Effects of maternal smoking on lung function and pulmonary signaling pathways in the offspring : a murine model (2015)

In humans, prenatal smoking has been related to low birth weight in the offspring. Furthermore, prenatally exposed children show lung function alterations until preschool years. Cohort studies revealed that lung function either tracks or declines but never improves later in life. Additionally, in utero cigarette smoke exposed children showed a higher prevalence of chronic obstructive airway disease such as asthma and COPD later in life, which might result from reduced lung function. For both diseases only symptomatic medication is available while curative therapies are lacking. Thus, there is an urgent need to develop novel and effective therapies and preventive strategies. Although prenatal smoking is well known to negatively affect the offspring, the underlying mechanisms of the disease development are largely unknown. Epidemiological studies indicate a transgenerational transmission of disease risk that might contribute to the rises of chronic airway diseases during the past decades. Further, it has been shown that environmental exposures can affect the regulation of essential genes at developmentally critical points. The emerging field of epigenetic mechanism may provide a link between early developmental exposures and disease susceptibility and therefore, might allow intervention and prevention strategies. The present study aimed to establish an animal model of prenatal exposure to active maternal smoking in order to be able to investigate the underlying mechanisms. The phenotype of our smoke exposed offspring closely resembled observations made in prenatally exposed children: First, birth weights were significantly reduced. Second, fetal lung growth was more affected in CS-exposed females pups. Third, lung function deficits were found after intrauterine CS-exposure in both sexes. Fourth, intrauterine CS-exposure seems to increase pulmonary remodeling processes (&alpha;-smooth muscle actin and collagen deposition). Therefore, the established murine model appeared to be suitable to investigate molecular alterations involved in the phenotypic development caused by intrauterine CS. The growth hormone Igf1 was significantly reduced after in utero cigarette smoke exposure in fetal lung. Epigenetic studies revealed a non-significant trend for decreased histone 3 tri-methylation at lysine residue 27 (H3K27met3) at the Igf1 promoter site in whole lung tissue. This histone mark is associated with silencing processes of developmental genes. However, in this context, reduced tri-methylation at H3K27 might result in an increased mRNA expression of the underlying gene. Global histone modification pattern were not affected upon intrauterine CS-exposure. In conclusion, the results suggest that prenatal smoking deregulates pulmonary growth hormones and these alterations might be associated with impaired lung function in the absence of an allergen challenge in adolescents. These results imply that deregulated pulmonary growth hormones may link prenatal cigarette smoke exposure to increased pulmonary disease susceptibility. This established model, is the first murine model with in depth analysis of the outcome of CS-exposure during pregnancy on the maternal and fetal site. Furthermore, the offspring&rsquo;s phenotype was investigated longitudinally which allows comparison to huan situation from the newborn until adulthood. This study suggesting a direct association between intrauterine CS-exposure, postnatal lung function deficits and alterations in a growth hormone which might be caused by changes of the histone code. &nbsp; &nbsp; &nbsp;