Transgenic
and
In Vivo Mutagenesis
Interest Group
REVIEW
Review of PNAS USA 99:15904-15907, 2002. Somers, CM, CL Yauk, PA White, CLJ Parfett, and JS Quinn. Air pollution induces heritable DNA mutations.
The 25th anniversary issue of Environmental and Molecular Mutagenesis (1994, 23,S24:3-6) commemorated the founding of the Environmental Mutagen Society in 1969 by pointing out the painful fact that the society had been founded with the major goal of identifying germline mutations, but that this had remained largely unachieved. The recent paper by Somers et al., in PNAS has made a major contribution toward demonstrating that environmental mutagens delivered from their environmental sources can affect germ line inheritance. They have utilized genetic techniques developed to detect germ line mutations based on expanded simple tandem repeats, ESTRs1-4. The high rate of spontaneous change of the repeat number reduces the number of offspring animals needed to detect mutations.
Somers et al. detected a significant increase above the spontaneous mutation frequency of ESTRs (20%) in the offspring of mice that were housed under identical conditions except for the location of their cages near steel mills in Hamilton Harbor, ON, CA, or 30 km away in the country. After 10 weeks of exposure, the mice were transferred to the laboratory for breeding 6 weeks later. The primary experimental difference in these groups was considered to be the difference in ambient air. Similar findings had been made with Herring gulls nesting nearby, but the increased mutation frequency could not be attributed to air pollution as opposed to differences in water, food, or disease1,2. The containment of laboratory mice in identical cages with identical sources of food and water eliminated these confounding factors.
Three different ESTRs were used for mutation evaluation, Ms6-hm, Hm-2, and MMS10, the latter of which was also used to verify pup parentage. Parent mice had different alleles based on repeat lengths so that mutations, identified by a change in length of the repeat region, could be assigned to either the paternal or maternal allele. By this method, most of the 1.5 to 2.0-fold increase in mutation frequency could be attributed to mutation of the male gamete. Exposure and breeding were timed so that offspring resulted from exposure to 2n-spermatogonia.
The possibility that human male exposure to industrial air pollution is contributing to the human genetic defect burden is a serious possible consequence of these results. Replication of these results will be important and it remains to be shown that these animals with mutations all pass the mutant allele to the next (F2) generation. This is important to rule out the possibility that somatic mosaicism has been detected rather than germ line inheritance. However, mutations arising in the F1 generation have already been shown to appear in the F2 for radiation-induced ESTR mutations and their doubling dose (F1 mutations) is comparable to measurements by the specific locus test for spermatogonial cells5. In addition, for radiation-treated F0 mice, ESTR mutation rates are also increased in F2 mice5. These assays give promise of detecting germ line mutations in environmentally exposed populations not only of animal, but also of human populations.
1Yauk, CL and JS Quinn. 1996. Multilocus DNA fingerprinting reveals high rate of heritable genetic mutation in herring gulls nesting in an industrialized urban site. PNAS USA 93:12137-12141.
2Yauk CL, GA Fox, BE McCarry, and JS Quinn. 2000. Induced minisatellite germline mutations in herring gulls (Larus argentatus) living near steel mills. Mutation Research 452: 211-218.
3Dubrova, YE, M Plumb, B Gutierrez, E Boulton, AJ Jeffreys. 2000. Transgenerational mutation by radiation. Nature 405:37.
4Dubrova, YE, M pLumb, J Brown, J Fennelly, P. Bois, D. Goodhead, and AJ Jeffreys. 1998. Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation.
5Barber, R, MA Plumb, E. Boulton, I Roux, and YE Dubrova. 2002. Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice. PNAS USA 99:6877-6882.
Submitted by Carrie R. Valentine
All submissions / suggestions considered. email to barry.ford@drdc-rddc.gc.ca