Decreased activation of placental mTOR family members is associated with the induction of intrauterine growth restriction by secondhand smoke in the mouse

Abstract

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.

Downregulation of Placental Amino Acid Transporter Expression and mTORC1 Signaling Activity Contributes to Fetal Growth Retardation in Diabetic Rats

“…mTORC1 signaling pathway has been considered as a nutrient sensor in the placenta. It has been well studied that placental mTORC1 activity was decreased in IUGR model [6,21], but few studies were taken to investigate the placental mTROC1 changes in pregnancies complicated with diabetes. Our results found that the activity of placental mTORC1 was significantly reduced in a rat model with severe pregestational diabetes.…”

In utero exposure to cigarette smoke and effects across generations: A conference of animals on asthma

“…Exposure to ETS during pregnancy leads to a deregulation of the placental and umbilical cord blood transcriptome in humans . Along this line, a 4‐day exposure to ETS in the last trimester of murine pregnancy decreased placental and fetal weights, which was accompanied by decreased placental activation of the mechanistic Target of Rapamycin (mTOR) family of proteins which are involved in regulation of cell growth via nutrient sensing . Another study demonstrated an increase of substance P airway innervation, neuropeptide Y (NPY) protein levels and density of NPY fibres in the lung, as well as pulmonary levels of nerve growth factor (NGF) later in life after prenatal and early postnatal ETS, which was paralleled by lower lung function .…”

“…As prohibition of smoking in public places is incomplete in many countries, pregnant women can be exposed to environmental tobacco smoke ([ETS], experimentally corresponding to sidestream smoke) at public places as well as at home. ETS is a known risk factor for asthma (reviewed in) and lower birth weight which is also seen in mice …”

“…67 sensing. 56 Another study demonstrated an increase of substance P airway innervation, neuropeptide Y (NPY) protein levels and density of NPY fibres in the lung, as well as pulmonary levels of nerve growth factor (NGF) later in life after prenatal and early postnatal ETS, which was paralleled by lower lung function. 63,68 ETS exposure in adolescent mice did not produce these changes suggesting altered pulmonary innervation developing in response to ETS in early life only.…”

Exercise initiated during pregnancy in rats born growth restricted alters placental mTOR and nutrient transporter expression

“…Cord blood concentrations of essential amino acids are decreased in growth-restricted babies (Jansson et al 2012;Lin et al 2012;Diaz et al 2014;Dimasuay et al 2016), which also often present with hypoglycaemia (Economides & Nicolaides, 1989;Jansson et al 2012;Diaz et al 2014), with both of these outcomes likely due to alterations in placental abundance and localization of glucose and amino acid transporters (Glazier et al 1997;Janzen et al 2013;Cuffe et al 2014;Gardebjer et al 2014;Dimasuay et al 2016;Zhang et al 2016). Interestingly, mTOR signalling is also downregulated in the placenta of IUGR humans (Roos et al 2007;Jansson et al 2012;Diaz et al 2014;Fahlbusch et al 2015) as well as in animal models of reduced fetal growth (Jansson et al 2012;Dimasuay et al 2016;Zhang et al 2016;Mejia et al 2017;Rosario et al 2017). Animal studies have eloquently demonstrated that the disease burden of being born small is not limited to the first directly affected generation (F1), but can be transmitted across generations (Aerts & Van Assche, 2006;Gallo et al 2012Gallo et al , 2013Cheong et al 2016a).…”