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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.

SUBMITTER: Marchetti F

PROVIDER: S-EPMC4286742 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair.

Marchetti Francesco F Bishop Jack J Gingerich John J Wyrobek Andrew J AJ

Scientific reports 20150108

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 ...[more]

PMID: 25567288

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Project description:BackgroundThe preimplantation embryo is sensitive to culture conditions in vitro and poor maternal diet in vivo. Such environmental perturbations can have long-lasting detrimental consequences for offspring health and physiology. However, early embryo susceptibility to other aspects of maternal health and their potential long-term influence into adulthood is relatively unexplored. In this study, we established an in vivo mouse model of maternal periconceptional systemic inflammation by intraperitoneal lipopolysaccharide (LPS) administration on the day of zygote formation and investigated the consequences into adulthood.ResultsIn the short term, maternal LPS challenge induced a transient and typical maternal sickness response (elevated serum proinflammatory cytokines and hypoactive behaviour). Maternal LPS challenge altered preimplantation embryo morphogenesis and cell lineage allocation, resulting in reduced blastocyst inner cell mass (ICM) cell number and a reduced ICM:trophectoderm cell ratio. In the long term, diverse aspects of offspring physiology were affected by maternal LPS treatment. Whilst birthweight, growth and adult blood pressure were unaltered, reduced activity in an open-field behaviour test, increased fat pad:body weight ratio and increased body mass index were observed in male, but not female, offspring. Most importantly, the maternal LPS challenge caused corticosterone-independent blunting of the serum proinflammatory cytokine response to innate immune challenge in both male and female offspring. The suppressed state of innate immunity in challenged offspring was dose-dependent with respect to the maternal LPS concentration administered.ConclusionsThese results demonstrate for the first time that the preimplantation embryo in vivo is sensitive to maternal systemic inflammation, with effects on blastocyst cell lineage allocation and consequences for behaviour, adiposity and innate immune response in adult offspring. Critically, we identify a novel mechanism mediated through maternal-embryonic interactions that confers plasticity in the development of the innate immune system, which is potentially important in setting postnatal tolerance to environmental pathogens. Our study extends the concept of developmental programming of health and disease to include maternal health at the time of conception.

Dataset Information

Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair.

Publications

Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair.

Similar Datasets

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