationship Drug Chemistry Bronchial Neoplasms NOX4 Dust Cobalt General Medicine Adenocarcinoma Bronchiolo-Alveolar Rats Inbred F344 Rats Pulmonary Alveoli Oxidative Stress A549 Cells Cancer research Female Phosphatidylinositol 3-Kinase Proto-Oncogene Proteins c-akt Oxidative stress |
| Zdroj: | Arch Toxicol |
| ISSN: | 1432-0738 0340-5761 |
| Popis: | Rodent alveolar/bronchiolar carcinomas (ABC) that arise either spontaneously or due to chemical exposure are similar to a subtype of lung adenocarcinomas in humans. B6C3F1/N mice and F344/NTac rats exposed to cobalt metal dust (CMD) by inhalation developed ABCs in a dose dependent manner. In CMD-exposed mice, the incidence of Kras mutations in ABCs was 67% with 80% of those being G to T transversions on codon 12 suggesting a role of oxidative stress in the pathogenesis. In vitro studies, such as DMPO (5,5-dimethyl-1-pyrroline N-oxide) immune-spin trapping assay, and dihydroethidium (DHE) fluorescence assay on A549 and BEAS-2B cells demonstrated increased oxidative stress due to cobalt exposure. In addition, significantly increased 8-oxo-dG adducts were demonstrated by immunohistochemistry in lungs from mice exposed to CMD for 90 days. Furthermore, transcriptomic analysis on ABCs arising spontaneously or due to chronic CMD-exposure demonstrated significant alterations in canonical pathways related to MAPK signaling (IL-8, ErbB, Integrin, and PAK pathway) and oxidative stress (PI3K/AKT and Melatonin pathway) in ABCs from CMD-exposed mice. Oxidative stress can stimulate PI3K/AKT and MAPK signaling pathways. Nox4 was significantly upregulated only in CMD-exposed ABCs and NOX4 activation of PI3K/AKT can lead to increased ROS levels in human cancer cells. The gene encoding Ereg was markedly up-regulated in CMD-exposed mice. Oncogenic KRAS mutations have been shown to induce EREG overexpression. Collectively, all these data suggest that oxidative stress plays a significant role in CMD-induced pulmonary carcinogenesis in rodents and these findings may also be relevant in the context of human lung cancers. |
| Databáze: | OpenAIRE |
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