New methods for assessing male germ line mutations in humans and genetic risks in their offspring.
Germ line mutations resulting from chemical or radiation exposure are a particular problem in toxicology as they affect not only the exposed generation but also an infinite number of generations thereafter. Established methods to show that these mutations occur in an F1 or subsequent population require the use of a large number of progeny for statistical significance. Consequently, many thousands of animals have been used in the past. Such a use is no longer considered desirable and is also very expensive. Several new molecular techniques (including analysis of tandem repeats and randomly amplified polymorphic DNA) now provide alternative methods of assessment, which also allow the quantification of individual mutations in individual sperm cells. These can also be applied to human offspring, making extrapolation obsolete. The downside of these methods is that they effectively determine the mutation rate in certain regions of DNA and the relevance of these to diseases, particularly cancer, is not always apparent. Therefore, it must be assumed that an increase in mutation rates in these selected regions correlates with altered phenotype. However, disease types linked to changes in tandem repeat length indicate that these may act as relevant markers for the development of phenotypes. Further research and evaluation are required to more closely link changes in DNA with altered phenotype and validate the use of tandem repeats and randomly amplified polymorphic DNA in transgenerational genotoxicity testing. This paper introduces and compares recently developed methods to assess mutations in sperm due to stem cell damage.
Verhofstad
Nicole
N
Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands.
Linschooten
Joost O
JO
van Benthem
Jan
J
Dubrova
Yuri E
YE
van Steeg
Harry
H
van Schooten
Frederik J
FJ
Godschalk
Roger W L
RW
D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity; D004252:DNA Mutational Analysis / Q000379:methods*; D005190:Family; D018095:Germ-Line Mutation; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D008954:Models, Biological; D009152:Mutagenicity Tests / Q000379:methods; D012306:Risk; D012377:Rodentia; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics
D002274:Carcinogens, Environmental