Genetic susceptibility: Genetic susceptibility to delayed effects following embryonic irradiation

FANC/AFCN : Genetic susceptibility to delayed effects following embryonic irradiation during the very early stages of pregnancy (contract, 2006-2010)

Various studies have shown that, in contrast to what was generally assumed, early embryos of several mouse strains are sensitive to radiation-induction of congenital anomalies (see above). Moreover, other studies performed by us and others suggested that mutations in particular genes could even increase the sensitivity of embryos to such effects but knowledge in that field remains extremely limited.

The aim of the investigations performed in the frame of this project is to determine whether mutations in genes involved in important cellular processes like DNA repair, cell cycle regulation and apoptosis (cell suicide of a damaged cell), can increase the radiation sensitivity of the mammalian embryo during sensitive stages of early pregnancy, leading to increased levels of embryonic death, congenital anomalies, changes in gene expression and/or genomic instability in the irradiated embryos. Emphasis is put on heterozygous mutations (in which only one of the two copies of the gene is mutated), which are relatively numerous in the human population and do generally not affect the viability and the fertility of individuals carrying them.

The embryonic stages chosen for the studies are the one-cell stage (first day of gestation in mammals) and the gastrula stage which immediately follows implantation (beginning of second week in humans and mice). Both stages occur while women are generally not aware of pregnancy.

The first gene whose mutation is investigated for its influence on the embryonic radiation sensitivity is p53, the so-called “genome guardian”, which exerts a key role in the regulation of cell cycle control and the apoptotic process. The two other genes are PARP (involved in the repair of the single-strand breaks in the DNA) and ATM (involved in cell cycle regulation, DNA repair and apoptosis).

This research has clear potential implications for radiation protection, particularly for the highest dose medical examinations performed during the very early developmental stages in women not aware of being pregnant. Since there is evidence in a number of significant areas that early development (the first 7-14 days) has many similarities among mammalian species, it seems reasonable to assume that the conclusions of animal experiments performed during that period could be applicable to the human embryo.

People

Dr. Jacquet Paul , Dr. S. Baatout, Dr. R. Benotmane, Dr. H. Derradji, J. Buset, L. Leyns, A. Michaux, M. Neefs