Decreased activation of placental mTOR family members is associated with the induction of intrauterine growth restriction by secondhand smoke in the mouse.
Cigarette smoke is known to be a risk for the development of intrauterine growth restriction (IUGR). Our objective was to assess the effects of secondhand smoke (SHS) during pregnancy and to what extent it regulates the activation of mTOR family members and murine trophoblast invasion. Mice were treated to SHS for 4 days. Placental and fetal weights were recorded at the time of necropsy. Immunohistochemistry was used to determine the level of placental trophoblast invasion. Western blots were utilized to assess the activation of caspase 3, XIAP, mTOR, p70 and 4EBP1 in treated and control placental lysates. As compared to controls, treated animals showed: (1) decreased placental (1.4-fold) and fetal (2.3-fold) weights (p < 0.05); (2) decreased trophoblast invasion; (3) significantly decreased active caspase 3 (1.3-fold; p < 0.02) and increased active XIAP (3.6-fold; p < 0.05) in the placenta; and (4) a significant decrease in the activation of placental mTOR (2.1-fold; p < 0.05), p70 (1.9-fold; p < 0.05) and 4EBP1 (1.3-fold; p < 0.05). Confirmatory in vitro experiments revealed decreased trophoblast invasion when SW71 cells were treated with 0.5 or 1.0 % cigarette smoke extract (CSE). Similar to primary smoking, SHS may induce IUGR via decreased activation of the mTOR family of proteins in the placenta. Increased activation of the placental XIAP protein could be a survival mechanism for abnormal trophoblast cells during SHS exposure. Further, CSE reduced trophoblast invasion, suggesting a direct causative effect of smoke on susceptible trophoblast cells involved in IUGR progression. These results provide important insight into the physiological consequences of SHS exposure and smoke-mediated placental disease.
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Camilo
C
Mejia
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Josh
J
Lewis
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Clinton
C
Jordan
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Juan
J
Mejia
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Connor
C
Ogden
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Troy
T
Monson
College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT, USA.
Duane
D
Winden
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Marc
M
Watson
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA.
Paul R
PR
Reynolds
Lung and Placenta Research Laboratory, Brigham Young University, Physiology and Developmental Biology, Provo, UT, USA. jarroyo@byu.edu.
Juan A
JA
Arroyo
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D005333:Fetus / Q000473:pathology; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014327:Trophoblasts / Q000473:pathology
D014028:Tobacco Smoke Pollution; D058570:TOR Serine-Threonine Kinases
IUGR; Placenta; Secondhand smoke; Trophoblast invasion; mTOR