Hu Xiaona, Wang Ranran, Shan Zhongyan, Dong Yujie, Zheng Hongzhi, Jesse Forrest Fabian, Rao Elizabeth, Takahashi Eiki, Li Weidong, Teng Weiping, Teng Xiaochun
1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University , Shenyang, China .
2 Department of Endocrinology, The People's Hospital of Liaoning Province , Shenyang, China .
Thyroid. 2016 Jul;26(7):891-900. doi: 10.1089/thy.2015.0293.
Both perinatal hypothyroxinemia and perinatal iron deficiency (ID) are associated with poor neurodevelopment in offspring. Iron is an important component of thyroid peroxidase, a key enzyme in the synthesis of thyroid hormone. The authors' previous study demonstrated that perinatal ID can lead to maternal hypothyroxinemia during pregnancy. The goal of this study was to determine whether perinatal ID-associated hypothyroxinemia can cause brain defects prior to neonatal brain iron depletion.
Two rat models were established to imitate the two common types of maternal ID (mild ID with anemia [ID + A] and ID without anemia [ID - A]), and iron limitation was initiated two weeks before pregnancy. Maternal and neonatal thyroid hormones in serum were analyzed at postnatal day (P) 0 and P10. Neonatal thyroid hormone, as well as mRNA expression of some thyroid hormone-responsive genes in the cerebral cortex and hippocampus, were measured at P10. Serum iron and brain iron concentrations were analyzed by inductively coupled plasma mass spectrometry. Liver iron concentration was determined using graphite furnace atomic absorption spectroscopy. Hemoglobin was analyzed with an automated blood coagulation analyzer. Surface righting reflex and vibrissae-evoked forelimb placing were measured to assess the sensorimotor behaviors.
It was found that pre-pregnant mild ID resulted in maternal hypothyroxinemia, which lasted from gestation day 13 to P10. Pre-pregnant mild ID decreased the neonatal brain total triiodothyronine level at P10. Consistent with a low total triiodothyronine level, the mRNA expression of some thyroid hormone-responsive genes (Mbp, RC3, and Srg1) were significantly reduced in the neonatal cerebral cortex and hippocampus in both ID rat models at P10. Furthermore, ID rat pups at P10 showed retarded sensorimotor skills. No significant difference was found between the control and the ID pups in terms of iron concentrations in the neonatal brain at P10.
This study demonstrates that perinatal ID-associated hypothyroxinemia is sufficient to impair early brain development, regardless of whether the neonatal brain iron level is normal, and monitoring thyroid hormone level is indicated in ID pregnant women.
围产期甲状腺素血症减低和围产期缺铁（ID）均与后代神经发育不良有关。铁是甲状腺过氧化物酶的重要组成部分，而甲状腺过氧化物酶是甲状腺激素合成中的关键酶。作者之前的研究表明，围产期ID可导致孕期母体甲状腺素血症减低。本研究的目的是确定围产期ID相关的甲状腺素血症减低是否会在新生儿脑铁耗竭之前导致脑缺陷。
建立两种大鼠模型以模拟两种常见的母体ID类型（伴有贫血的轻度ID [ID + A]和不伴有贫血的ID [ID - A]），并在怀孕前两周开始限制铁摄入。在出生后第（P）0天和P10天分析母体和新生儿血清中的甲状腺激素。在P10天测量新生儿甲状腺激素以及大脑皮层和海马体中一些甲状腺激素反应性基因的mRNA表达。通过电感耦合等离子体质谱分析血清铁和脑铁浓度。使用石墨炉原子吸收光谱法测定肝脏铁浓度。用自动血液凝固分析仪分析血红蛋白。测量表面翻正反射和触须诱发的前肢放置以评估感觉运动行为。
发现孕前轻度ID导致母体甲状腺素血症减低，从妊娠第13天持续至P10。孕前轻度ID降低了P10天时新生儿脑总三碘甲状腺原氨酸水平。与低总三碘甲状腺原氨酸水平一致，在P10天时，两种ID大鼠模型的新生儿大脑皮层和海马体中一些甲状腺激素反应性基因（Mbp、RC3和Srg1）的mRNA表达均显著降低。此外，P10天的ID大鼠幼崽表现出感觉运动技能发育迟缓。在P10天时，对照组和ID幼崽在新生儿脑铁浓度方面未发现显著差异。
本研究表明，围产期ID相关的甲状腺素血症减低足以损害早期脑发育，无论新生儿脑铁水平是否正常，并且建议对ID孕妇监测甲状腺激素水平。
