Madhulika B Gupta1,2,3, Majida Abu Shehab1, Karen Nygard4, Kyle Biggar5, Sahil S Singal2, Nanette Santoro6, Theresa L Powell6,7, Thomas Jansson6. 1. Department of Pediatrics, University of Western Ontario, London, Ontario, Canada. 2. Department of Biochemistry, University of Western Ontario, London, Ontario, Canada. 3. Children's Health Research Institute, London, Ontario, Canada. 4. Biotron Laboratory, University of Western Ontario, London, Ontario, Canada. 5. Institute of Biochemistry, Carleton University, Ottawa, Ontario, Canada. 6. Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 7. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Abstract
Context: The mechanisms underpinning intrauterine growth restriction (IUGR), as a result of placental insufficiency, remain poorly understood, no specific treatment is available, and clinically useful biomarkers for early detection are lacking. Objective: We hypothesized that human IUGR is associated with inhibition of mechanistic target of rapamycin (mTOR) and activation of amino acid response (AAR) signaling, increased protein kinase casein kinase-2 (CK2) activity, and increased insulin-like growth factor-binding protein 1 (IGFBP-1) expression and phosphorylation in decidua and that maternal plasma IGFBP-1 hyperphosphorylation in the first trimester predicts later development of IUGR. Design, Setting, and Participants: Decidua [n = 16 appropriate-for-gestational age (AGA); n = 16 IUGR] and maternal plasma (n = 13 AGA; n = 13 IUGR) were collected at delivery from two different cohorts. In addition, maternal plasma was obtained in the late first trimester from a third cohort of women (n = 7) who later delivered an AGA or IUGR infant. Main Outcome Measures: Total IGFBP-1 expression and phosphorylation (Ser101/Ser119/Ser169), mTOR, AAR, and CK2 activity in decidua and IGFBP-1 concentration and phosphorylation in maternal plasma. Results: We show that decidual IGFBP-1 expression and phosphorylation are increased, mTOR is markedly inhibited, and AAR and CK2 are activated in IUGR. Moreover, IGFBP-1 hyperphosphorylation in first-trimester maternal plasma is associated with the development of IUGR. Conclusions: These data are consistent with the possibility that the decidua functions as a nutrient sensor linking limited oxygen and nutrient availability to increased IGFBP-1 phosphorylation, possibly mediated by mTOR and AAR signaling. IGFBP-1 hyperphosphorylation in first-trimester maternal plasma may serve as a predictive IUGR biomarker, allowing early intervention.
Context: The mechanisms underpinning intrauterine growth restriction (IUGR), as a result of placental insufficiency, remain poorly understood, no specific treatment is available, and clinically useful biomarkers for early detection are lacking. Objective: We hypothesized that human IUGR is associated with inhibition of mechanistic target of rapamycin (mTOR) and activation of amino acid response (AAR) signaling, increased protein kinase casein kinase-2 (CK2) activity, and increased insulin-like growth factor-binding protein 1 (IGFBP-1) expression and phosphorylation in decidua and that maternal plasma IGFBP-1 hyperphosphorylation in the first trimester predicts later development of IUGR. Design, Setting, and Participants: Decidua [n = 16 appropriate-for-gestational age (AGA); n = 16 IUGR] and maternal plasma (n = 13 AGA; n = 13 IUGR) were collected at delivery from two different cohorts. In addition, maternal plasma was obtained in the late first trimester from a third cohort of women (n = 7) who later delivered an AGA or IUGR infant. Main Outcome Measures: Total IGFBP-1 expression and phosphorylation (Ser101/Ser119/Ser169), mTOR, AAR, and CK2 activity in decidua and IGFBP-1 concentration and phosphorylation in maternal plasma. Results: We show that decidual IGFBP-1 expression and phosphorylation are increased, mTOR is markedly inhibited, and AAR and CK2 are activated in IUGR. Moreover, IGFBP-1 hyperphosphorylation in first-trimester maternal plasma is associated with the development of IUGR. Conclusions: These data are consistent with the possibility that the decidua functions as a nutrient sensor linking limited oxygen and nutrient availability to increased IGFBP-1 phosphorylation, possibly mediated by mTOR and AAR signaling. IGFBP-1 hyperphosphorylation in first-trimester maternal plasma may serve as a predictive IUGR biomarker, allowing early intervention.
Authors: Amanda N Sferruzzi-Perri; Julie A Owens; Prue Standen; Robyn L Taylor; Gary K Heinemann; Jeffrey S Robinson; Claire T Roberts Journal: Am J Physiol Endocrinol Metab Date: 2006-10-24 Impact factor: 4.310
Authors: Ian Damerill; Kyle K Biggar; Majida Abu Shehab; Shawn Shun-Cheng Li; Thomas Jansson; Madhulika B Gupta Journal: Mol Endocrinol Date: 2015-12-29
Authors: Anne M Lynch; Jan E Hart; Ogechi C Agwu; Barbra M Fisher; Nancy A West; Ronald S Gibbs Journal: Am J Obstet Gynecol Date: 2013-12-07 Impact factor: 8.661
Authors: Jenica H Kakadia; Bhawani B Jain; Kyle Biggar; Austen Sutherland; Karen Nygard; Cun Li; Peter W Nathanielsz; Thomas Jansson; Madhulika B Gupta Journal: Am J Physiol Endocrinol Metab Date: 2020-08-03 Impact factor: 4.310
Authors: Madhulika B Gupta; Kyle K Biggar; Cun Li; Peter W Nathanielsz; Thomas Jansson Journal: J Histochem Cytochem Date: 2022-07-08 Impact factor: 4.137