Maternal smoking and the retinoid pathway in the developing lung.
BACKGROUND
Maternal smoking is a risk factor for pediatric lung disease, including asthma. Animal models suggest that maternal smoking causes defective alveolarization in the offspring. Retinoic acid signaling modulates both lung development and postnatal immune function. Thus, abnormalities in this pathway could mediate maternal smoking effects. We tested whether maternal smoking disrupts retinoic acid pathway expression and functioning in a murine model.


METHODS
Female C57Bl/6 mice with/without mainstream cigarette smoke exposure (3 research cigarettes a day, 5 days a week) were mated to nonsmoking males. Cigarette smoke exposure continued throughout the pregnancy and after parturition. Lung tissue from the offspring was examined by mean linear intercept analysis and by quantitative PCR. Cell culture experiments using the type II cell-like cell line, A549, tested whether lipid-soluble cigarette smoke components affected binding and activation of retinoic acid response elements in vitro.


RESULTS
Compared to tobacco-naïve mice, juvenile mice with tobacco toxin exposure had significantly (P < 0.05) increased mean linear intercepts, consistent with an alveolarization defect. Tobacco toxin exposure significantly (P < 0.05) decreased mRNA and protein expression of retinoic acid signaling pathway elements, including retinoic acid receptor alpha and retinoic acid receptor beta, with the greatest number of changes observed between postnatal days 3-5. Lipid-soluble cigarette smoke components significantly (P < 0.05) decreased retinoic acid-induced binding and activation of the retinoic acid receptor response element in A549 cells.


CONCLUSIONS
A murine model of maternal cigarette smoking causes abnormal alveolarization in association with altered retinoic acid pathway element expression in the offspring. An in vitro cell culture model shows that lipid-soluble components of cigarette smoke decrease retinoic acid response element activation. It is feasible that disruption of retinoic acid signaling contributes to the pediatric lung dysfunction caused by maternal smoking.
Department of Medicine, Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA.
Sara E
SE
Manoli
Lacey A
LA
Smith
Carrie A
CA
Vyhlidal
Chang Hyeok
CH
An
Yolanda
Y
Porrata
Wellington V
WV
Cardoso
Rebecca M
RM
Baron
Kathleen J
KJ
Haley
D000818:Animals; D002460:Cell Line; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000254:growth & development*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*
C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C082925:retinoic acid receptor beta