Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
A micronucleus (MN) is a small nucleus formed from a chromosome fragment due to chromosome instability or mitotic abnormalities. Although MN has been used as a marker of chromosomal aberrations in the safety assessment of chemicals, its biological significance and the effects on the micronucleated cells remained unclear. However, recent studies have shown that MN could be the cause of cancer via chromothripsis. Chromothripsis is a phenomenon in which chromosomes are disrupted and rearranged in the MN, then leak into the cytoplasm through the rupture of the nuclear envelope and are incorporated into the primary nucleus during cell division. It is believed that the incorporated abnormal chromosomes cause drastic gene mutations, resulting in changes in the expression of several genes involved in tumor development and progression. Indeed, massive chromosomal rearrangements considered to be caused by chromothripsis have been found in a variety of human tumors by whole-genome sequencing using next-generation sequencer, suggesting that chromothripsis occurs in tumorigenesis and malignant transformation. On the other hand, such phenomena have not been reported in chemical carcinogenesis, although there are a number of clastogens and aneugens that form MNs in chemicals. Recently, we found that a rat hepatocarcinogen, acetamide, induces characteristic large MNs in the liver. In addition, molecular pathological analysis of large micronuclei and whole genome sequencing of acetamide-induced liver tumors revealed that acetamide induces chromothripsis-like chromosomal aberrations in the process of tumorigenesis. In this presentation, I will present the results of these studies and discuss the possible involvement of chromothripsis in chemical carcinogenesis.
