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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. Unfortunately, mainstream, but also side stream (SS) smoke, increase miscarriage and stillbirth rates. Infants may be born with congenital cardiac defects as well as skeletal defects showing as growth retardation. In 2005, the California EPA estimated that between 24,300 and 71,900 low birth weight or preterm deliveries occur each year in the US as a result of exposure to SS only. However, the molecular mechanisms underlying the actions of mainstream and SS smoke in the developing heart and skeleton are poorly understood and need to be better defined to assess the risk of smoking on the development of embryos and fetuses. Notably, harm-reduction products that claim reduced carcinogen content had similar effects on embryos stressing that harm-reduction products may not be more beneficial to embryo health than conventional brands. However, the rate at which new harm-reduction products are still appearing in the marketplace, untested for safety, is alarming. Because the differential toxicity and teratogenicity of harm-reduction products is not well understood, it is important to compare different brands of harm-reduction products to conventional products and establish baseline information regarding their relative toxicity. The intention of this proposal is to provide new information about the sensitivity of developing cells and organs to harm-reduction and conventional tobacco products and provide quantitative data on multiple morphological and molecular endpoints that could be the basis for determining the safety of various harm-reduction products as well as the basis for possible interventions for those who are not able to stop smoking, especially during pregnancy. It will further increase our understanding of the etiology and pathogenesis of tobacco smoke-induced infertility in women. This goal will be achieved by employing a unique cellular model, the only model that is able to model human embryonic development in vitro: human embryonic stem cells (hESCs). First, I will characterize the molecular mechanism caused by conventional tobacco products on early development. From a mechanistic perspective, cigarette smoke has been described as a potent oxidant leading to oxidative stress in cells. Stem cells are very sensitive to oxidative stress to the extent that their fate can be altered. Under any type of stress, maintaining an undifferentiated state becomes a difficult task for stem cells, and they may rescue themselves from apoptosis by simple differentiation. Previous data confirm that key mediators of oxidative stress responses, the FoxO transcription factors, crosstalk to pathways that normally regulate stem cell fate (Wnt/beta-catenin). I hypothesize that this crosstalk is brought out of balance under influence of tobacco products. Ultimately, if stem cells are redirected at key decision points of development, developmental trajectories may be altered or blocked, explaining the deleterious effects on the developing embryo. Secondly, I will assess risk of harm on the developing fetus caused by harm-reduction tobacco products. Particularly, I will examine risk on the developing heart and skeleton, two organ systems that seem to be affected by tobacco products in the developing fetus with higher priority than other tissues. Achievement of my goal will advance our understanding of the causes of infertility and embryo maldevelopment upon tobacco exposure and therefore will provide new data that could be helpful to health care workers counseling patients. Moreover, my data will have implications for our entire population and how its reproductive health could be affected by both conventional and harm-reduction tobacco products. I will be able to establish the relative safety of various harm-reduction products and obtain data that may be transferred from the laboratory to the clinic, potentially ameliorating adverse health effects to adults and the unborn due to use of traditional and harm-reduction tobacco products. |
