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

ABSTRACT: 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.

SUBMITTER: Huebner SM

PROVIDER: S-EPMC6317737 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Huebner Shane M SM Helfrich Kaylee K KK Saini Nipun N Blohowiak Sharon E SE Cheng Adrienne A AA Kling Pamela J PJ Smith Susan M SM

Alcoholism, clinical and experimental research 20180519 6

<h4>Background</h4>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 hom ...[more]

PMID: 29672865

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Project description:Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of these defects in the offspring. Because the placenta is central in supporting fetal development, we investigated whether maternal iron status similarly modulates alcohol's effects in the placenta. We hypothesized that PAE causes placental insufficiency by decreasing placental weight and efficiency, and we hypothesized that these are worsened by maternal iron deficiency (ID) and alleviated by dietary iron fortification (IF). We also determined whether altered placental iron flux and inflammatory balance contribute to placental insufficiency. Pregnant Long-Evans rats consumed an iron-deficient (ID; 2-6 ppm), iron-sufficient (IS; 100 ppm), or iron-fortified (IF; 500 ppm) diet. Alcohol (5 g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE reduced fetal weight (p < 0.0001), placental weight (p = 0.0324), and placental efficiency (p = 0.0043). PAE downregulated placental transferrin receptor (p = 0.0032); it also altered placental Il1b and Tnf expression and the Il6:Il10 ratio (p = 0.0337, 0.0300, and 0.0034, respectively) to generate a response favoring inflammation. ID-PAE further reduced fetal growth and placental efficiency and induced a heightened pro-inflammatory placental profile. IF did not rescue the alcohol-reduced fetal weight, but it normalized placental efficiency and decreased placental inflammation. These placental cytokines correlated with fetal and placental growth, and explained 45% of the variability in fetal weight and 20% of the variability in placental efficiency. In summary, alcohol induces placental insufficiency and is associated with a pro-inflammatory cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because the placenta is closely linked to intrauterine growth, the placental insufficiency reported here may correlate with the lower birth weights in a subgroup of individuals who experienced PAE.

Project description:Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional ferroportin-independent homeostasis mechanisms.

Project description:Background: Iron accrued in utero is critical for fetal and infant neurocognitive development. Psychosocial stress and obesity can each suppress fetal iron accrual. Their combined effects and differences by fetal sex are not known. In an observational pregnancy cohort study in Mexico City, we investigated associations of maternal prenatal life stressors, psychological dysfunction, and prepregnancy BMI with fetal iron status at delivery.Objectives: We hypothesized that greater maternal prenatal psychosocial stress and prepregnancy overweight and obesity are associated with lower cord blood ferritin and hemoglobin (Hb), with stronger associations in boys than girls.Methods: Psychosocial stress in multiple domains of life stress (negative life events, perceived stress, exposure to violence) and psychological dysfunction symptoms (depression, generalized anxiety, and pregnancy-specific anxiety) were assessed with validated questionnaires during pregnancy. Prepregnancy BMI was predicted with a validated equation and categorized as normal/overweight/obese. Cord blood ferritin and Hb associations with prenatal psychosocial stress and BMI were modeled in multivariable linear regressions adjusted for maternal age, socioeconomic status, child sex, and prenatal iron supplementation. Interactions with child sex and 3-way stress-overweight/obesity-sex interactions were tested with product terms and likelihood ratio tests.Results: In 493 dyads, median (IQR) cord blood ferritin and Hb concentrations were 185 µg/L (126-263 g/dL) and 16 g/dL (14.7-17.1 g/dL), respectively. Ferritin was lower in infants of mothers with higher prenatal perceived stress (-23%; 95% CI: -35%, -9%), violence exposure (-28%; 95% CI: -42%, -12%), anxiety symptoms (-16%; 95% CI: -27%, -4%), and obesity (-17%; 95% CI: -31%, 0.2%). Interaction models suggested sex differences and synergism between maternal stress and overweight/obesity. No associations were observed between stress or BMI and Hb.Conclusions: Multiple prenatal psychosocial stressors and excess prepregnancy BMI were each inversely associated with fetal iron status at birth. Pregnancies and infants at elevated risk of impaired fetal iron accrual may be identifiable according to observed synergism between maternal stress and obesity and differential associations with fetal iron status by infant sex.

Project description:BackgroundPrenatal alcohol exposure (PAE) is associated with postnatal iron deficiency (ID), which has been shown to exacerbate deficits in growth, cognition, and behavior seen in fetal alcohol spectrum disorders. However, the mechanisms underlying PAE-related ID remain unknown.ObjectivesWe aimed to examine biochemical measures of iron homeostasis in the mother, placenta, neonate, and 6.5-month-old infant.MethodsIn a prenatally recruited, prospective longitudinal birth cohort in South Africa, 206 gravidas (126 heavy drinkers and 80 controls) were interviewed regarding alcohol, cigarette, and drug use and diet at 3 prenatal visits. Hemoglobin, ferritin, and soluble transferrin receptor (sTfR) were assayed twice during pregnancy and urinary hepcidin:creatinine was assayed once. Infant ferritin and hemoglobin were measured at 2 weeks and 6.5 months and sTfR was measured at 6.5 months. Histopathological examinations were conducted on 125 placentas and iron transport assays (iron regulatory protein-2, transferrin receptor-1, divalent metal transporter-1, ferroportin-1, and iron concentrations) were conducted on 63.ResultsIn multivariable regression models, prenatal drinking frequency (days/week) was related to higher maternal hepcidin and to sequestration of iron into storage at the expense of erythropoiesis in mothers and neonates, as evidenced by a lower hemoglobin (g/dL)-to-log(ferritin) (ug/L) ratio [mothers: raw regression coefficient (β) = -0.21 (95% CI: -0.35 to -0.07); neonates: β = -0.15 (95% CI: -0.24 to -0.06)]. Drinking frequency was also related to decreased placental ferroportin-1:transferrin receptor-1 (β = -0.57 for logged values; 95% CI: -1.03 to -0.10), indicating iron-restricted placental iron transport. At 6.5 months, drinking frequency was associated with lower hemoglobin (β = -0.18; 95% CI: -0.33 to -0.02), and increased prevalences of ID (β = 0.09; 95% CI: 0.02-0.17) and ID anemia (IDA) (β = 0.13; 95% CI: 0.04-0.23). In causal inference analyses, the PAE-related increase in IDA was partially mediated by decreased neonatal hemoglobin:log(ferritin), and the decrease in neonatal hemoglobin:log(ferritin) was partially mediated by decreased maternal hemoglobin:log(ferritin).ConclusionsIn this study, greater PAE was associated with an unfavorable profile of maternal-fetal iron homeostasis, which may play mechanistic roles in PAE-related ID later in infancy.

Dataset Information

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

Publications

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

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