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.
Environ Pollut. 2021 Aug 15;283:117135. doi: 10.1016/j.envpol.2021.117135. Epub 2021 Apr 12.
The thyroperoxidase (TPO) enzyme is expressed by the thyroid follicular cells and is required for thyroid hormone synthesis. In turn, thyroid hormones are essential for brain development, thus inhibition of TPO in early life can have life-long consequences for brain function. If environmental chemicals with the capacity to inhibit TPO in vitro can also alter brain development in vivo through thyroid hormone dependent mechanisms, however, remains unknown. In this study we show that the in vitro TPO inhibiting pesticide amitrole alters neuronal migration and induces periventricular heterotopia; a thyroid hormone dependent brain malformation. Perinatal exposure to amitrole reduced pup serum thyroxine (T4) concentrations to less than 50% of control animals and this insufficiency led to heterotopia formation in the 16-day old pup's brain. Two other in vitro TPO inhibitors, 2-mercaptobenzimidazole and cyanamide, caused reproductive toxicity and had only minor sporadic effects on the thyroid hormone system; consequently, they did not cause heterotopia. This is the first demonstration of an environmental chemical causing heterotopia, a brain malformation until now only reported for rodent studies with the anti-thyroid drugs propylthiouracil and methimazole. Our results highlight that certain TPO-inhibiting environmental chemicals can alter brain development through thyroid hormone dependent mechanisms. Improved understanding of the effects on the brain as well as the conditions under which chemicals can perturb brain development will be key to protect human health.
甲状腺过氧化物酶（TPO）酶由甲状腺滤泡细胞表达，是甲状腺激素合成所必需的。反过来，甲状腺激素对大脑发育至关重要，因此，TPO 在生命早期的抑制作用可能对大脑功能产生终身影响。然而，目前尚不清楚具有体外抑制 TPO 能力的环境化学物质是否也可以通过甲状腺激素依赖的机制改变体内的大脑发育。在这项研究中，我们表明，体外 TPO 抑制性农药阿米妥尔改变了神经元迁移并诱导了脑室周围异位；这是一种甲状腺激素依赖性脑畸形。围产期暴露于阿米妥尔会将幼仔血清甲状腺素（T4）浓度降低到对照组动物的 50%以下，这种不足会导致 16 天大的幼仔大脑中的异位形成。另外两种体外 TPO 抑制剂，2-巯基苯并咪唑和氰胺，引起生殖毒性，对甲状腺激素系统只有轻微的零星影响；因此，它们不会引起异位。这是第一个证明环境化学物质引起异位的例证，这种脑畸形以前只在抗甲状腺药物丙基硫氧嘧啶和甲巯咪唑的啮齿动物研究中报道过。我们的结果强调了某些 TPO 抑制性环境化学物质可以通过甲状腺激素依赖的机制改变大脑发育。更好地了解这些化学物质对大脑的影响以及它们在何种条件下可以干扰大脑发育，将是保护人类健康的关键。
