Secondhand Smoke and Human Prenatal Development
Abstracts
Initial Award Abstract |
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Our proposal addresses the effects of two specific chemicals (3-ethylpyridine and pyrazine) in secondhand smoke on the development and health of humans prior to birth. Unborn humans are generally far more sensitive to environmental chemicals than adults. However, most prior work on secondhand smoke chemicals has been done using adult animal models and rarely have such studies experimentally investigated prenatal development using human cells. In animal models, 3-ethylpyridine and pyrazine inhibit blood vessel development, growth of embryonic membranes, and functioning of hamster oviducts at low doses. When pregnant hamsters were exposed to these chemicals, anatomical abnormalities occurred in reproductive organs and fetuses were smaller than normal. These toxicants are found in commercial cigarettes at concentrations that greatly exceed the lowest effective doses in our bioassays. Our proposed study will be the first to compare the potency of these chemicals using adult and prenatal human cells and will provide new information on how secondhand smoke effects human development prior to birth. In our first Specific Aim, we will identify the types of cells that are targeted by 3-ethylpyridine and pyrazine in humans and the response (cell death or proliferation) of each targeted cell to these chemicals. We will use in vitro cultures of cells from various human sources to determine the doses that produce a 50% effect and the lowest observable adverse effect for each targeted cell type. We will also determine if developing cells are affected by lower doses than adult cells. In our second Specific Aim, we will perform experiments to characterize the effect of secondhand smoke toxicants (3-ethylpyridine and pyrazine) on the process of differentiation of human endothelial cells and their subsequent survival using a novel high throughput assay. Endothelial cells line the blood vessels of all organs and are essential for normal development and growth. Anything that comprises differentiation of endothelial could have adverse consequences on health both prior to and after birth. We will use the best model currently available for toxicological studies on human prenatal development. This model uses aggregates of human embryonic stem cells, called embryoid bodies, whose differentiation into endothelial cells can be controlled. This assay offers an excellent opportunity to perform experiments that can not be done with human embryos, and thereby gain new information on how secondhand smoke affects the unborn. This assay will be used in dose response experiments to determine the effect of 3-ethylpyridine and pyrazine on initiation of differentiation of endothelial cells and on their survival once differentiation has begun. Benefits to the public: It is important to understand how chemicals in secondhand smoke affect prenatal development in human smokers. Our experiments will be the first to investigate the effects of 3-ethylpyridine and pyrazine on developing human cells. 3-Ethylypyridine and pyrazine are commonly added to cigarettes and other consumer products. Even harm reduction cigarettes have high enough levels of these chemicals to be inhibitory in our bioassays. Our data may persuade tobacco companies to stop adding these chemicals to cigarettes and may lead to a more cautious use of these chemicals in consumer products, thereby reducing overall human exposure. Our data will also be useful to physicians trying to persuade pregnant women not to smoke actively or passively. It is likely that our data will be of general interest to medicine as many of the cells we will study (such as those lining blood vessels) occur throughout the body. It is also likely that our results could impact policy and law-making on smoking in public places. Finally, our work will advance the development and use a new high throughput assay for toxicity testing which will provide data directly relevant to prenatal development in humans and reduce the need for animal research. Finally, these studies will form the framework for future work on other toxicants in secondhand smoke and on more detailed characterization of their actions on human cells. |
