Ausó Eva, Lavado-Autric Rosalía, Cuevas Estela, Del Rey Francisco Escobar, Morreale De Escobar Gabriella, Berbel Pere
Instituto de Neurociencias, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Apartado de correos 18, San Juan, 03550 Alicante, Spain.
Endocrinology. 2004 Sep;145(9):4037-47. doi: 10.1210/en.2004-0274. Epub 2004 Apr 15.
Epidemiological studies and case reports show that even a relatively minor degree of maternal hypothyroxinemia during the first half of gestation is potentially dangerous for optimal fetal neurodevelopment. Our experimental approach was designed to result in a mild and transient period of maternal hypothyroxinemia at the beginning of corticogenesis. Normal rat dams received the goitrogen 2-mercapto-1-methyl-imidazole for only 3 d, from embryonic d 12 (E12) to E15. Maternal thyroid hormones decreased transiently to 70% of normal serum values, without clinical signs of hypothyroidism. Dams were injected daily with 5-bromo-2'-deoxyuridine (BrdU) during 3 d, from E14-E16 or E17-E19. Their pups were tested for audiogenic seizure susceptibility 39 d after birth (P39) and killed at P40. Cells that had incorporated BrdU were identified by immunocytochemistry, and quantified: numerous heterotopic cells were found, whether labeled at E14-E16 or E17-E19, that were identified as neurons. The cytoarchitecture and the radial distribution of BrdU-labeled neurons was significantly affected in the somatosensory cortex and hippocampus of 83% of the pups. The radial distribution of gamma-aminobutyric acidergic neurons was, however, normal. The infusion of dams with T4 between E13 and E15 avoided these alterations, which were not prevented when the T4 infusion was delayed to E15-E18. In total, 52% of the pups born to the goitrogen-treated dams responded to an acoustic stimulus with wild runs, followed in some by seizures. When extrapolated to man, these results stress the need for prevention of hypothyroxinemia before midpregnancy, however moderate, and whichever the underlying cause.
流行病学研究和病例报告表明，孕期前半期即使是相对轻微的母体甲状腺素血症，对胎儿最佳神经发育也可能存在潜在危险。我们的实验方法旨在使母体在皮质发生开始时出现轻度且短暂的甲状腺素血症期。正常大鼠母鼠仅在胚胎第12天（E12）至E15天接受致甲状腺肿物质2-巯基-1-甲基咪唑3天。母体甲状腺激素短暂降至正常血清值的70%，无甲状腺功能减退的临床症状。在E14 - E16或E17 - E19的3天内，母鼠每天注射5-溴-2'-脱氧尿苷（BrdU）。它们的幼崽在出生后39天（P39）接受听源性惊厥易感性测试，并在P40处死。通过免疫细胞化学鉴定并定量掺入BrdU的细胞：无论在E14 - E16还是E17 - E19标记，都发现了大量被鉴定为神经元的异位细胞。在83%的幼崽的体感皮层和海马体中，BrdU标记神经元的细胞结构和径向分布受到显著影响。然而，γ-氨基丁酸能神经元的径向分布正常。在E13至E15期间给母鼠输注甲状腺素可避免这些改变，而当甲状腺素输注延迟至E15 - E18时则无法预防这些改变。总体而言，接受致甲状腺肿物质处理的母鼠所生的幼崽中有52%对声音刺激产生狂奔反应，有些随后发生惊厥。外推至人类时，这些结果强调了在孕中期之前预防甲状腺素血症的必要性，无论程度如何轻微，也无论潜在原因是什么。
