Induced genomic instability in irradiated germ cells and in the offspring; reconciling discrepancies among the human and animal studies

Abstract

Many studies confirmed that radiation induces genomic instability in whole-body systems. However, the results of the studies are not always consistent with each other. Attempts are made in the present review to resolve the discrepancies. Many of the studies in human and experimental animals utilize the length change mutation of minisatellite sequences as a marker of genomic instability. Minisatellite sequences frequently change their length, and the data obtained by conventional Southern blotting give rather qualitative information, which is sometimes difficult to scrutinize quantitatively. This is the problem inevitably associated with the study of minisatellite mutations and the source of some conflicts among studies in humans and mice. Radiation induction of genomic instability has also been assessed in whole-body experimental systems, using other markers such as the mouse pink-eyed unstable allele and the specific pigmentation loci of medaka fish (Oryzias latipes). Even though there are some contradictions, all these studies have demonstrated that genomic instability is induced in the germ cells of irradiated parents, especially of males, and in offspring born to them. Among these, transmission of genomic instability to the second generation of irradiated parents is limited to the mouse minisatellite system, and awaits further clarification in other experimental systems.

New germline mutations in the hypervariable minisatellite CEB1 in the parents of children with leukaemia

“…These and other data suggest that minisatellite mutation rates may be useful biomarkers of germline genetic effects caused by environmental mutagens such as IR (Yauk, 2004;Bouffler et al, 2006). As minisatellites do not appear to be the direct target of mutagen-induced DNA damage (Dubrova et al, 1996(Dubrova et al, , 1997, it is thought that they may act as a marker for general genome sensitivity or instability (Niwa, 2003).…”

Epigenetic changes and nontargeted radiation effects—Is there a link?

“…Other studies focused on heritable alterations in cancer incidence and teratogenesis following the parental preconception irradiation [Mohr et al, 1999;Pils et al, 1999;Nomura, 2003;Nomura et al, 2004;Dasenbrock et al, 2005]. In addition to this classic evidence for transmitted effects, it is now apparent that risks to the progeny of irradiated parents also include transgeneration genomic instability [Carls and Schiestl, 1999;Mohr et al, 1999;Barber et al, 2002Shiraishi et al, 2002;Dubrova, 2003a,b;Morgan, 2003b;Niwa, 2003;Nomura, 2003;Nomura et al, 2004;Slovinska et al, 2004;Dasenbrock et al, 2005;Tawn, 2005;Singer et al, 2006].…”

Comments on the Paper by Wickliffeet al.(Radiat. Res.159, 458–464, 2003)

“…Additionally, in some studies the extent to which somatic mutations (as revealed by mosaicism) are included in the scores is not clear. Niwa (69) points out that the discrepancies may be due to different end points being measured in the two laboratories: embryonic instability after latestage exposures and direct germline mutation after pre-meiotic exposures.…”

“…A number of authors have suggested that epigenetic changes may be involved in transgenerational ESTR mutation (40,42,69). Epigenetic modifications will alter DNA function without changing the underlying nucleotide sequence; one example is that of genes that can be silenced through the methylation of CpG dinucleotides in their regulatory sequences.…”