Cord Blood-Derived Exosomal CNTN2 and BDNF: Potential Molecular Markers for Brain Health of Neonates at Risk for Iron Deficiency

Paulina S Marell, Sharon E Blohowiak, Michael D Evans, Michael K Georgieff, Pamela J Kling, Phu V Tran

Maternal iron deficiency anemia, obesity, and diabetes are prevalent during pregnancy. All are associated with neonatal brain iron deficiency (ID) and neurodevelopmental impairment. Exosomes are extracellular vesicles involved in cell-cell communication. Contactin-2 (CNTN2), a neural-specific glycoprotein, and brain-derived neurotrophic factor (BDNF) are important in neurodevelopment and found in exosomes. We hypothesized that exosomal CNTN2 and BDNF identify infants at risk for brain ID....

Published: 10/19/2019

Nutrients pmid:31623079

Alcohol's Dysregulation of Maternal-Fetal IL-6 and p-STAT3 Is a Function of Maternal Iron Status

Nipun Saini, Kaylee K Helfrich, Sze Ting Cecilia Kwan, Shane M Huebner, Juna Abazi, George R Flentke, Sharon E Blohowiak, Pamela J Kling, Susan M Smith

CONCLUSIONS: These findings suggest that alcohol-driven stimulation of the IL-6/JAK2/STAT3 pathway mediates the elevated hepcidin observed in the PAE dam and fetus. Normalization of these signals by IF suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL-6/JAK2/STAT3 pathway. Prenatal dietary IF represents a potential therapeutic approach for PAE that warrants further investigation.

Published: 09/17/2019

Alcoholism, clinical and experimental research pmid:31524964

Maternal Perceived Stress during Pregnancy Increases Risk for Low Neonatal Iron at Delivery and Depletion of Storage Iron at One Year

Danielle N Rendina, Sharon E Blohowiak, Christopher L Coe, Pamela J Kling

CONCLUSIONS: Maternal recall of stress during pregnancy was associated with lower iron stores at birth. High cord blood ZnPP/H, reflecting low erythrocyte iron, was correlated with the likelihood of stage 1 iron deficiency at 1 year, when rapid growth can deplete storage iron in breastfed infants.

Published: 06/18/2018

The Journal of pediatrics pmid:29908648

The impact of erythropoietin and iron status on brain myelination in the newborn rat

Karen P Flores, Sharon E Blohowiak, Joy J Winzerling, Michael K Georgieff, Pamela J Kling

Erythropoietin (Epo) drives iron (Fe) utilization for erythropoiesis, but the potentially resultant tissue iron deficiency (ID) can also impede brain development. Conversely, Epo binds to Epo receptors (EpoR) on immature brain oligodendrocytes and neurons, promoting growth and differentiation. The objective of the study was to examine the interaction between Epo and Fe on myelination in brain development during daily Epo treatment. Male and female Sprague-Dawley rats from postnatal day (P)...

Published: 04/27/2018

Journal of neuroscience research pmid:29696692

Dietary Iron Fortification Normalizes Fetal Hematology, Hepcidin, and Iron Distribution in a Rat Model of Prenatal Alcohol Exposure

Shane M Huebner, Kaylee K Helfrich, Nipun Saini, Sharon E Blohowiak, Adrienne A Cheng, Pamela J Kling, Susan M Smith

CONCLUSIONS: Maternal oral iron fortification mitigated PAE's disruption of fetal iron homeostasis and improved brain iron content, hematologic indices, and hepcidin production in this rat PAE model. Clinical studies show maternal ID substantially enhances fetal vulnerability to PAE, and our work supports increased maternal dietary iron intake may improve fetal iron status in alcohol-exposed pregnancies.

Published: 04/20/2018

Alcoholism, clinical and experimental research pmid:29672865

Impact of the ovarian cycle and pregnancy on plasma chemistry values in ewes

Micaela E Zywicki, Sharon E Blohowiak, Ronald R Magness, Jeffrey L Segar, Pamela J Kling

Normative data for plasma chemistry values in pregnant and non-pregnant reproductive age ewes are scant. Availability of data would aid monitoring of ewe health for both research and veterinary medicine. We determined specific plasma chemistry 95% confidence reference intervals (RIs) in non-pregnant and pregnant ewes. Mixed Western-breed ewes were grouped based on phase of ovarian cycle: luteal ( n = 15), follicular ( n = 17), or late-gestation pregnant ( n = 102). Plasma samples were collected...

Published: 01/03/2018

Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc pmid:29291683

Ovine uterine space restriction causes dysregulation of the renin-angiotensin system in fetal kidneys

Rachel A Kranch-Shorthouse, Adam S Bauer, Ronald R Magness, Gladys E Lopez, Jeffrey L Segar, Sharon E Blohowiak, Pamela J Kling

CONCLUSIONS: : By late gestation, USR upregulated renal angiotensin receptor expression, an effect with potential functional implications.

Published: 04/11/2017

Biology of reproduction pmid:28395333

Increasing fetal ovine number per gestation alters fetal plasma clinical chemistry values

Micaela Zywicki, Sharon E Blohowiak, Ronald R Magness, Jeffrey L Segar, Pamela J Kling

Intrauterine growth restriction (IUGR) is interconnected with developmental programming of lifelong pathophysiology. IUGR is seen in human multifetal pregnancies, with stepwise rises in fetal numbers interfering with placental nutrient delivery. It remains unknown whether fetal blood analyses would reflect fetal nutrition, liver, and excretory function in the last trimester of human or ovine IUGR In an ovine model, we hypothesized that fetal plasma biochemical values would reflect progressive...

Published: 08/28/2016

Physiological reports pmid:27565903

Prenatal Alcohol Exposure Alters Fetal Iron Distribution and Elevates Hepatic Hepcidin in a Rat Model of Fetal Alcohol Spectrum Disorders

Shane M Huebner, Sharon E Blohowiak, Pamela J Kling, Susan M Smith

CONCLUSIONS: PAE altered fetal iron distribution independent of maternal iron status in rats. The elevated iron content of fetal liver suggests that PAE may have limited iron availability for fetal erythropoiesis and brain development. Altered fetal iron distribution may partly explain why maternal ID substantially worsens growth and behavioral outcomes in PAE.

Published: 05/06/2016

The Journal of nutrition pmid:27146918

Impact of Growth Restriction and Other Prenatal Risk Factors on Cord Blood Iron Status in Prematurity

Patrick J McCarthy, Hannah R Zundel, Kimberly R Johnson, Sharon E Blohowiak, Pamela J Kling

CONCLUSION: Growth-restricted preterm newborns are at risk for poor iron endowment, likely due to uteroplacental insufficiency. Other RFs were less impactful on iron status of premature newborns than in term newborns, likely reflecting that disruptive effects of RFs are more impactful in the third trimester. Understanding RFs for poor iron endowment is important for clinical recognition and treatment of premature babies.

Published: 02/25/2016

Journal of pediatric hematology/oncology pmid:26907656

Dietary-induced gestational iron deficiency inhibits postnatal tissue iron delivery and postpones the cessation of active nephrogenesis in rats

Mary Y Sun, Joseph C Woolley, Sharon E Blohowiak, Zachary R Smith, Ashajyothi M Siddappa, Ronald R Magness, Pamela J Kling

Gestational iron deficiency (ID) can alter developmental programming through impaired nephron endowment, leading to adult hypertension, but nephrogenesis is unstudied. Iron status and renal development during dietary-induced gestational ID (<6 mg Fe kg-1 diet from Gestational Day 2 to Postnatal Day (PND) 7) were compared with control rats (198 mg Fe kg-1 diet). On PND2-PND10, PND15, PND30 and PND45, blood and tissue iron status were assessed. Nephrogenic zone maturation (PND2-PND10), radial...

Published: 02/16/2016

Reproduction, fertility, and development pmid:26876724

Neonatal iron status is impaired by maternal obesity and excessive weight gain during pregnancy

A K Phillips, S C Roy, R Lundberg, T W Guilbert, A P Auger, S E Blohowiak, C L Coe, P J Kling

CONCLUSION: Obesity during pregnancy and excessive weight gain are independent risk factors for iron deficiency in the newborn.

Published: 03/22/2014

Journal of perinatology : official journal of the California Perinatal Association pmid:24651737

Ovine fetal renal development impacted by multiple fetuses and uterine space restriction

K M Meyer-Gesch, M Y Sun, J M Koch, J Ramadoss, S E Blohowiak, R R Magness, P J Kling

Intrauterine growth restriction (IUGR) from uteroplacental dysfunction causes impaired nephrogenesis and ultimately hypertension, but it is unknown whether IUGR caused by insufficient space for placental development seen in uterine anomalies and/or multifetal gestation exerts the same effects. Fetal renal development and metabolism were studied in an ovine space-restriction model by combining unilateral horn surgical ligation and/or multifetal gestation. Reduced placental attachment sites and...

Published: 10/26/2013

Journal of developmental origins of health and disease pmid:24159370

Ovine uterine space restriction alters placental transferrin receptor and fetal iron status during late pregnancy

Mary Y Sun, Jason M Habeck, Katie M Meyer, Jill M Koch, Jayanth Ramadoss, Sharon E Blohowiak, Ronald R Magness, Pamela J Kling

CONCLUSION: Fetal iron was regulated in an organ-specific manner. In USR fetuses, NO-mediated placental adaptations may prevent the normal upregulation of placental TfR at GD130.

Published: 12/04/2012

Pediatric research pmid:23202722

Impact of multiple prenatal risk factors on newborn iron status at delivery

Heather M McLimore, Alyssa K Phillips, Sharon E Blohowiak, Daphne Q-D Pham, Christopher L Coe, Beth A Fischer, Pamela J Kling

BACKGROUND: Maternal anemia and several complications of pregnancy can affect fetal iron acquisition.

Published: 10/09/2012

Journal of pediatric hematology/oncology pmid:23042017

Iron deficiency and renal development in the newborn rat

Keri A Drake, Molly J Sauerbry, Sharon E Blohowiak, Kristin S Repyak, Pamela J Kling

Iron is essential for fetal organ development, but the effect of isolated iron deficiency on nephrogenesis is unknown. Human premature infants are at risk for disrupted nephrogenesis because glomerular development is incomplete until 36-wk gestation. We modeled the effects of iron on postnatal glomerulogenesis in four groups of immature rats from P4 to P12: dam fed controls (DF), dam fed with sham gastrostomy surgery (DF + SS), iron-deficiency anemia (IDA), fed iron-deficient formula through...

Published: 09/05/2009

Pediatric research pmid:19730160

Cord blood zinc protoporphyrin/heme ratio in minority neonates at risk for iron deficiency

Nicole L Baumann-Blackmore, Elizabeth Goetz, Sharon E Blohowiak, Olamide Zaka, Pamela J Kling

We measured cord blood zinc protoporphyrin/heme (ZnPP/H) and plasma ferritin in healthy African-American and Hispanic newborns, matched by gestation with Caucasian newborns. In these at-risk minorities, cord ZnPP/H was higher and plasma ferritin lower, supporting the feasibility of screening newborns at-risk for iron deficiency at birth.

Published: 06/24/2008

The Journal of pediatrics pmid:18571551

Reticulocyte enrichment of zinc protoporphyrin/heme discriminates impaired iron supply during early development

Sharon E Blohowiak, Melinda E Chen, Kristin S Repyak, Nicole L Baumann-Blackmore, David P Carlton, Michael K Georgieff, Thomas D Crenshaw, Pamela J Kling

In infants and children, elevated whole blood zinc protoporphyrin/heme (ZnPP/H) measures iron-deficient (ID) erythropoiesis. Because immature erythrocytes are less dense than mature erythrocytes, we hypothesized that the sensitivity of ZnPP/H is improved if measured in the least dense cells. Blood was collected from control suckling, mildly and severely ID suckling rats. Cord blood was collected after uncomplicated pregnancies (control), diabetic pregnancies (severe ID) and after pregnancies...

Published: 03/25/2008

Pediatric research pmid:18360311

Enteral erythropoietin and iron stimulate erythropoiesis in suckling rats

Pamela J Kling, Andrea Willeitner, Bohuslav Dvorak, Sharon E Blohowiak

CONCLUSIONS: If combined with sufficient iron supplementation, high-dose Epo artificially fed to suckling rats exerted a systemic erythropoietic effect in addition to the previously reported local trophic effects.

Published: 01/29/2008

Journal of pediatric gastroenterology and nutrition pmid:18223381

Zinc protoporphyrin/heme in large-for-gestation newborns

Kelsey J Kleven, Sharon E Blohowiak, Pamela J Kling

CONCLUSIONS: Despite 33% greater body hemoglobin mass observed in healthy large, compared to appropriately grown newborns, mean ZnPP/H was normal. Iron incorporation into erythrocytes in large newborns appears adequate. Because the association of ZnPP/H with size and estimated body hemoglobin was observed only in large newborns, factors determining ZnPP/H may differ between large and appropriately grown newborns.

Published: 03/16/2007

Neonatology pmid:17361092