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Effects of tobacco-induced gamete damage on embryogenesis

Institution: Lawrence Livermore National Laboratory
Investigator(s): Francesco Marchetti, Ph.D.
Award Cycle: 2004 (Cycle 13) Grant #: 13RT-0140 Award: $158,853
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
This research is important for identifying the biological mechanisms that increase a couple's risk for an abnormal pregnancy or unhealthy child when the prospective father smokes. There is substantial evidence from human studies associating tobacco smoking with an increased possibility of abnormal pregnancy outcomes such as spontaneous abortion, malformation, neonatal death, and childhood cancer. However, little is known about the mechanisms by which tobacco smoke induces damage in paternal germ cells and how this may affect the developing embryo. Also, it is not known whether male germ cells are equally sensitive to mainstream and sidestream tobacco smoke, and why only some pregnancies are affected.

This study will investigate whether animal exposure to mainstream and sidestream tobacco smoke induces lesions in male germ cells that are transmitted to the progeny as chromosomal aberrations. Additionally, we will also investigate whether exposure of male germ cells to tobacco smoke alters gene expression during the early stages of embryonic development and whether these changes are dependent on the presence of chromosomal aberrations.

We have selected the mouse as a model species for this research due to the ethical and legal restrictions on performing this research using human embryos, and because the genetics of the mouse are well characterized and there is a high degree of similarity between mouse and human reproduction and development. We propose to expose male mice to mainstream and sidestream tobacco smoke during the last two weeks prior to mating and to analyze one-cell embryos for chromosomal abnormalities using a procedure developed at our institute. We will then examine the effects of paternal tobacco exposure on gene expression in the early mouse embryo and whether the effects are dependent on the type of exposure (i.e., mainstream vs. sidestream smoke) and on the amount of transmitted damage. For these studies we will use the microarray technology which will allow us to characterize the expression of thousands of genes at once. Finally, we will use bioinformatic tools to identify the regulatory elements that control the embryonic responses to damage transmitted by the sperm.

This project represents an important first-step towards understanding the mechanisms by which paternal factors immediately before fertilization may influence a couple's susceptibility for abnormal pregnancy outcome resulting from exposure to tobacco smoke. Once these effects are demonstrated in mice, these findings will provide information to educate prospective parents that their contributions to healthy pregnancies requires germ cells that have not been exposed to tobacco smoke.

Mechanisms and Consequnces of Paternally Transmitted Chromosomal Abnormalities
Periodical: Birth Defects Research Index Medicus:
Authors: Francesco Marchetti and Andrew Wyrobek ART
Yr: 2005 Vol: C Nbr: 75 Abs: Pg: 112-129