Tobacco sensitive regulation of pro-osteogenic promoters

Birth defects are the leading cause of infant mortality in the United States. Defects that affect the bones alone account for 6% of all infant deaths. A strong risk factor for developing such a defect is exposure of the mother to tobacco during pregnancy. Most women begin smoking in their teenage years, become addicted to nicotine early in life, and find it very difficult to quit, even during pregnancy. Smoking is associated with these adverse health consequences because cigarette smoke is made of a large mixture of toxic substances which may enter the babies' system when mothers smoke voluntarily. Also, the World Health Organization has estimated that 10% of the world population is involuntarily exposed to environmental smoke, which represents another route of exposure for the developing baby. In fact, 45% of fathers are smoking at a child’s birth in a survey of 21 centers in 17 countries. However, the molecular mechanism of how tobacco contributes to these birth defects is not known.

The aim of this proposal is to provide first insight into such molecular regulatory mechanisms of tobacco-associated birth defects with a particular focus on birth defects involving bones and the skeleton. Because it is unethical to do testing on humans embryos, human stem cells will be used to model the growth of an embryo in a dish. The first aim of this project will assess changes to the molecular gene expression signature caused by popular tobacco products when stem cells develop into bone tissue. Specifically, three tobacco products that we have previously shown to inhibit the deposition of calcium, a hallmark of bone tissue, will be used for these studies. The second aim will determine the capability of these products to alter the levels of regulators of such gene expression changes in response to tobacco exposure. Experiments will evaluate how these regulators can stop bone production in a manner dependent on tobacco.
This proposal is expected to yield new data on the elucidation of how bone abnormalities arise in newborns due to the toxicity of tobacco. Specifically, the proposed project addresses TRDRP’s research priority 2 as it will help in uncovering the mode of action of tobacco in inducing disease. Ultimately, it will provide insights as to how children from environments in which their parents frequently smoked develop diseases prior to birth. This new information on birth defects will help the TRDRP in updating policy to regulate tobacco products.