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1.
Nutrients ; 11(10)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623079

RESUMO

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. Umbilical cord blood samples were measured for iron status. Maternal anemia, diabetes, and body mass index (BMI) were recorded. Cord blood exosomes were isolated and validated for the exosomal marker CD81 and the neural-specific exosomal marker CNTN2. Exosomal CNTN2 and BDNF levels were quantified by ELISA. Analysis of CNTN2 and BDNF levels as predictors of cord blood iron indices showed a direct correlation between CNTN2 and ferritin in all neonates (n = 79, ß = 1.75, p = 0.02). In contrast, BDNF levels inversely correlated with ferritin (ß = -1.20, p = 0.03), with stronger association in female neonates (n = 37, ß = -1.35, p = 0.06), although there is no evidence of a sex-specific effect. Analysis of maternal risk factors for neonatal brain ID as predictors of exosomal CNTN2 and BDNF levels showed sex-specific relationships between infants of diabetic mothers (IDMs) and CNTN2 levels (Interaction p = 0.0005). While male IDMs exhibited a negative correlation (n = 42, ß = -0.69, p = 0.02), female IDMs showed a positive correlation (n = 37, ß = 0.92, p = 0.01) with CNTN2. A negative correlation between BNDF and maternal BMI was found with stronger association in female neonates (per 10 units BMI, ß = -0.60, p = 0.04). These findings suggest CNTN2 and BNDF are respective molecular markers for male and female neonates at risk for brain ID. This study supports the potential of exosomal markers to assess neonatal brain status in at-risk infants.

2.
Alcohol Clin Exp Res ; 43(11): 2332-2343, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31524964

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) causes long-term growth and neurodevelopmental deficits that are worsened by maternal iron deficiency (ID). In our preclinical rat model, PAE causes fetal anemia, brain ID, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron-fortified (IF) diet. Here, we hypothesize that iron status and PAE dysregulate the major upstream pathways that govern hepcidin production-EPO/BMP6/SMAD and IL-6/JAK2/STAT3. METHODS: Pregnant, Long Evans rat dams consumed ID (2 to 6 ppm iron), iron-sufficient (IS, 100 ppm iron), or IF (500 ppm iron) diets and received alcohol (5 g/kg) or isocaloric maltodextrin daily from gestational days (GD) 13.5 to 19.5. Protein and gene expression were quantified in the 6 experimental groups at GD 20.5. RESULTS: PAE did not affect Epo or Bmp6 expression, but reduced p-SMAD1/5/8/SMAD1/5/8 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.01). In contrast, PAE stimulated maternal hepatic expression of Il-6 (p = 0.03) and elevated p-STAT3/STAT3 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.02). PAE modestly elevated maternal Il-1ß, Tnf-α, and Ifn-γ. Fetal cytokine responses to PAE were muted compared with dams, and PAE did not affect hepatic Il-6 (p = 0.78) in IS and ID fetuses. Dietary iron fortification sharply attenuated Il-6 expression in response to PAE, with IF driving a 150-fold decrease (p < 0.001) in maternal liver and a 10-fold decrease (p < 0.01) in fetal liver. The IF diet also normalized p-STAT3/STAT3 ratios in both maternal and fetal liver. 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.

3.
J Pediatr ; 200: 166-173.e2, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29908648

RESUMO

OBJECTIVE: To investigate the impact of maternal stress during pregnancy on newborn iron and stage 1 iron deficiency at 1 year of age. STUDY DESIGN: In total, 245 mothers and their newborn infants (52% male; 72% white) were recruited at the Meriter Hospital Birthing Center on the basis of known risk factors for iron deficiency. Umbilical cord blood hemoglobin and zinc protoporphyrin/heme (ZnPP/H) were determined to evaluate erythrocyte iron and plasma ferritin was determined to reflect storage iron. Mothers retrospectively reported stress experienced previously during pregnancy on a 25-item questionnaire. Blood was also was collected from 79 infants who were breastfed at 1 year of age. RESULTS: Maternal recall of distress and health concerns during pregnancy correlated with cord blood ZnPP/H indices (r = 0.21, P < .01), even in the absence of major traumatic events. When concurrent with other known risks for iron deficiency, including maternal adiposity, socioeconomic status, and race, maternal stress had a summative effect, lowering cord blood iron. At 1 year, 24% of infants who were breastfed had moderate iron deficiency (plasma ferritin <12 µg/L). Higher cord blood ZnPP/H was predictive of this moderate iron deficiency (95% CI 0.26-1.47, P = .007). When coincident with maternal reports of gestational stress, the likelihood of low plasma ferritin at 1 year increased 36-fold in breastfed infants as compared with low-stress pregnancies (95% CI 1.33-6.83, P = .007). 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.


Assuntos
Anemia Ferropriva/sangue , Recém-Nascido Prematuro/sangue , Exposição Materna/efeitos adversos , Complicações na Gravidez , Estresse Psicológico/sangue , Adolescente , Adulto , Anemia Ferropriva/epidemiologia , Anemia Ferropriva/etiologia , Feminino , Ferritinas/sangue , Seguimentos , Idade Gestacional , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Wisconsin/epidemiologia , Adulto Jovem
4.
Alcohol Clin Exp Res ; 42(6): 1022-1033, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29672865

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) causes neurodevelopmental disability. Clinical and animal studies show gestational iron deficiency (ID) exacerbates PAE's behavioral and growth deficits. In rat, PAE manifests an inability to establish iron homeostasis, increasing hepcidin (maternal and fetal), and fetal liver iron while decreasing brain iron and promoting anemia. Here, we hypothesize dietary iron fortification during pregnancy may mitigate alcohol's disruption of fetal iron homeostasis. METHODS: Pregnant Long-Evans rats, fed iron-sufficient (100 ppm iron) or iron-fortified (IF; 500 ppm iron) diets, received either 5 g/kg alcohol (PAE) or isocaloric maltodextrin daily on gestational days (GD) 13.5 through 19.5. Maternal and fetal outcomes were evaluated on GD20.5. RESULTS: PAE reduced mean fetal weight (p < 0.001) regardless of maternal iron status, suggesting iron fortification did not improve fetal growth. Both PAE (p < 0.01) and IF (p = 0.035) increased fetal liver iron. In fetal brain, PAE (p = 0.015) affected total (p < 0.001) and nonheme iron (p < 0.001) such that iron fortification normalized (p = 0.99) the alcohol-mediated reductions in brain iron and nonheme iron. Iron fortification also improved fetal hematologic indices in PAE including hemoglobin, hematocrit, and mean cell volume (ps<0.001). Iron fortification also normalized hepcidin expression in alcohol-exposed maternal and fetal liver. Neither diet nor PAE affected transferrin (Tf) and ferritin (FTN) content in fetal liver, nor Tf or transferrin receptor in fetal brain. However, IF-PAE fetal brains trended to less FTN content (p = 0.074), suggesting greater availability of nonstorage iron. In PAE, hepcidin levels were linearly related to increased liver iron stores and decreased red blood cell count and brain iron. 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.


Assuntos
Feto/irrigação sanguínea , Hepcidinas/biossíntese , Ferro na Dieta/farmacologia , Ferro/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Índices de Eritrócitos/efeitos dos fármacos , Feminino , Ferritinas/metabolismo , Desenvolvimento Fetal , Feto/efeitos dos fármacos , Hematócrito , Hemoglobinas/efeitos dos fármacos , Homeostase , Fígado/metabolismo , Masculino , Gravidez , Ratos , Receptores da Transferrina/biossíntese , Transferrina/metabolismo
5.
J Neurosci Res ; 96(9): 1586-1599, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29696692

RESUMO

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) P4-P12 modeled premature newborns. Dam-fed Fe-sufficient (IS) or postnatal ID groups were given daily subcutaneous sham or erythropoietic Epo injections (425 U. kg-1. d-1 ), ± oral Fe (6 mg. kg-1. d-1 ). Tissues and blood were collected and studied at P12. Epo in the ID groups, in the absence of oral Fe, stimulated microcytic ID anemia along with raising inflammatory markers. Both the microcytic anemia and inflammation improved in the ID + Epo + Fe group. Fe treatment positively impacted erythropoiesis and body Fe (µg/g) in all groups. Relative brain Fe (µg/g rat) was improved in the IS + Epo + Fe group. Brain Fe was not worsened in +Epo groups. Brain weight and brain Fe were related to plasma Epo levels. Amount of myelination was impacted by feeding type, but was not inhibited by Epo. Expression of a protein in myelin, mylein basic protein, was greater in all +Fe groups than -Fe groups. With therapeutic Epo, available body Fe was prioritized for erythropoiesis instead of brain, but Epo did not worsen brain Fe and potentially Epo improved myelination and maturation in the brain.


Assuntos
Cerebelo/fisiologia , Eritropoetina/metabolismo , Hipocampo/fisiologia , Ferro/metabolismo , Animais , Animais Recém-Nascidos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Eritropoese , Eritropoetina/administração & dosagem , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ferro/administração & dosagem , Masculino , Proteína Básica da Mielina/metabolismo , Bainha de Mielina , Ratos Sprague-Dawley
6.
J Vet Diagn Invest ; 30(2): 238-244, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29291683

RESUMO

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 for analysis on a commercial biochemical analyzer. For RIs, chemistry panels for the 3 groups of ewes included nutrients and metabolites (glucose, triglycerides, cholesterol, urea, creatinine, total protein, albumin, and bilirubin), enzymes (lactate dehydrogenase, aspartate transaminase, gamma-glutamyl transferase, alanine aminotransferase, and alkaline phosphatase [ALP]), and micronutrients (calcium, phosphorus, iron, sodium, potassium, and chloride). Sample chemistry values for glucose and total protein in pregnant ewes were lower than in follicular ewes; cholesterol was lower in pregnant and luteal ewes than in follicular ewes. In addition, total bilirubin in pregnant ewes differed from that in luteal ewes, and that in follicular ewes also differed from luteal ewes. ALP in pregnant ewes was higher than other groups; phosphorus in pregnant ewes was lower than in luteal ewes. Iron was higher in pregnant ewes than in luteal ewes, with iron in luteal ewes lower than in follicular ewes. These data provide clinical RIs comparing pregnant and non-pregnant ewes for use in monitoring ewe health in both human research and veterinary medicine.


Assuntos
Alanina Transaminase/sangue , Ciclo Estral/fisiologia , Prenhez/fisiologia , Ovinos/sangue , Albuminas/metabolismo , Animais , Bilirrubina/sangue , Análise Química do Sangue/veterinária , Glicemia , Colesterol/sangue , Ciclo Estral/sangue , Feminino , Micronutrientes/sangue , Gravidez , Prenhez/sangue , Valores de Referência , Triglicerídeos/sangue
7.
Biol Reprod ; 96(1): 211-220, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395333

RESUMO

In ovine pregnancy, uterine space restriction (USR) resulting from decreased space for placental attachment caused intrauterine growth restriction and impaired nephrogenesis. The fetal kidney renin-angiotensin system (RAS) is involved in nephrogenesis, fluid balance, and iron deposition. Angiotensin II exerts its effects via multiple receptors: angiotensin II 1-8 receptor type 1 (AT 1 R) and type 2 (AT 2 R), and angiotensin II 1-7 Mas receptor (MASR). Objective: : To test the hypothesis that ovine USR is associated with dysregulation of the fetal renal RAS. Methods: : Multiparous pregnant ewes (n = 32), 16 with surgical bifurcated disconnection of one uterine horn to further reduce placental attachment sites, were studied. USR (n = 31) ovine fetuses were compared to nonspace restricted (NSR) singleton controls (n = 22) on gestational day (GD) 120 or GD130, term GD147. Fetal plasma was collected to evaluate plasma renin activity and iron indices. Fetal kidney AT 1 R, AT 2 R, and MASR proteins were assessed by Western immunoblotting and immunohistochemistry. Results: : AT 1 R, AT 2 R, and MASR protein expression was higher in USR at GD130 than aged-matched NSR and USR at GD120, ( P < 0.05 all). AT 1 R and AT 2 R localization was homogenous throughout proximal and distal tubules in both USR and NSR at both gestational dates. MASR localization was punctate throughout renal cortical structures including tubules and glomeruli in both USR and NSR, shifted to intranuclear at GD130. Plasma renin activity was inversely related to plasma osmolarity ( P < 0.02) and was downregulated in USR at GD130 ( P < 0.05). Conclusions: : By late gestation, USR upregulated renal angiotensin receptor expression, an effect with potential functional implications.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Córtex Renal/metabolismo , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Animais , Creatinina/sangue , Modelos Animais de Doenças , Feminino , Ferro/metabolismo , Concentração Osmolar , Gravidez , Renina/sangue , Ovinos
8.
Physiol Rep ; 4(16)2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27565903

RESUMO

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 placental, fetal liver, and fetal kidney dysfunction as the number of fetuses per gestation rose. To determine fetal plasma biochemical values in singleton, twin, triplet, and quadruplet/quintuplet ovine gestation, we investigated morphometric measures and comprehensive metabolic panels with nutritional measures, liver enzymes, and placental and fetal kidney excretory measures at gestational day (GD) 130 (90% gestation). As anticipated, placental dysfunction was supported by a stepwise fall in fetal weight, fetal plasma glucose, and triglyceride levels as fetal number per ewe rose. Fetal glucose and triglycerides were directly related to fetal weight. Plasma creatinine, reflecting fetal renal excretory function, and plasma cholesterol, reflecting placental excretory function, were inversely correlated with fetal weight. Progressive biochemical disturbances and growth restriction accompanied the rise in fetal number. Understanding the compensatory and adaptive responses of growth-restricted fetuses at the biochemical level may help explain how metabolic pathways in growth restriction can be predetermined at birth. This physiological understanding is important for clinical care and generating interventional strategies to prevent altered developmental programming in multifetal gestation.


Assuntos
Sangue Fetal/química , Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/fisiopatologia , Feto/fisiologia , Placenta/fisiologia , Prenhez , Gravidez Múltipla/fisiologia , Carneiro Doméstico/crescimento & desenvolvimento , Animais , Química Clínica , Feminino , Sangue Fetal/metabolismo , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Idade Gestacional , Tamanho do Órgão , Placenta/metabolismo , Gravidez , Ovinos , Carneiro Doméstico/fisiologia
9.
J Nutr ; 146(6): 1180-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27146918

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) causes neurodevelopmental disabilities, and gestational iron deficiency (ID) selectively worsens learning and neuroanatomical and growth impairments in PAE. It is unknown why ID worsens outcomes in alcohol-exposed offspring. OBJECTIVE: We hypothesized that PAE alters maternal-fetal iron distribution or its regulation. METHODS: Nulliparous, 10-wk-old, Long-Evans rats were mated and then fed iron-sufficient (100 mg Fe/kg) or iron-deficient (≤4 mg Fe/kg) diets. On gestational days 13.5-19.5, dams received either 5.0 g ethanol/kg body weight (PAE) or isocaloric maltodextrin by oral gavage. On gestational day 20.5, maternal and fetal clinical blood counts, tissue mineral and iron transport protein concentrations, and hepatic hepcidin mRNA expression were determined. RESULTS: In fetal brain and liver (P < 0.001) and in maternal liver (P < 0.005), ID decreased iron (total and nonheme) and ferritin content by nearly 200%. PAE reduced fetal bodyweight (P < 0.001) and interacted with ID (P < 0.001) to reduce it by an additional 20%. Independent of maternal iron status, PAE increased fetal liver iron (30-60%, P < 0.001) and decreased brain iron content (total and nonheme, 15-20%, P ≤ 0.050). ID-PAE brains had lower ferritin, transferrin, and transferrin receptor content (P ≤ 0.002) than ID-maltodextrin brains. PAE reduced fetal hematocrit, hemoglobin, and red blood cell numbers (P < 0.003) independently of iron status. Unexpectedly, and also independent of iron status, PAE increased maternal and fetal hepatic hepcidin mRNA expression >300% (P < 0.001). 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.


Assuntos
Transtornos do Espectro Alcoólico Fetal/sangue , Hepcidinas/metabolismo , Ferro/sangue , Ferro/deficiência , Anemia Ferropriva/sangue , Animais , Peso Corporal , Encéfalo/metabolismo , Dieta , Modelos Animais de Doenças , Feminino , Ferritinas/genética , Ferritinas/metabolismo , Hematócrito , Hemoglobinas/metabolismo , Hepcidinas/genética , Ferro/administração & dosagem , Fígado/metabolismo , Troca Materno-Fetal , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Long-Evans , Receptores da Transferrina/metabolismo , Transferrina/metabolismo
10.
J Pediatr Hematol Oncol ; 38(3): 210-5, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26907656

RESUMO

OBJECTIVE: To determine whether prenatal risk factors (RFs) that predict cord blood iron status in term newborns also predict iron status of premature newborns. STUDY DESIGN: Cord blood iron indices from 80 preterm newborns were compared with historical and demographic RFs for developing iron deficiency if born at term. RESULT: The presence of multiple RFs did not incrementally interfere with cord iron status in preterm newborns. Poorer iron status accompanied being small for gestational age in prematurity, but other RFs, including diabetes, had relatively little impact. 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.


Assuntos
Sangue Fetal/química , Retardo do Crescimento Fetal/sangue , Recém-Nascido Prematuro/sangue , Ferro/sangue , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez/sangue , Estudos Prospectivos , Fatores de Risco
11.
Reprod Fertil Dev ; 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26876724

RESUMO

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 glomerular counts (RGCs), glomerular size density and total planar surface area (PND15 and PND30) were also assessed. Blood pressure (BP) was measured in offspring. ID rats were smaller, exhibiting lower erythrocyte and tissue iron than control rats (PND2-PND10), but these parameters returned to control values by PND30-PND45. Relative kidney iron (µg g-1 wet weight) at PND2-PND10 was directly related to transport iron measures. In ID rats, the maturation of the active nephrogenic zone was later than control. RGCs, glomerular size, glomerular density, and glomerular planar surface area were lower than control at PND15, but returned to control by PND30. After weaning, the kidney weight/rat weight ratio (mg g-1) was heavier in ID than control rats. BP readings at PND45 were lower in ID than control rats. Altered kidney maturation and renal adaptations may contribute to glomerular size, early hyperfiltration and long-term renal function.

12.
Pediatr Res ; 73(3): 277-85, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23202722

RESUMO

BACKGROUND: Fetal growth restriction is reported to be associated with impaired placental iron transport. Transferrin receptor (TfR) is a major placental iron transporter in humans but has not been studied in sheep. TfR is regulated by both iron and nitric oxide (NO), the molecule produced by endothelial nitric oxide synthase (eNOS). We hypothesized that limited placental development downregulates both placental TfR and eNOS expression, thereby lowering fetal tissue iron. METHODS: An ovine surgical uterine space restriction (USR) model, combined with multifetal gestation, tested the extremes of uterine and placental adaptation. Blood, tissues, and placentomes from non-space restricted (NSR) singletons were compared with USR fetuses at gestational day (GD) 120 or 130. RESULTS: When expressed proportionate to fetal weight, liver iron content did not differ, whereas renal iron was higher in USR vs. NSR fetuses. Renal TfR protein expression did not differ, but placental TfR expression was lower in USR fetuses at GD130. Placental levels of TfR correlated to eNOS. TfR was localized throughout the placentome, including the hemophagous zone, implicating a role for TfR in ovine placental iron transport. 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.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Ferro/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Placenta/metabolismo , Receptores da Transferrina/metabolismo , Útero/fisiologia , Análise de Variância , Animais , Western Blotting , Pesos e Medidas Corporais , Feminino , Feto , Imuno-Histoquímica , Rim/anatomia & histologia , Rim/metabolismo , Tamanho do Órgão/fisiologia , Placentação , Gravidez , Ovinos , Útero/anatomia & histologia
13.
J Pediatr Hematol Oncol ; 35(6): 473-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23042017

RESUMO

BACKGROUND: Maternal anemia and several complications of pregnancy can affect fetal iron acquisition. AIM: Because it is unknown whether the effects of demographic and maternal risk factors (RF) are summative, we examined cord iron status in newborns with multiple RF for acquiring iron deficiency. METHODS: Cord blood indices from healthy control newborns with and without RF for newborn or infant iron deficiency were studied. RESULTS: Newborns with greater RF had poorer erythrocyte and storage iron status. Poorest status was seen if mothers with comorbid obesity and diabetes delivered large-for-gestation newborns. Findings highlight the importance of identifying RF.


Assuntos
Anemia Ferropriva/sangue , Sangue Fetal/química , Ferro/sangue , Complicações na Gravidez/sangue , Adolescente , Adulto , Peso ao Nascer , Diabetes Mellitus , Contagem de Eritrócitos , Feminino , Sangue Fetal/metabolismo , Hemoglobinas/análise , Humanos , Masculino , Obesidade/complicações , Gravidez , Fatores de Risco , Adulto Jovem
14.
Pediatr Res ; 66(6): 619-24, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19730160

RESUMO

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 gastrostomy apart from the dam, and IDA plus simultaneous enteral iron rescue (IDA+Fe). Hematocrit, plasma ferritin, and body and kidney tissue iron contents were measured. Tissue was examined. Rats grew similarly, but IDA rats exhibited lower hematocrit, plasma ferritin, and body and kidney iron contents than DF, DF + SS, or IDA + Fe. IDA exhibited 1.7 fewer radial glomerular counts (RGCs), 26% reduced glomerular density, and 29% less planar glomerular surface area than DF, with partial improvement in IDA + Fe. Compared with DF or DF + SS, we observed elevated plasma CRP levels and tubulointerstitial fibrosis in the IDA and IDA + Fe groups. IDA reduced glomerular density, glomerular surface area, and promoted fibrosis. Iron substantially rescued renal growth and development, supporting the critical role of iron in late nephrogenesis.


Assuntos
Anemia Ferropriva/fisiopatologia , Rim/crescimento & desenvolvimento , Modelos Biológicos , Análise de Variância , Animais , Animais Recém-Nascidos , Ensaio de Imunoadsorção Enzimática , Feminino , Ferritinas/sangue , Hematócrito , Rim/química , Ratos , Ratos Sprague-Dawley
15.
J Pediatr ; 153(1): 133-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18571551

RESUMO

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.


Assuntos
Anemia Ferropriva/diagnóstico , Ferritinas/sangue , Sangue Fetal/metabolismo , Heme/biossíntese , Ferro/deficiência , Protoporfirinas/sangue , Afro-Americanos , Anemia Ferropriva/etnologia , Proteína C-Reativa/biossíntese , Estudos de Casos e Controles , Feminino , Hispano-Americanos , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Risco
16.
Pediatr Res ; 64(1): 63-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18360311

RESUMO

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 at-risk for iron deficiency (mild ID). ZnPP/H was measured before and after a two-step density centrifugation to obtain the lightest 6.25% of erythrocyte (top fraction). The difference between whole blood and top fraction was defined as DeltaZnPP/H. In rats, although the whole or top ZnPP/H differed by postnatal age, DeltaZnPP/H was greatest after the interval with least body iron accrual. In either rats or humans with mild ID, whole blood ZnPP/H was similar to, but DeltaZnPP/H was greater than controls. In rats and newborn humans, DeltaZnPP/H is more sensitive than whole blood ZnPP/H in identifying conditions associated with impaired erythrocyte iron delivery and may become a useful tool in measuring erythrocyte iron incorporation in early development.


Assuntos
Anemia Ferropriva/diagnóstico , Anemia Neonatal/diagnóstico , Eritropoese , Sangue Fetal/metabolismo , Heme/metabolismo , Ferro/metabolismo , Protoporfirinas/sangue , Reticulócitos/metabolismo , Fatores Etários , Anemia Ferropriva/sangue , Anemia Ferropriva/etiologia , Anemia Neonatal/sangue , Anemia Neonatal/etiologia , Animais , Animais Recém-Nascidos , Animais Lactentes , Biomarcadores/sangue , Feminino , Humanos , Recém-Nascido , Valor Preditivo dos Testes , Gravidez , Gravidez em Diabéticas/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
17.
J Pediatr Gastroenterol Nutr ; 46(2): 202-7, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18223381

RESUMO

OBJECTIVES: A primary objective was to evaluate whether addition of enteral iron supplementation will facilitate a systemic erythropoietic effect when feeding erythropoietin (Epo) to suckling rats. A secondary objective was to confirm that iron does not alter the previous finding that enteral Epo exerts local trophic effects on the small intestine. METHODS: Four-day-old Sprague-Dawley rats underwent gastrostomy and were fed a cow's milk-based rat milk substitute for 8 days. We studied rats fed rat milk substitute alone (control), enteral Epo 425 U x kg(-1) x day(-1), and enteral Epo 1700 U x kg(-1) x day(-1), and the effects of oral iron sulfate (Fe) therapy (6 mg x kg(-1) x day(-1)). Blood was collected to measure hemoglobin (Hb), reticulocytes, red cell indices, and zinc protoporphyrin/heme. To confirm previous work describing trophic effects of enteral Epo on the intestine, duodenal villous height was measured. RESULTS: Hb levels in control (84 +/- 1 g/L) were similar to Epo 425 (87 +/- 1 g/L). Hb levels in control+Fe (97 +/- 1 g/L), Epo 425+Fe (97 +/- 1 g/L), and Epo 1700 (94 +/- 1 g/L) were higher than control, P < 0.001, but mean Hb level in Epo 1700+Fe was higher (105 +/- 1 g/L) than the other groups, P < 0.003. Mean cell volume was higher in rats receiving iron supplementation, compared with those without iron, P < 0.005. Duodenal villous height was taller in Epo 1700+Fe compared with control + Fe, P < 0.01. 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.


Assuntos
Nutrição Enteral , Eritropoese/efeitos dos fármacos , Eritropoetina/administração & dosagem , Ferro na Dieta/administração & dosagem , Animais , Animais Lactentes , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Duodeno/efeitos dos fármacos , Duodeno/crescimento & desenvolvimento , Índices de Eritrócitos , Eritropoese/fisiologia , Eritropoetina/farmacologia , Gastrostomia , Hemoglobinas/análise , Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Doenças do Prematuro/tratamento farmacológico , Ferro na Dieta/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes
18.
Neonatology ; 92(2): 91-5, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17361092

RESUMO

BACKGROUND: Zinc protoporphyrin/heme (ZnPP/H) ratios are indicators of incomplete erythrocyte iron delivery. ZnPP/H is more sensitive than measures of iron stores, such as plasma ferritin, in identifying early pre-anemic iron-deficient erythropoiesis. Cord ZnPP/H ratios are elevated in conditions associated with fetal hypoxia, such as diabetes mellitus during pregnancy. In chronic fetal hypoxemia, erythrocyte and hemoglobin syntheses are accelerated and iron is incorporated into erythrocytes. Cord ZnPP/H ratios are correlated with fetal size after diabetic pregnancy. Because fetal size is a surrogate for diabetes control, it is unclear whether glycemic control in diabetes mellitus or fetal size was the major determinant of ZnPP/H ratios and disturbed erythrocyte iron delivery. OBJECTIVE: Our goal was to examine whether ZnPP/H ratios were elevated or were associated with growth in large-for-gestation newborns born to mothers without the diagnosis of diabetes mellitus. METHODS: In cord blood samples from large and appropriately grown healthy newborns, we measured ZnPP/H and indices of erythropoiesis and iron status. Analyses included simple linear regression, Fisher's exact, and unpaired t testing. RESULTS: In the absence of diabetes mellitus, ZnPP/H in 25 large and 24 appropriately grown healthy newborns was similar, and the ratios were within the limits of previously reported normal cord ZnPP/H. Ratios were not correlated with plasma ferritin levels. In large newborns, but not appropriately grown newborns, ZnPP/H ratios were positively correlated with fetal growth (p < 0.03) and estimates of body hemoglobin (p <0.04). 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.


Assuntos
Peso ao Nascer , Heme/análise , Recém-Nascido/sangue , Protoporfirinas/sangue , Estudos de Coortes , Sangue Fetal/química , Idade Gestacional , Humanos , Estudos Prospectivos
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