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.
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References
Ahmed A (2014) Molecular mechanisms and therapeutic implications of the carbon monoxide/hmox1 and the hydrogen sulfide/CSE pathways in the prevention of pre-eclampsia and fetal growth restriction. Pregnancy Hypertension 4:243–244
Aiko K, Tsujisawa T, Koseki T, Hashimoto S, Morimoto Y, Amagasa T, Nishihara T (2002) Involvement of cytochrome c and caspases in apoptotic cell death of human submandibular gland ductal cells induced by concanamycin A. Cell Signal 14:717–722
Arffin F, Al-Bayaty FH, Hassan J (2012) Environmental tobacco smoke and stress as risk factors for miscarriage and preterm births. Arch Gynecol Obstet 286:1187–1191
Arroyo JA, Winn VD (2008) Vasculogenesis and angiogenesis in the IUGR placenta. Semin Perinatol 32:172–177
Arroyo JA, Anthony RV, Galan HL (2008) Decreased placental X-linked inhibitor of apoptosis protein in an ovine model of intrauterine growth restriction. Am J Obstet Gynecol 199:80–88
Arroyo JA, Brown LD, Galan HL (2009) Placental mammalian target of rapamycin and related signaling pathways in an ovine model of intrauterine growth restriction. Am J Obstet Gynecol 201(616):e611–e617
Arroyo JA, Li C, Schlabritz-Loutsevitch N, McDonald T, Nathanielsz P, Galan HL (2010) Increased placental XIAP and caspase 3 is associated with increased placental apoptosis in a baboon model of maternal nutrient reduction. Am J Obstet Gynecol 203(364):e313–e368
Barker DJ (1993) Fetal origins of coronary heart disease. Br Heart J 69:195–196
Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS (1993) Fetal nutrition and cardiovascular disease in adult life. Lancet 341:938–941
Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365
Brar HS, Rutherford SE (1988) Classification of intrauterine growth retardation. Semin Perinatol 12:2–10
Chung T, Crilly KS, Anderson WH, Mukherjee JJ, Kiss Z (1997) ATP-dependent choline phosphate-induced mitogenesis in fibroblasts involves activation of pp 70 S6 kinase and phosphatidylinositol 3'-kinase through an extracellular site. Synergistic mitogenic effects of choline phosphate and sphingosine 1-phosphate. J Biol Chem 272:3064–3072
Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, Chellappan S (2006) Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci U S A 103:6332–6337
Dasgupta P, Rizwani W, Pillai S, Kinkade R, Kovacs M, Rastogi S, Banerjee S, Carless M, Kim E, Coppola D, Haura E, Chellappan S (2009) Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines. Int J Cancer 124:36–45
Dempsey DA, Benowitz NL (2001) Risks and benefits of nicotine to aid smoking cessation in pregnancy. Drug Saf 24:277–322
Detmar J, Rennie MY, Whiteley KJ, Qu D, Taniuchi Y, Shang X, Casper RF, Adamson SL, Sled JG, Jurisicova A (2008) Fetal growth restriction triggered by polycyclic aromatic hydrocarbons is associated with altered placental vasculature and AhR-dependent changes in cell death. Am J Physiol Endocrinol Metab 295:E519–E530
Eguchi S, Iwasaki H, Ueno H, Frank GD, Motley ED, Eguchi K, Marumo F, Hirata Y, Inagami T (1999) Intracellular signaling of angiotensin II-induced p70 S6 kinase phosphorylation at Ser(411) in vascular smooth muscle cells. Possible requirement of epidermal growth factor receptor, Ras, extracellular signal-regulated kinase, and Akt. J Biol Chem 274:36843–36851
Esposito ER, Horn KH, Greene RM, Pisano MM (2008) An animal model of cigarette smoke-induced in utero growth retardation. Toxicology 246:193–202
Galan HL (2011) Timing delivery of the growth-restricted fetus. Semin Perinatol 35:262–269
Galan HL, Anthony RV, Rigano S, Parker TA, de Vrijer B, Ferrazzi E, Wilkening RB, Regnault TR (2005) Fetal hypertension and abnormal Doppler velocimetry in an ovine model of intrauterine growth restriction. Am J Obstet Gynecol 192:272–279
Gray PH, O’Callaghan MJ, Harvey JM, Burke CJ, Payton DJ (1999) Placental pathology and neurodevelopment of the infant with intrauterine growth restriction. Dev Med Child Neurol 41:16–20
Gruslin A, Qiu Q, Tsang BK (2001) X-linked inhibitor of apoptosis protein expression and the regulation of apoptosis during human placental development. Biol Reprod 64:1264–1272
Guan J, Mao C, Xu F, Zhu L, Liu Y, Geng C, Zhang L, Xu Z (2009) Low doses of nicotine-induced fetal cardiovascular responses, hypoxia, and brain cellular activation in ovine fetuses. Neurotoxicology 30:290–297
Holcik M, Korneluk RG (2001) XIAP, the guardian angel. Nat Rev Mol Cell Biol 2:550–556
Holemans K, Van BR, Verhaeghe J, Aerts L, Van Assche FA (1993) In vivo glucose utilization by individual tissues in virgin and pregnant offspring of severely diabetic rats. Diabetes 42:530–536
Hung TH, Skepper JN, Charnock-Jones DS, Burton GJ (2002) Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res 90:1274–1281
Iijima Y, Laser M, Shiraishi H, Willey CD, Sundaravadivel B, Xu L, McDermott PJ, Kuppuswamy D (2002) c-Raf/MEK/ERK pathway controls protein kinase C-mediated p70S6K activation in adult cardiac muscle cells. J Biol Chem 277:23065–23075
Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T, Maruo T (2002) Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 186:158–166
Jacobsson B, Hagberg G (2004) Antenatal risk factors for cerebral palsy. Best Pract Res Clin Obstet Gynaecol 18:425–436
Jansson N, Pettersson J, Haafiz A, Ericsson A, Palmberg I, Tranberg M, Ganapathy V, Powell TL, Jansson T (2006) Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet. J Physiol 576:935–946
Jansson T, Aye IL, Goberdhan DC (2012) The emerging role of mTORC1 signaling in placental nutrient-sensing. Placenta 33(Suppl 2):e23–e29
Jeon SY, Lee HJ, Na KH, Cha DH, Kim JK, Park JW, Yoon TK, Kim GJ (2013) Hypoxia-induced downregulation of XIAP in trophoblasts mediates apoptosis via interaction with IMUP-2: implications for placental development during pre-eclampsia. J Cell Biochem 114:89–98
Keogh RJ (2010) New technology for investigating trophoblast function. Placenta 31:347–350
Khader YS, Al-Akour N, Alzubi IM, Lataifeh I (2011) The association between second hand smoke and low birth weight and preterm delivery. Matern Child Health J 15:453–459
Kimball R, Wayment M, Merrill D, Wahlquist T, Reynolds PR, Arroyo JA (2015) Hypoxia reduces placental mTOR activation in a hypoxia-induced model of intrauterine growth restriction (IUGR). Physiol Rep 3(12)
Knuth A, Liu L, Nielsen H, Merril D, Torry DS, Arroyo JA (2014) Placenta Growth Factor Induces Invasion and Activates p70 during Rapamycin Treatment in Trophoblast Cells. Am J Reprod Immunol 73(4):330–340
Kraus DM, Feng L, Heine RP, Brown HL, Caron KM, Murtha AP, Grotegut CA (2014) Cigarette smoke-induced placental adrenomedullin expression and trophoblast cell invasion. Reprod Sci 21:63–71
Levy R, Nelson DM (2000) To be, or not to be, that is the question. Apoptosis in human trophoblast. Placenta 21:1–13
Li J, Sasaki H, Sheng YL, Schneiderman D, Xiao CW, Kotsuji F, Tsang BK (2000) Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant? Biol Signals Recept 9:122–130
Mayhew TM, Ohadike C, Baker PN, Crocker IP, Mitchell C, Ong SS (2003) Stereological investigation of placental morphology in pregnancies complicated by pre-eclampsia with and without intrauterine growth restriction. Placenta 24:219–226
Milnerowicz-Nabzdyk E, Bizon A (2014) Effect of cigarette smoking on vascular flows in pregnancies complicated by intrauterine growth restriction. Reprod Toxicol 50:27–35
Ming XF, Burgering BM, Wennstrom S, Claesson-Welsh L, Heldin CH, Bos JL, Kozma SC, Thomas G (1994) Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature 371:426–429
Mund M, Louwen F, Klingelhoefer D, Gerber A (2013) Smoking and pregnancy--a review on the first major environmental risk factor of the unborn. Int J Environ Res Public Health 10:6485–6499
Patti ME, Brambilla E, Luzi L, Landaker EJ, Kahn CR (1998) Bidirectional modulation of insulin action by amino acids. J Clin Investig 101:1519–1529
Phipps K, Barker DJ, Hales CN, Fall CH, Osmond C, Clark PM (1993) Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36:225–228
Pollack RN, Divon MY (1992) Intrauterine growth retardation: definition, classification, and etiology. Clin Obstet Gynecol 35:99–107
Rahim S, Uren A (2011) A real-time electrical impedance based technique to measure invasion of endothelial cell monolayer by cancer cells. J Vis Exp Apr 1;(50)
Reusens-Billen B, Remacle C, Hoet JJ (1989) The development of the fetal rat intestine and its reaction to maternal diabetes. II. Effect of mild and severe maternal diabetes. Diabetes Res Clin Pract 6:213–219
Reynolds PR, Cosio MG, Hoidal JR (2006) Cigarette smoke-induced Egr-1 upregulates proinflammatory cytokines in pulmonary epithelial cells. Am J Respir Cell Mol Biol 35:314–319
Reynolds PR, Kasteler SD, Cosio MG, Sturrock A, Huecksteadt T, Hoidal JR (2008) RAGE: developmental expression and positive feedback regulation by Egr-1 during cigarette smoke exposure in pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 294:L1094–L1101
Roos S, Jansson N, Palmberg I, Saljo K, Powell TL, Jansson T (2007) Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J Physiol 582:449–459
Roos S, Powell TL, Jansson T (2009) Placental mTOR links maternal nutrient availability to fetal growth. Biochem Soc Trans 37:295–298
Rosenberg A (2008) The IUGR newborn. Semin Perinatol 32:219–224
Ross JC, Fennessey PV, Wilkening RB, Battaglia FC, Meschia G (1996) Placental transport and fetal utilization of leucine in a model of fetal growth retardation. Am J Physiol 270:E491–E503
Smith SC, Baker PN, Symonds EM (1997) Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol 177:1395–1401
Subramoney S, d’Espaignet ET, Gupta PC (2010) Higher risk of stillbirth among lower and middle income women who do not use tobacco, but live with smokers. Acta Obstet Gynecol Scand 89:572–577
Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R (2001) X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and −7 in distinct modes. J Biol Chem 276:27058–27063
Triche EW, Hossain N (2007) Environmental factors implicated in the causation of adverse pregnancy outcome. Semin Perinatol 31:240–242
Varvarigou AA, Asimakopoulou A, Beratis NG (2009) Impact of maternal smoking on birth size: effect of parity and sex dimorphism. Neonatology 95:61–67
Volarevic S, Thomas G (2001) Role of S6 phosphorylation and S6 kinase in cell growth. Prog Nucleic Acid Res Mol Biol 65:101–127
Wahabi HA, Alzeidan RA, Fayed AA, Mandil A, Al-Shaikh G, Esmaeil SA (2013) Effects of secondhand smoke on the birth weight of term infants and the demographic profile of Saudi exposed women. BMC Public Health 13:341
Wen HY, Abbasi S, Kellems RE, Xia Y (2005) mTOR: a placental growth signaling sensor. Placenta 26 Suppl A:S63-S69
Winden DR, Barton DB, Betteridge BC, Bodine JS, Jones CM, Rogers GD, Chavarria M, Wright AJ, Jergensen ZR, Jimenez FR, Reynolds PR (2014) Antenatal exposure of maternal secondhand smoke (SHS) increases fetal lung expression of RAGE and induces RAGE-mediated pulmonary inflammation. Respir Res 15:129
Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484
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This study was supported in part by grant 7R00HD055054-06
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Mejia, C., Lewis, J., Jordan, C. et al. Decreased activation of placental mTOR family members is associated with the induction of intrauterine growth restriction by secondhand smoke in the mouse. Cell Tissue Res 367, 387–395 (2017). https://doi.org/10.1007/s00441-016-2496-5
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DOI: https://doi.org/10.1007/s00441-016-2496-5