Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Kgs. Lyngby, DK-2800, Denmark.
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institut für Experimentelle Endokrinologie, 10115, Berlin, Germany.
Toxicol Lett. 2022 Jan 1;354:44-55. doi: 10.1016/j.toxlet.2021.10.010. Epub 2021 Oct 29.
Disruption of the thyroid hormone system during development can impair brain development and cause irreversible damage. Some thyroid hormone system disruptors act by inhibiting the thyroperoxidase (TPO) enzyme, which is key to thyroid hormone synthesis. For the potent TPO-inhibiting drug propylthiouracil (PTU) this has been shown to result in thyroid hormone system disruption and altered brain development in animal studies. However, an outstanding question is which chemicals beside PTU can cause similar effects on brain development and to what degree thyroid hormone insufficiency must be induced to be able to measure adverse effects in rats and their offspring. To start answering these questions, we performed a perinatal exposure study in pregnant rats with two TPO-inhibitors: the drug methimazole (MMI) and the triazole herbicide amitrole. The study involved maternal exposure from gestational day 7 through to postnatal day 22, to MMI (8 and 16 mg/kg body weight/day) or amitrole (25 and 50 mg/kg body weight/day). Both MMI and amitrole reduced serum T4 concentrations in a dose-dependent manner in dams and offspring, with a strong activation of the hypothalamic-pituitary-thyroid axis. This reduction in serum T4 led to decreased thyroid hormone-mediated gene expression in the offspring's brains and caused adverse effects on brain function, seen as hyperactivity and decreased habituation in preweaning pups. These dose-dependent effects induced by MMI and amitrole are largely the same as those observed with PTU. This demonstrates that potent TPO-inhibitors can induce effects on brain development in rats and that these effects are driven by T4 deficiency. This knowledge will aid the identification of TPO-inhibiting thyroid hormone system disruptors in a regulatory context and can serve as a starting point in search of more sensitive markers of developmental thyroid hormone system disruption.
发育过程中甲状腺激素系统的破坏会损害大脑发育并造成不可逆转的损伤。一些甲状腺激素系统破坏剂通过抑制甲状腺过氧化物酶（TPO）起作用，TPO 是甲状腺激素合成的关键。对于强效 TPO 抑制剂丙基硫氧嘧啶（PTU），动物研究已表明这会导致甲状腺激素系统破坏和大脑发育改变。然而，一个悬而未决的问题是，除了 PTU 之外，还有哪些化学物质会对大脑发育产生类似的影响，以及必须诱导多大程度的甲状腺激素不足才能在大鼠及其后代中测量到不良反应。为了开始回答这些问题，我们在怀孕的大鼠中进行了一项围产期暴露研究，使用了两种 TPO 抑制剂：药物甲巯咪唑（MMI）和三唑类除草剂阿米特洛尔。该研究涉及从妊娠第 7 天到产后第 22 天的母体暴露，给予 MMI（8 和 16 mg/kg 体重/天）或阿米特洛尔（25 和 50 mg/kg 体重/天）。MMI 和阿米特洛尔均以剂量依赖的方式降低母鼠及其后代血清 T4 浓度，强烈激活下丘脑-垂体-甲状腺轴。这种血清 T4 的减少导致后代大脑中甲状腺激素介导的基因表达减少，并导致大脑功能出现不良反应，表现为幼鼠的多动和习惯化减少。MMI 和阿米特洛尔引起的这些剂量依赖性影响与 PTU 观察到的基本相同。这表明强效 TPO 抑制剂可诱导大鼠大脑发育异常，这些影响是由 T4 缺乏引起的。这一知识将有助于在监管背景下识别 TPO 抑制剂甲状腺激素系统破坏剂，并可作为寻找更敏感的发育性甲状腺激素系统破坏标志物的起点。
