Prenatal smoking is one of the most common preventable causes of infant morbidity and mortality;in the United States, it is estimated that about 13.8% of women smoke during pregnancy. In utero smoke (IUS) exposure has been associated with both perinatal morbidity and the development of complex diseases in later childhood. Additionally, IUS exposure has been associated with alterations in fetal lung development and consequent decreased pulmonary function, early-onset wheeze, and asthma in childhood. DNA methylation is one type of epigenetic change that results in the alteration of gene expression without affecting DNA sequence. In adults, cigarette smoking has been associated with alterations in DNA methylation, which influences the development of adult onset lung diseases such as COPD and lung cancer. In the maternal-fetal system, placental gene expression is a critical element for guiding in utero development. Environmental exposures including nicotine have been demonstrated to cross the placental barrier and impact placental gene expression. In addition to being a source of compounds, maternal cigarette smoking impacts placental hypoxia;placental hypoxia has been associated with up-regulation of genes intrinsic to DNA methylation and epigenetic processes. The major goal of this project is to demonstrate that IUS exposure results in epigenetic changes in the placenta and developing fetus that have downstream impact on the expression of genes crucial to normal human lung development. This application specifically seeks to define the DNA methylation profile of normal early fetal lung development, its correlation with normal gene expression, its relationship to DNA methylation in the developing placenta, and how each of these is altered via IUS. To explore our global hypothesis we will: (1) examine DNA methylation status of greater than 450,000 CpG sites across the epigenome in DNA from 48 IUS-unexposed and 48 IUS-exposed fetal lung samples to identify methylation patterns critical during to the pseudoglandular and canalicular stages of lung development and altered in the setting of IUS exposure;and (2) use placental tissue from the same fetuses from which the lung samples are obtained to identify the epigenomic and genomic profiles of 48 IUS-exposed and 48 IUS-unexposed placentas. We will subsequently compare these profiles within placenta and between placenta and the developing lung. The correlation of epigenomic and genomic profiles within the developing lung will provide a direct functional link to the epigenomics of fetal IUS exposure and set the stage for future work focused on the relevance of these changes to the development of airways disease or other IUS-associated childhood diseases. Moreover, if significant, by sampling placental tissue as a marker of other fetal organs, the placental/fetal lung epigenomic correlation has direct translational implications for the field of neonatology, and efforts to link early-life fetal programming to the development of complex human disease.
This project seeks to identify DNA methylation marks associated with normal and in utero smoke-exposed lung development and with the genetic expression signature during those times. By demonstrating that these marks also correlate with gene expression, the marks can be inferred to have a functional role in smoking-related changes in the developing fetus. This may eventually be used to formulate novel prenatal therapeutic and preventative strategies. Since in utero smoke exposure remains a leading cause of perinatal morbidity and mortality and a major risk factor for the development of complex childhood disease, including asthma, these strategies have the potential to substantially decrease the morbidity and financial burden related to prenatal smoking.
|Chhabra, Divya; Sharma, Sunita; Kho, Alvin T et al. (2014) Fetal lung and placental methylation is associated with in utero nicotine exposure. Epigenetics 9:1473-84|
|Sharma, Sunita; Chhabra, Divya; Kho, Alvin T et al. (2014) The genomic origins of asthma. Thorax 69:481-7|
|Kho, Alvin T; Sharma, Sunita; Qiu, Weiliang et al. (2013) Vitamin D related genes in lung development and asthma pathogenesis. BMC Med Genomics 6:47|