Paternal exposure to ethylnitrosourea results in transgenerational genomic instability in mice.
Recent data shows that the effects of ionizing radiation are not restricted to the directly exposed parental germ cells, but can also manifest in their nonexposed offspring, resulting in elevated mutation rates and cancer predisposition. The mechanisms underlying these transgenerational changes remain poorly understood. One of the most important steps in elucidating these mechanisms is to investigate the initial cellular events that trigger genomic instability. Here we have analyzed the effects of paternal treatment by ethylnitrosourea, an alkylating agent which is known to form specific types of DNA adducts, on the transgenerational effects in the first-generation (F1) offspring of exposed CBA/Ca and BALB/c male mice. Mutation rates at two expanded simple tandem repeat loci were significantly elevated in the F1 germline of both strains. Pre and postmeiotic exposures resulted in similar increases in mutation rate in the F1 germline. Within each strain mutation rates were equally elevated in the germline of male and female F1 offspring of the directly exposed males. The results of our study suggest that transgenerational instability is not attributed to a specific sub-set of DNA lesions, such as double strand breaks, and is most probably triggered by a stress-like response to a generalized DNA damage.
Dubrova
Yuri E
YE
Department of Genetics, University of Leicester, Leicester, United Kingdom. yed2@le.ac.uk
Hickenbotham
Peter
P
Glen
Colin D
CD
Monger
Karen
K
Wong
Hiu-Pak
HP
Barber
Ruth C
RC
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D005038:Ethylnitrosourea / Q000633:toxicity*; D042822:Genomic Instability; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D018812:Paternal Exposure / Q000009:adverse effects*
D000477:Alkylating Agents; D004247:DNA; D005038:Ethylnitrosourea