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Maternal DNA repair of tobacco-induced sperm lesions

Institution: Lawrence Livermore National Laboratory
Investigator(s): Andrew Wyrobek, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0073 Award: $1,046,880
Subject Area: General Biomedical Science
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
This research is important for identifying the genetic mechanisms that might alter a couple's risk for an abnormal pregnancy or defective child when the prospective father smokes cigarettes. There is substantial evidence from human studies associating father's cigarette smoking with reduced semen quality, increased genetic defects in sperm, abnormal pregnancy outcomes such as spontaneous abortion, malformation, neonatal death, and childhood cancer. However, very little is known of the biological mechanisms by which paternal smoking might cause genetic and/or fetal damage, or why some pregnancies are affected and others are not.

This study will investigate the interaction between paternal smoking, damage to sperm and/or embryonic DNA (mutagenesis), and maternal risk for having an abnormal offspring. Research will be conducted to determine whether genetic lesions accumulate in sperm after chronic whole-animal exposure to tobacco smoke constituents and whether specific maternal DNA repair functions are involved in repairing genetic damage in the fertilizing sperm.

Little is known of' the mutagenic effects of mainstream and secondhand tobacco smoke on germ cells and early embryonic development. We have selected the mouse as the model species for this research because the genetics of the mouse are well understood and there is a high degree of similarity between mouse and human DNA repair genes. We propose to expose male mice to a mutagen derived from tobacco smoke and mate them with unexposed female mice to examine chromosomal abnormalities using a new chromosome-painting procedure developed at our institute. Then we will determine the roles of specific DNA repair functions in the maternal processing of genetically-damaged sperm. These methods will be applied to determine whether there is genetic variation in the capacities of certain strains of female mice to change sperm lesions into chromosomal aberrations.

This project represents an important first step towards understanding the mechanisms by which paternal and maternal factors (immediately before and after fertilization) might influence a couple's susceptibility for an abnormal pregnancy resulting from paternal exposure to the mutagenic compounds in tobacco smoke. Once these effects are demonstrated and understood in mice, future studies will determine whether there are corresponding maternal susceptibility genes in humans. This would help to identify families that are at increased risk for a chromosomally defective offspring due to father's exposure to tobacco smoke.
Publications

Differential expression of p53 and DNA repair genes in early mouse embryos
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Lowe X, Marchetti F, Wyrobek AJ ABS
Yr: 1999 Vol: 40 Nbr: Abs: Pg: 155

Does DNA damage accumulate during the post-meiotic phase of spermatogenesis and increase the risk of chromosomal abnormalities in offspring?
Periodical: Environmental and Molecular Mutagenesis Index Medicus:
Authors: Marchetti F, Wyrobek AJ ART
Yr: 2000 Vol: 36 Nbr: Abs: Pg: 41

DNA repair gene expression in mouse oocyte, zygote, and two-cell embryo
Periodical: Environmental and Molecular Mutagenesis Index Medicus:
Authors: Mabery SL, Schahin-Reed D, Marchetti F, Coleman MA, Wyrobek AJ ART
Yr: 2001 Vol: 37 Nbr: Abs: Pg: 49

Localization of double strand break repair proteins during early stages of mouse development
Periodical: Environmental and Molecular Mutagenesis Index Medicus:
Authors: Marchetti F, Hwang M, Wyrobek AJ ART
Yr: 2000 Vol: 37 Nbr: Abs: Pg: 50

Database mining and gene-specific PCR to identify DNA repair genes expressed in early development
Periodical: Environmental and Molecular Mutagenesis Index Medicus:
Authors: Marsh BJ, Mabery S, Coleman MA, Wyrobek AJ ART
Yr: 2001 Vol: 37 Nbr: Abs: Pg: 50

RT-PCR analysis of mouse oocytes and cumulus cells show differential expression of Ku80
Periodical: Environmental and Molecular Mutagenesis Index Medicus:
Authors: Schahin-Reed D, Mabery SL, Marchetti F, Wyrobek AJ ART
Yr: 2001 Vol: 37 Nbr: Abs: Pg: 67

Paternal exposure to cyclophosphamide and dieposybutane induces chromosomal damage and alters the mRNA expression profile during early mouse development.
Periodical: Environmental and Molecular Mutagenesis Index Medicus:
Authors: Cosentino L, Marchetti F, Coleman M, Raja R, Bishop J, and Wyrobek AJ ABS
Yr: 2002 Vol: 39 Nbr: 33 Abs: Pg: 21