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Effect of maternal smoking on early human development

Institution: University of California, San Francisco
Investigator(s): Susan Fisher, Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12RT-0059 Award: $505,975
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
Smoking cigarettes during pregnancy endangers the mother and her unborn child. Humans, unlike most other species, have great difficulty reproducing. The inherent problems increase when women smoke, because smoking makes it much harder for them to become pregnant. Once pregnancy is established, smoking mothers are more prone to early pregnancy loss and serious pregnancy complications than nonsmokers. As a result, the statistics are grim. In 2000, the most recent period for which data are available, the infant mortality rate among smoking mothers was 10.7 in 2,000 births, 65% higher than the rate for nonsmokers. Despite this fact, ~22% of pregnant women smoke. As a result, the costs of smoking during pregnancy, in terms of both dollar amounts and human suffering, are enormous.

Our goal is to understand why smoking does so much harm to the mother and the baby. We hypothesize that one major cause is damage to the placenta. This transient organ, which is made from the baby’s own cells, surrounds the child like a protective bubble. As such, it performs many specialized functions that determine pregnancy outcome. For example, it attaches the baby to the mother’s uterus and taps a blood supply from her vessels. Additionally, the placenta functions like a regulatable sponge that transports food and air to the growing child, while also removing harmful substances.

In work funded by the Tobacco-Related Disease Research Program, we used our knowledge of how the placenta forms and functions in normal pregnancy to understand the damage done by maternal smoking. We took two approaches. First, we collected placentas from women who smoked during pregnancy and studied the expression of molecules that are key regulators of its ability to grow and function normally. Second, in the laboratory we modeled the effects of maternal smoking by exposing placental cells to nicotine, one of the chemicals in cigarette smoke that change the way cells work. We also simulated the effects of exposing placental cells to oxygen starvation, another consequence of smoking. The results of these studies gave us a clear picture, at a molecular level, of the exact mechanisms by which maternal smoking damages the placenta. Remarkably, we found many of the same signs of damage in the placentas of nonsmoking women who were exposed to secondhand cigarette smoke. Together our results explain, in part, why smoking during pregnancy is so dangerous.

Now we propose to examine the effects of maternal smoking and exposure to secondhand cigarette smoke on key steps in the initial stages of human placental and embryonic development. The proposed research plan is based on very recent work from our group. First, we discovered a key component of the mechanism that initiates pregnancy. Specifically, we learned how cells that will become the placenta first attach cells that will become the baby (i.e., embryo) to the uterus. Accordingly, our first goal is to examine the effects of cigarette smoking on this attachment mechanism. Second, we are using unspecified cells of the embryo, termed embryonic stem cells, to study the initial stages of human development in the laboratory. Accordingly, our second specific aim is to examine the effects of cigarette smoking on early embryonic development.

We are very interested in using data from our study to educate reproductive-age women about the dangers of smoking during pregnancy. In addition, our work shows that exposure to secondhand smoke can have the same negative consequences as maternal smoking, information that is critical to prenatal care. At a conceptual level, our findings can be easily incorporated into patient education materials designed to enhance the desire to quit smoking during pregnancy. Specifically, this information lends itself to a graphic depiction of the harm that a mother’s cigarette smoking does to her unborn infant. Finally, pregnancy is an ideal time to approach women about the benefits of smoking cessation because many mothers have increased motivation. If a woman stops on a short-term basis, she may quit permanently, and this would have tremendous health benefits for her and her family.

Cultured human embryonic stem cells as an in vitro model for studying the effects of nicotine on early development.
Periodical: TRDRP Annual Report to the State of California Legislature Index Medicus:
Authors: Genbacev O, Zdravkovic T, Nath A, Fisher S ABS
Yr: 2003 Vol: Nbr: Abs: Pg:

The adverse effects of maternal smoking on the human placenta, A review.
Periodical: Placenta Index Medicus:
Authors: Fisher, SJ, Zdravkovic T, Genbacev O, McMaster MT ART
Yr: 2005 Vol: 26 Nbr: Abs: Pg: S81 - S86

2005 Highlights for phenols, quinolines , Indoles, Benzene and 2- Cyclopenten 1 ones are oviduct Toxicants in Cigarette smoke.
Periodical: Toxicological Sciences Index Medicus:
Authors: Fisher, S, Genbacev O ART
Yr: 0 Vol: Nbr: Abs: Pg:

Nicotine downregulates the L- Selection system that mediates cytotrophoblast emigration from cell columns and attachment to the uterine wall
Periodical: Reproductive Toxicology Index Medicus:
Authors: Zdravkovic T, Genbacev O, Prakobphol A, Cvetkovic M, Schanz A, McMaster M, Fisher SJ, ART
Yr: 2006 Vol: 22 Nbr: Abs: Pg: 69-76

Nicotine downregulates the L-selectin system that mediates cytotrophoblast emigration from cell columns and attachment to the uterine wall
Periodical: Reproductive Toxicology Index Medicus:
Authors: Zadravkovic T, Genbacev O, Prakobphol A, Cvetkovic M, Schanz A, McMaster M, Fisher SJ ABS
Yr: 0 Vol: 22 Nbr: Abs: Pg: 69-76