title: Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair.
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.
authors.affiliation: 1] Environmental Health Science Research Bureau, Health Canada, Ottawa, Ontario, Canada, K1A 0K9 [2] Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA 94720 [3] Biosciences Department, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.affiliation: National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Bishop
authors.affiliation: Environmental Health Science Research Bureau, Health Canada, Ottawa, Ontario, Canada, K1A 0K9.
authors.forename: John
authors.initials: J
authors.lastname: Gingerich
authors.affiliation: 1] Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA 94720 [2] Biosciences Department, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wyrobek
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D008297:Male; D008540:Meiosis / Q000187:drug effects*; D008558:Melphalan / Q000633:toxicity*; D051379:Mice; D013094:Spermatozoa / Q000187:drug effects / Q000502:physiology; D015053:Zygote / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*
chemical_list: D008558:Melphalan