Gestational Stress and Impaired Iron Homeostasis in the Young Infant

描述(由申请人提供)：慢性炎症状态、类固醇激素暴露和压力会影响铁相关的生物学，铁是婴儿生长和正常大脑发育所必需的微量营养素。这个项目将调查一个新的假设，即紧张的产前环境的一些致残效应是通过破坏母体铁的胎盘转移来调节的，这会导致发育中的婴儿体内铁储存的耗尽。非人灵长类动物模型将被用来确定妊娠应激如何损害胎盘转移、隔离和幼婴对铁的利用。一个目标是研究妊娠障碍的发生时间，比较怀孕早期、中期或晚期母亲应激的影响。为了量化胎盘转运和新生儿体内铁的生物利用度，将使用一种具有稳定铁同位素的创新方法，对比口服57Fe和58Fe静脉输注到怀孕女性体内的吸收和转移。然后，将对应激和未受干扰的对照妊娠的发育中的婴儿进行铁敏感血液学措施的监测，以证明出生后铁缺乏与大脑和肾功能异常的发生暂时相关。根据以前在贫血猴子身上的发现，神经功能障碍将通过使用蛋白质印迹和核磁共振技术的脑脊液蛋白质和代谢物图谱来指标化。为了进一步证明这些缺陷的临床意义，将验证在其他物种中观察到的产前应激和贫血对肾功能的影响。当婴儿8个月大时，将测量肾小球滤过率和肾交感神经输入。第二项研究将支持铁调节假说的准确性，表明孕期口服铁补充可以减轻产前应激对发育中婴儿的影响。这两项研究由126对母婴恒河猴组成，每个婴儿从出生到第一年的行为和生理都进行了前瞻性的评估。这项研究将有助于人们越来越多地认识到胎儿期在为产后健康奠定基础方面的形成作用。证明妊娠应激影响铁的动态平衡将揭示出一种可以治疗的缺陷。缺铁具有广泛的公共卫生意义，因为它是世界上最普遍的单一营养素缺乏症。公共卫生相关性：孕期母亲的压力、疾病和炎症过程会损害胎儿的发育，影响早产和产科并发症的可能性，并增加儿童出生后出现许多行为和健康问题的风险。这个项目将研究妊娠应激如何干扰胎盘转移和婴儿对母亲铁的利用，铁是生长和正常大脑发育所需的一种重要微量营养素。有关铁缺乏的研究与低SES、贫血和压力大的母亲的高危婴儿特别相关，对于怀孕合并糖尿病和高血压的婴儿也具有重要意义。这些发现可能会揭示出可以预防和治疗的缺陷。

DESCRIPTION (provided by applicant): Chronic inflammatory states, steroid hormone exposure, and stress can affect iron-related biology, an essential micronutrient needed for infant growth and normal brain development. This project will investigate the novel hypothesis that some of the disabling effects of a stressful prenatal environment are mediated by undermining the placental transfer of maternal iron, which results in the subsequent depletion of iron stores in the growing infant. A nonhuman primate model will be used to determine how gestational stress impairs the placental transfer, sequestering, and use of iron by the young infant. One aim focuses on the timing of the gestational disturbance, comparing the effects of maternal stress during early, mid, or late pregnancy. To quantify placental transfer and bioavailability of iron in the neonate, an innovative approach with stable iron isotopes will be employed, contrasting absorption and transfer of 57Fe provided orally to 58Fe infused intravenously into the pregnant female. Iron-sensitive hematological measures will then be monitored in the developing infants from the stressed and undisturbed control pregnancies to prove that the postnatal iron deficiency is temporally associated with the occurrence of abnormal brain and renal functions. Based on previous findings in anemic monkeys, neural dysfunction will be indexed by the protein and metabolite profile of cerebrospinal fluid using Western blot and nuclear Magnetic Resonance Spectroscopy techniques. To further demonstrate the clinical significance of these deficits, the effects of prenatal stress and anemia on renal functioning observed in other species will be verified. When infants are 8 months of age, measures of glomerular filtration rate and renal sympathetic input will be obtained. A second study will support the veracity of iron mediation hypothesis by showing that oral iron supplementation during pregnancy can lessen the effects of prenatal stress on the developing infants. The two studies are comprised of 126 mother-infant pairs of rhesus monkeys, with the behavior and physiology of each infant evaluated prospectively from birth across the first year of life. This research will contribute to the growing awareness about the formative role of the fetal period in laying the foundation for postnatal health. Demonstrating that gestational stress affects iron homeostasis would reveal a deficit amenable to treatment. Iron deficiency has a broad public health significance because it is the most prevalent single nutrient deficiency worldwide. PUBLIC HEALTH RELEVANCE: Maternal stress, illness, and inflammatory processes during pregnancy can impair fetal growth, affect the likelihood of premature birth and obstetrical complications, and increase the risk for a number of postnatal behavioral and health problems in children. This project will investigate how gestational stress interferes with the placental transfer and utilization of maternal iron by the young baby, an important micronutrient needed for growth and normal brain development. Studies on iron deficiency are of particular relevance to the higher risk infants of low SES, anemic and stressed mothers, as well as of significance for babies from pregnancies complicated by diabetes and hypertension. The findings may reveal deficits that are amenable to prevention and treatment.