Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice

Abstract

Mutation rates at two expanded simple tandem repeat loci were studied in the germ line of first-and second-generation offspring of inbred male CBA͞H, C57BL͞6, and BALB͞c mice exposed to either high linear energy transfer fission neutrons or low linear energy transfer x-rays. Paternal CBA͞H exposure to either x-rays or fission neutrons resulted in increased mutation rates in the germ line of two subsequent generations. Comparable transgenerational effects were observed also in neutron-irradiated C57BL͞6 and xirradiated BALB͞c mice. The levels of spontaneous mutation rates and radiation-induced transgenerational instability varied between strains (BALB͞c>CBA͞H>C57BL͞6). Pre-and postmeiotic paternal exposure resulted in similar increases in mutation rate in the germ line of both generations of CBA͞H mice, which together with our previous results suggests that radiation-induced expanded simple tandem repeat instability is manifested in diploid cells after fertilization. The remarkable finding that radiationinduced germ-line instability persists for at least two generations raises important issues of risk evaluation in humans.

Radiation-induced transgenerational alterations in genome stability and DNA damage

“…For both strains, a statistically significant B2-2.8-fold increase in the mean mutation frequency was found in all tissues of the offspring of irradiated males (Table 1). These data therefore confirm our previous results obtained in the germ line of F 1 offspring of irradiated males, using the more traditional pedigree-based approach (Dubrova et al, 2000;Barber et al, 2002) and additionally show that transgenerational genomic instability at ESTR loci is also manifested in somatic tissues. Most importantly, the frequency of ESTR mutation was elevated in the germline (sperm) and somatic tissues of all the offspring of irradiated males (Figure 2a and b).…”

“…Our results therefore demonstrate that transgenerational increases in ESTR mutation rates also reflect corresponding changes at protein-coding genes, mutation at which may result in human genetic disorders. Given that in the male offspring of irradiated males the X-linked hprt locus is transmitted from the non-exposed mothers, these data also confirm the previous conclusion that transgenerational changes in mutation rates equally affect both alleles derived from the irradiated fathers and the unexposed mothers, thus implying a genome-wide destabilization after fertilization (Niwa and Kominami, 2001;Barber et al, 2002;Shiraishi et al, 2002;Dubrova, 2003).…”

“…In our previous studies, we have shown that mutation rates at expanded simple tandem repeat (ESTR) loci were substantially elevated in the germ line of non-exposed offspring of irradiated male mice (Dubrova et al, 2000;Barber et al, 2002). Our results also indicate that most of the offspring of irradiated males show elevated mutation rates in their germ line, therefore providing important evidence for the involvement of epigenetic mechanisms in transgenerational instability.…”

“…Given that the development of cancer is a multistep process in which cells acquire mutations in a specific clonal lineage (Loeb et al, 2003), it would therefore appear that ongoing genomic instability may significantly enhance radiationinduced carcinogenesis (Huang et al, 2003). The data showing elevated mutation rates in the offspring of irradiated parents (Dubrova et al, 2000;Barber et al, 2002) also indicate a potential contribution of genomic instability to transgenerational carcinogenesis (Dubrova, 2003;Nomura, 2003). Taken together, these results imply that the genetic risk of ionizing radiation for humans could be greater than predicted previously.…”

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

“…In addition, somatic mutation of the Ms6-hm sequence can be induced by radiation in highly proliferating tissues such as spleen, but not in the nonproliferating brain cells (Yauk et al, 2002). In contrast, Dubrova and his group indicated that spermatozoa are again insensitive to radiation induction of minisatellite mutation (Barber et al, 2002). Thus, the discrepancy on the spermatozoa radiosensitivity is not resolved at present.…”