Children born to mothers who smoked during their pregnancy have a higher incidence of lower respiratory tract infections and wheezing during the first year of life. Children born to such mothers also have a higher incidence of persistent wheezing and asthma.

A rapid decline in pulmonary function tests is seen even in non-smoking adults who are exposed to tobacco toxins (TT) in early childhood. Therefore, it is probable that exposure to tobacco toxins in the womb, during lung development might affect its growth and also impair its functioning.

The mechanism by which this lung injury is caused in children exposed to maternal smoking has not been fully explained. One possible pathway that could mediate these deformities is the retinoic acid (RA) signalling pathway.

Retinoic acid (a derivative of vitamin A) is an essential component of cell-cell signaling during vertebrate organogenesis. It is produced due to vitamin A metabolism by successive oxidative reactions from retinyl esters and carotenoids.

Retinoids are critical mediators of alveolar development. They are also involved in the maintenance of normal postnatal lung epithelium and immune responses.

Researchers tested whether maternal smoking causes abnormalities in the retinoic acid (RA) signalling pathway in the lungs of offspring of female mice. These female mice with/without mainstream cigarette smoke exposure (3 research cigarettes a day, 5 days a week) were mated to non-smoking male mice. Exposure to the cigarette smoke was continued throughout the pregnancy and even after delivery. The lung tissue from the offspring was examined by mean linear intercept analysis (it reflects average distance between gas exchange elements) and by quantitative PCR. Cell culture experiments were performed to test whether lipid-soluble cigarette smoke components affected binding and activation of retinoic acid response elements in vitro.

Mice studies have revealed that maternal smoking causes defective alveolarization in the offspring. The beta carotene level in smokers is lower as compared to that of non-smokers. It was found that pregnant adult female mice exposed to cigarette smoke had greater plasma levels of nicotine metabolite (cotinine) and increased levels of median placental cotinine compared to mice with no tobacco exposure. The average litter size and weight of the offspring of the smoking female mice was significantly smaller than the average litter size and weight o the offspring of non-smoking mice. Compared to mice with no exposure to tobacco toxin, juvenile mice with tobacco toxin exposure had significantly increased mean linear intercepts, consistent with an alveolarization defect, that is, the airspace was increased in mice with TT exposure during lung development.

Researchers found that exposure to the tobacco toxin significantly decreased mRNA and protein expression of retinoic acid signaling pathway elements, including retinoic acid receptor alpha and retinoic acid receptor beta. Maximum changes were observed between postnatal days 3-5.

Cigarette smoke condensate decreases RA response element activation in-vitro. Maternal smoking also decreases the expression of RA regulated genes in-vivo. Decreased RA pathway activity may be a mechanism of lung disease caused due to prenatal tobacco exposure. Defective alveolarization following TT exposure during gestational period and neo-natal lung development suggests that the immature lung may have a heightened susceptibility to the effects of TT.

Thus lung development defects related to maternal smoking may be associated with a disruption in retinoic acid signaling, as shown by reduced expression of retinoic acid signaling pathway elements in mice exposed to TT via maternal smoking during lung development. Disruption of RA signalling contributes to the pediatric lung dysfunction.

Reference: Maternal smoking and the retinoid pathway in the developing lung; Sara Manoli et al; BMC Research 2012.


Source-Medindia