Centre for Public Health and Environmental Assessment, US Environmental Protection Agency, Office of Research and Development, Research Triangle Park, North Carolina 27711, USA.
Office of Air Quality Planning and Standards, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA.
Toxicol Sci. 2022 Jun 28;188(1):117-130. doi: 10.1093/toxsci/kfac038.
Iodine is essential for the production of thyroid hormones. Perchlorate is an environmental contaminant that interferes with iodine uptake into the thyroid gland to reduce thyroid hormone synthesis. As thyroid hormones are critical for brain development, exposure to perchlorate during pregnancy is of concern for the developing fetal brain. In this study, we (1) define profiles of thyroid hormone in the maternal and fetal compartments of pregnant rats in response to inhibition of the sodium-iodide symporter (NIS) by perchlorate and (2) expand inquiry previously limited to serum to include fetal thyroid gland and brain. Perchlorate was added to the drinking water (0, 1, 30, 300, and 1000 ppm) of pregnant rat dams from gestational days (GD) 6-20. On GD20, blood, thyroid gland, and brain were collected from the fetus and dam for thyroid hormone and molecular analyses. Thyroid gland and serum thyroid hormones were dose-dependently reduced, with steeper declines evident in the fetus than in the dam. The thyroid gland revealed perturbations of thyroid hormone-action with greater sensitivity in the fetus than the dam. Thyroid hormones and thyroid hormone-responsive gene expression were reduced in the fetal cortex portending effects on brain development. These findings are the first quantitative assessments of perchlorate-induced deficits in the fetal thyroid gland and fetal brain. We provide a conceptual framework to develop a quantitative NIS adverse outcome pathway for serum thyroid hormone deficits and the potential to impact the fetal brain. Such a framework may also serve to facilitate the translation of in vitro bioactivity to the downstream in vivo consequences of NIS inhibition in the developing fetus.
碘是甲状腺激素生成所必需的。高氯酸盐是一种环境污染物，它会干扰碘进入甲状腺的摄取，从而减少甲状腺激素的合成。由于甲状腺激素对大脑发育至关重要，因此孕妇在怀孕期间接触高氯酸盐会引起人们对胎儿大脑发育的关注。在这项研究中，我们（1）定义了母体和胎儿甲状腺激素在受高氯酸盐抑制钠-碘转运体（NIS）的情况下的变化情况；（2）将以前仅限于血清的研究扩展到包括胎儿甲状腺和大脑。从妊娠第 6 天到第 20 天，将高氯酸盐添加到孕鼠的饮用水中（0、1、30、300 和 1000ppm）。在 GD20 时，从胎儿和母鼠中采集血液、甲状腺和大脑，用于甲状腺激素和分子分析。甲状腺和血清甲状腺激素呈剂量依赖性降低，胎儿的下降幅度比母鼠更为明显。与母鼠相比，胎儿的甲状腺显示出对甲状腺激素作用的扰动，敏感性更高。胎儿皮质中的甲状腺激素和甲状腺激素反应基因表达减少，预示着对大脑发育的影响。这些发现是首次对胎儿甲状腺和胎儿大脑中高氯酸盐诱导的甲状腺激素缺乏进行定量评估。我们提供了一个概念框架，用于开发血清甲状腺激素缺乏的定量 NIS 不良结局途径，以及对胎儿大脑产生潜在影响的途径。该框架还可以促进体外生物活性向发育中胎儿 NIS 抑制的下游体内后果的转化。
