Chromosome aberrations induced in vitro: Mechanisms, delayed expression, and intriguing questions

Abstract

Chromosome aberrations, including breakage and rearrangement and numerical changes, are important in carcinogenesis, heritable mutations, embryonic loss, and developmental abnormalities. We can detect DNA reactive agents in in-vitro chromosome aberrations assays, but aberrations are also induced by chemical that do not directly interact with DNA. This article discusses briefly some important aspects of using aberrations in genetic toxicology testing but concentrates on highlights of recent research on aberrations, in particular two areas: (1) persistence through multiple cell cycles of changes that lead to chromosome aberrations, and (2) the relations among DNA synthesis inhibition, DNA damage, cell cycle regulation, and genomic instability, expressed as chromosome breakage, gene amplification, and aneuploidy. An understanding of these mechanisms not only may lead to insights into carcinogenesis but ultimately may help us to interpret results of chromosome aberration tests and to develop a rational assessment of the degree of human risk implied by a positive aberration test.

Comparison of gene expression changes induced in mouse and human cells treated with direct‐acting mutagens

“…Previous studies have reported that human cells have different control mechanisms over the cell cycle and a significantly different DNA-repair system from rodent cells. Human cells have a strict mitotic control system so that DNA lesions usually result in cell cycle delay or, alternatively, cell death [Kung et al, 1990;Schimke et al, 1991;Kat et al, 1993;Galloway et al, 1994]. In our study, this was evident in Table III. the response of the human TK6 cells to MMS, where gene expression data showed that many DNA-repair and apoptosis genes were induced, and the cell cycle arrest gene (P21…”

“…Alternatively, it has been reported that rodent cells do not have such strict control mechanisms, and cells with DNA damage can proceed through the cell cycle, resulting in lower sensitivity to cytotoxicity and higher sensitivity to chromosomal aberration induction (genetic toxicity) [Kung et al, 1990;Schimke et al, 1991;Kat et al, 1993;Galloway et al, 1994]. In our study, mouse lymphoma L5178Y cells with mutated p53 apparently were unable to undergo the same level of DNA repair and apoptosis as TK6 cells.…”

Antioxidant and Pro-Oxidant Effects of Polyphenolic Compounds and Structure-Activity Relationship Evidence

“…It is known that one of the endpoints of the oxidation of this biomolecule are chromosomal aberrations (CA) which are changes in chromosome structure, visible by light microscopy (Astley & Lindsay, 2002 ). Physical or chemical agents capable of inducing these mechanisms are called clastogens (Bender et al, 1974;Galloway, 1994;Ishidate et al, 1988). The clastogen prediction, starting from a structural analysis, has been postulated by Estrada et al (2006).…”

Biomarkers of Cancer Risk and Therapeutic Benefit: New Technologies, New Opportunities, and Some Challenges

“…The need for methods that allow assessment of in vivo mutagenic risk is highlighted by recent findings that extreme exposure conditions in vitro, which would not be expected to occur under conditions of human or laboratory animal exposure, may cause mutagenicity in the regulatory test battery (Galloway, 1994;Hilliard et al, 1998). Many mutagens act via mechanisms expected to exhibit thresholds below which significant DNA damage would not occur, and this has led to recommendations that factors that may influence activity in vivo must be considered in decision-making related to genotoxic risks (Kirkland and Müller, 2000;Müller and Kasper, 2000).…”