Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair
- DOI
- Language of the publication
- English
- Date
- 2015-01-08
- Type
- Article
- Author(s)
- Marchetti, Francesco
- Bishop, Jack
- Gingerich, John
- Wyrobek, Andrew J.
- Publisher
- Nature Research
Abstract
De novo point mutations and chromosomal structural aberrations (CSA) detected in offspring of unaffected parents show a preferential paternal origin with higher risk for older fathers. Studies in rodents suggest that heritable mutations transmitted from the father can arise from either paternal or maternal misrepair of damaged paternal DNA, and that the entire spermatogenic cycle can be at risk after mutagenic exposure. Understanding the susceptibility and mechanisms of transmission of paternal mutations is important in family planning after chemotherapy and donor selection for assisted reproduction. We report that treatment of male mice with melphalan (MLP), a bifunctional alkylating agent widely used in chemotherapy, induces DNA lesions during male mouse meiosis that persist unrepaired as germ cells progress through DNA repair-competent phases of spermatogenic development. After fertilization, unrepaired sperm DNA lesions are mis-repaired into CSA by the egg's DNA repair machinery producing chromosomally abnormal offspring. These findings highlight the importance of both pre- and post-fertilization DNA repair in assuring the genomic integrity of the conceptus.
Plain language summary
There is compelling evidence that many agents present in drugs, food and the environment can cause DNA damage in germ cells (i.e., sperm and eggs) and that if this damage is transmitted to the progeny it can increase the risk of genetic disease in the offspring. Approaches to identify chemicals that cause DNA damage in germ cells are an identified key testing gap. Health Canada is developing methodologies for identifying chemicals that have the potential to cause DNA damage in germ cells and elucidating the biological mechanisms that govern the induction of DNA damage in germ cells, the repair of induced DNA damage and its transmission to the next generation. In the present study, Health Canada used three highly sensitive methods to assess the induction of DNA damage in male germ cells after exposure of mice to the model drug melphalan and to determine whether chromosomal damage was created before or after fertilization. The results showed that although melphalan induced DNA damage before fertilization, chromosomal damage was not created until after fertilization when the egg attempted its repair. These findings highlight the importance of post fertilization events in determining how much DNA damage transmitted by the sperm is converted into chromosomal aberrations that affect the health of the developing embryo. These results increase our understanding of the molecular events that are involved in the transmission of DNA damage from the parents to the offspring and help in developing better approaches to identify chemicals that can affect germ cells and ultimately improve Health Canada’s ability to protect future generations from chemically-induced heritable damage.
Subject
- Health,
- Health and safety