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.