Spring S R, Bastian T W, Wang Y, Kosian P, Anderson G W, Gilbert M E
Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA.
College of Pharmacy, University of Minnesota, Duluth, MN, USA.
Neurotoxicol Teratol. 2016 Jul-Aug;56:41-46. doi: 10.1016/j.ntt.2016.05.007. Epub 2016 May 20.
Thyroid hormones (TH) are critical for brain development and insufficiencies can lead to structural abnormalities in specific brain regions. Administration of the goitrogen propylthiouracil (PTU) reduces TH production by inhibiting thyroperoxidase (TPO), an enzyme that oxidizes iodide for the synthesis of TH. TPO activity is iron (Fe)-dependent and dietary iron deficiency (FeD) also reduces circulating levels of TH. We have previously shown that modest degrees of TH insufficiency induced in pregnant rat dams alters the expression of TH-responsive genes in the cortex and hippocampus of the neonate, and results in the formation of a subcortical band heterotopia (SBH) in the corpus callosum (Royland et al., 2008, Bastian et al., 2014, Gilbert et al., 2014). The present experiment investigated if FeD alone was sufficient to induce a SBH or if FeD would augment SBH formation at lower doses of PTU. One set of pregnant rats was administered 0, 1, 3, or 10ppm of PTU via drinking water starting on gestational day (GD) 6. FeD was induced in a 2nd set of dams beginning on GD2. A third set of dams received the FeD diet from GD2 paired with either 1ppm or 3ppm PTU beginning on GD6. All treatments continued until the time of sacrifice. On PN18, one female pup from each litter was sacrificed and the brain examined for SBH. We observed lower maternal, PN2 and PN18 pup serum T4 in response to PTU. FeD reduced serum T4 in pups on PN16, but did not affect serum T4 in dams or PN2 pups. Neither did FeD in combination with PTU alter T4 levels in dams on PN18 or pups on PN2 compared to PTU treatment alone. By PN16, however more severe T4 reductions were observed in pups when FeD was combined with PTU. SBH increased with increasing dosage of PTU, but counter to our hypothesis, no SBH was detected in the offspring of FeD dams. As such, T4 levels in dams and newborn pups rather than older neonates appear to be a better predictor SBH associated with TH insufficiency. These data indirectly support previous work indicating prenatal TH insufficiency but not postnatal TH insufficiency in offspring is required for SBH formation.
甲状腺激素（TH）对大脑发育至关重要，其不足会导致特定脑区出现结构异常。给予致甲状腺肿药物丙硫氧嘧啶（PTU）可通过抑制甲状腺过氧化物酶（TPO）来减少TH的产生，TPO是一种氧化碘以合成TH的酶。TPO活性依赖于铁（Fe），饮食中铁缺乏（FeD）也会降低TH的循环水平。我们之前已经表明，在怀孕大鼠母体中诱导适度程度的TH不足会改变新生大鼠皮质和海马中TH反应性基因的表达，并导致胼胝体中形成皮质下带异位（SBH）（Royland等人，2008年；Bastian等人，2014年；Gilbert等人，2014年）。本实验研究单独的FeD是否足以诱导SBH，或者FeD是否会在较低剂量的PTU下增强SBH的形成。一组怀孕大鼠从妊娠第6天（GD6）开始通过饮用水给予0、1、3或10ppm的PTU。在第二组母体中从GD2开始诱导FeD。第三组母体从GD2开始接受FeD饮食，并从GD6开始与1ppm或3ppm的PTU配对。所有处理持续到处死时间。在出生后第18天（PN18），从每窝中处死一只雌性幼崽，并检查大脑是否有SBH。我们观察到母体、PN2和PN18幼崽血清T4水平因PTU而降低。FeD降低了PN16幼崽的血清T4，但不影响母体或PN2幼崽的血清T4。与单独的PTU处理相比，FeD与PTU联合使用也未改变PN18母体或PN2幼崽的T4水平。然而，到PN16时，当FeD与PTU联合使用时，幼崽中观察到更严重的T4降低。SBH随着PTU剂量的增加而增加，但与我们的假设相反，在FeD母体的后代中未检测到SBH。因此，母体和新生幼崽而非较大新生儿的T4水平似乎是与TH不足相关的SBH的更好预测指标。这些数据间接支持了先前的研究工作，表明后代中产前TH不足而非产后TH不足是SBH形成所必需的。
