Chromosome aberrations induced by the non-mutagenic carcinogen acetamide involve in rat hepatocarcinogenesis through micronucleus formation in hepatocytes

Chromosome aberrations (CAs), i.e. changes in chromosome number or structure, are known to cause chromosome rearrangements and subsequently tumorigenesis. However, the involvement of CAs in chemical-induced carcinogenesis is unclear. In the current study, we aimed to clarify the possible involvement...

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Bibliographic Details
Published in:Archives of toxicology 2021-08, Vol.95 (8), p.2851-2865
Main Authors: Nakamura, Kenji, Ishii, Yuji, Takasu, Shinji, Nohmi, Takehiko, Shibutani, Makoto, Ogawa, Kumiko
Format: Article
Language:English
Subjects:
Acetamides - administration & dosage
Acetamides - toxicity
Animals
Biomedical and Life Sciences
Biomedicine
Carcinogenesis
Carcinogenesis - chemically induced
Carcinogens
Carcinogens - administration & dosage
Carcinogens - toxicity
Chromosome aberrations
Chromosome Aberrations - chemically induced
Chromosome number
Chromosome rearrangements
Chromosomes
Deoxyribonucleic acid
DNA
DNA damage
Environmental Health
Genotoxicity and Carcinogenicity
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - pathology
In vivo methods and tests
Liver Neoplasms - chemically induced
Liver Neoplasms - pathology
Male
Micronucleus Tests
Occupational Medicine/Industrial Medicine
Pharmacology/Toxicology
Rats
Rats, Inbred F344
Time Factors
Tumorigenesis
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Summary:Chromosome aberrations (CAs), i.e. changes in chromosome number or structure, are known to cause chromosome rearrangements and subsequently tumorigenesis. However, the involvement of CAs in chemical-induced carcinogenesis is unclear. In the current study, we aimed to clarify the possible involvement of CAs in chemical carcinogenesis using a rat model with the non-mutagenic hepatocarcinogen acetamide. In an in vivo micronucleus (MN) test, acetamide was revealed to induce CAs specifically in rat liver at carcinogenic doses. Acetamide also induced centromere-positive large MN (LMN) in hepatocytes. Immunohistochemical and electron microscopic analyses of the LMN, which can be histopathologically detected as basophilic cytoplasmic inclusion, revealed abnormal expression of nuclear envelope proteins, increased heterochromatinization, and massive DNA damage. These molecular pathological features in LMN progressed with acetamide exposure in a time-dependent manner, implying that LMN formation can lead to chromosome rearrangements. Overall, these data suggested that CAs induced by acetamide play a pivotal role in acetamide-induced hepatocarcinogenesis in rats and that CAs can cause chemical carcinogenesis in animals via MN formation.
ISSN:0340-5761
1432-0738
DOI:10.1007/s00204-021-03099-9