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Prenatal Nicotine Exposure and Epigenetic Regulation of AT2R

Institution: Loma Linda University
Investigator(s): DaLiao Xiao, Ph.D.
Award Cycle: 2013 (Cycle 22) Grant #: 22XT-0022 Award: $316,000
Subject Area: Environmental Exposure/Toxicology
Award Type: Exploratory/Developmental Award

Initial Award Abstract

Cigarette smoking during pregnancy is associated with numerous adverse outcomes for the developing fetus, as well as an increased risk of poor health in adulthood. Despite negative publicity, however, approximately 15-20% of all women smoke throughout pregnancy, overshadowing the abuse of illicit drugs. In addition, approximately 75% of pregnant smokers report the desire to quit smoking and use nicotine replacement therapy (NRT) for smoking cessation. Although the safety of NRT use during pregnancy has been evaluated in short-term human trials, the long-term effects of fetal nicotine exposure are uncertain. Human and animal studies suggest that nicotine alone may be a key chemical response for many of the long-term effects on the offspring that are associated with maternal cigarette smoking on the offspring. Indeed, our recent studies have discovered that fetal exposure to nicotine impairs cardiovascular function and increases blood pressure responses in the adult male offspring of laboratory rats.

This exciting discovery suggests that smoking during pregnancy may exert a direct effect on fetal development and lead to an increased risk of hypertension in the offspring later in life. The regulation of blood pressure by the peptide hormone Angiotensin II is mediated through its receptors on cell surfaces. We have recently discovered that the nicotine-induced hypertensive response is associated with the altered gene expression of the Angiotensin II receptor type 2 (AT2R). However, a key and complex question that arises is how AT2R gene expression is altered by fetal nicotine exposure. To answer this question, this exploratory/developmental project will explore the cellular/molecular mechanisms underlying in utero exposure to nicotine-induced alteration of AT2R gene expression. This will enable us to develop a working model of how the altered AT2R gene leads to increased vascular resistance and increased susceptibility of elevated blood pressure in the offspring. We also want to understand why this effect occurs in male but not in female offspring.

Project outcomes are expected to provide new evidence that nicotine exposure during pregnancy causes vascular oxidase stress, leading to modification of gene expression by certain genes ( for example, AT2R) through the mechanism of DNA methylation. Our studies will provide a potential mechanistic link between smoking/nicotine patch and gum use by pregnant women, and the development of cardiovascular disease in their offspring. Understanding the mechanisms responsible for the adaptation of the circulatory system in response to nicotine exposure is of fundamental physiologic importance in its own right, as well as having considerable clinical relevance for improving cardiovascular function, and reducing high blood pressure.