Gestational Stress and Impaired Iron Homeostasis in the Young Infant

描述（由申请人提供）：慢性炎症状态、类固醇激素暴露和应激可影响铁相关生物学，铁是婴儿生长和正常大脑发育所需的必需微量营养素。本项目将研究一种新的假设，即产前压力环境的一些致残作用是通过破坏母体铁的胎盘转移来介导的，这导致随后生长中的婴儿铁储备的耗尽。将使用非人灵长类动物模型来确定妊娠应激如何损害胎盘转移、螯合和幼儿对铁的使用。一个目的是关注妊娠期障碍的发生时间，比较妊娠早期、中期或晚期母体压力的影响。为了量化新生儿铁的胎盘转移和生物利用度，将采用具有稳定铁同位素的创新方法，将口服提供的57 Fe的吸收和转移与静脉输注到妊娠女性中的58 Fe进行对比。然后，将在应激和未受干扰对照妊娠的发育中婴儿中监测铁敏感性血液学指标，以证明出生后缺铁与异常脑和肾功能的发生在时间上相关。基于先前在贫血猴中的发现，将使用蛋白质印迹和核磁共振光谱技术通过脑脊液的蛋白质和代谢物谱来索引神经功能障碍。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，将获得肾小球滤过率和肾交感神经输入的测量结果。第二项研究将支持铁调解假说的准确性，表明怀孕期间口服铁补充剂可以减轻产前压力对发育中婴儿的影响。这两项研究由126对恒河猴母婴组成，从出生到生命的第一年，对每个婴儿的行为和生理进行了前瞻性评估。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。证明妊娠期应激影响铁稳态将揭示一个赤字服从治疗。铁缺乏症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：母亲在怀孕期间的压力、疾病和炎症过程会损害胎儿的生长，影响早产和产科并发症的可能性，并增加儿童产后行为和健康问题的风险。该项目将研究妊娠压力如何干扰胎盘转移和幼儿对母体铁的利用，铁是生长和正常大脑发育所需的重要微量营养素。对铁缺乏的研究与低社会经济地位、贫血和压力母亲的高风险婴儿特别相关，对妊娠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.