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 CBA/H, C57BL/6, and BALB/c mice exposed to either high linear energy transfer fission neutrons or low linear energy transfer x-rays. Paternal CBA/H 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 C57BL/6 and x-irradiated BALB/c mice. The levels of spontaneous mutation rates and radiation-induced transgenerational instability varied between strains (BALB/c>CBA/H>C57BL/6). Pre- and postmeiotic paternal exposure resulted in similar increases in mutation rate in the germ line of both generations of CBA/H 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 radiation-induced germ-line instability persists for at least two generations raises important issues of risk evaluation in humans.

Figure 1

Design of the transgenerational study. The exposed male and its offspring are in black; control parents with no history of irradiation are in white.

Figure 2

ESTR mutation rates in the germ line of male (open boxes) and female (hatched boxes) parents. The dates are given for controls, F₀-exposed males, nonexposed females, and F₁/F₂ offspring of irradiated males. The 95% confidence intervals (CIs) for mutation rate estimated from the Poisson distribution and the probabilities of difference between male and female mutation rates in the F₁ and F₂ parents (Fisher's exact test, two-sided) within each generation are shown. The F₀ data for premeiotic exposure (6 weeks after irradiation) are shown.

Figure 3

Transgenerational increases in ESTR germ-line mutation rate. (a) Mutation rates in the germ line of F₁ and F₂ offspring CBA/H male mice exposed to either 0.4 Gy of fission neutrons or 2 Gy of x-rays. (b) Mutation rates in the germ line of F₁ offspring of CBA/H male mice conceived 3 and 6 weeks after paternal exposure to ionizing radiation and in the germ line of pre- and postmeiotically exposed grandfathers (F₂). Aggregated data for the offspring of male mice exposed to x-rays and fission neutrons are given. The probabilities of difference between mutation rates within each generation are shown (a and b). (c) Comparison of spontaneous mutation rates and transgenerational effects in the germ line of three inbred strains of mice. (d) Individual mutation rates in the germ line of F₁ and F₂ parents of exposed males.