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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: 2006 (Cycle 15) Grant #: 15RT-0037 Award: $489,025
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
Maternal smoking is the largest preventable cause of infertility and pregnancy complications in women who would otherwise have uneventful pregnancies. In addition, the babies of women who smoke during pregnancy weigh significantly less than the babies of nonsmoking women. Why is this observation troubling? We now know that restricting infant growth before birth predisposes these individuals to developing cardiovascular disease and diabetes when they become adults. Therefore, the offspring of women who smoke suffer the consequences for the rest of their lives.

Can we as scientists who study human reproduction explain the negative effects of maternal smoking on pregnancy outcome? Our group has been addressing this question in terms of placental function, which we think is the common denominator. We are focusing on the placenta because this transient organ controls pregnancy outcome. For example, its specialized cells regulate the process whereby the embryo attaches to the uterine wall, the first step in pregnancy. If this initial event fails, then the end result is either infertility or early pregnancy loss. Once pregnancy is established, the placenta continues to play an important role by extracting food and oxygen from maternal blood and returning waste products that are produced by the baby. Thus, before birth the placenta performs functions that are taken over by the digestive system, lungs and kidneys after birth. For this reason it is logical to hypothesize that, in many cases, infertility, pregnancy complications and impaired growth of the baby can all be traced to abnormal placental development caused by exposure to cigarette smoke. During the last several years, work from our group has proved this theory correct. Remarkably, we found that exposure to secondhand cigarette smoke often does as much damage as active smoking. Additionally, during the current grant period, we modeled the effects of maternal smoking on early embryonic development by analyzing the effects of cigarette smoke constituents on federally approved human embryonic stem cell lines. Once again, the results revealed an interesting spectrum of specific functional deficits.

Now we propose a different approach for understanding how active and passive maternal smoking adversely affects pregnancy outcome. Instead of targeting specific pathways for analysis, we want to use a different study design, termed a global analysis. In this approach, investigators seek an overview of the effects of the experimental variables they are testing. In our case we want to model the effects of active and passive smoking during pregnancy by exposing human placental and embryonic stem cells to nicotine, a constituent of cigarette smoke that does a great deal of damage. For one thing, nicotine restricts blood flow to the placenta, which, in turn, dangerously reduces oxygen delivery to the baby. To model this situation, we will reduce the amount of oxygen in the laboratory environment in which the cells are maintained. In some cases, we will test the effects of both variables, i.e., adding nicotine and lowering the oxygen environment. Then we will use sophisticated instrumentation to determine, at a global level, how the building blocks (proteins) on which all cellular functions are based are affected.

We think our experiments will yield very significant results. For example, we could discover novel pathways whereby exposure to smoke disrupts normal pregnancy. Furthermore, there is a good possibility that at least a portion of the effects we observe will be applicable to other cells that are harmed by cigarette smoke exposure, such as those that compose the heart and blood vessels. Finally, if the building blocks that change in abundance are secreted into maternal blood, their levels might allow clinicians to assess the extent to which maternal cigarette exposure harms a pregnancy. We envision that this type of test could constitute a powerful inducement for women to stop smoking during pregnancy, which could possibly lead to permanent cessation of smoking, with enormous health benefits to women and their families.

Human embryonic stem cells as a model system for studying the effects of smoke exposure on the embryo
Periodical: Reproductive Toxicology Index Medicus:
Authors: Zdravkovic, T., Genbacev, O., LaRocque, N., McMaster, M., Fisher, S. ART
Yr: 2008 Vol: Nbr: Abs: Pg: