Genetic background and window of exposure contribute to thyroid dysfunction promoted by low-dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice.
Genetic background and window of exposure contribute to thyroid dysfunction promoted by low-dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice.
复制标题
DOI：
10.1038/s41598-018-34427-2
复制
发表时间：
2018-11-05
影响因子：
4.6
通讯作者：
Ambrosino C
中科院分区：
文献类型：
--
作者：
Reale C;Porreca I;Russo F;Marotta M;Roberto L;Russo NA;Carchia E;Mallardo M;De Felice M;Ambrosino C
遗传和环境因素会导致甲状腺疾病。尽管仍有争议，2,3,7,8-四氯二苯并-对二恶英（TCDD）被认为会诱发人类和啮齿动物的甲状腺功能障碍。本文所报道的数据指出了暴露窗口和遗传背景在介导低剂量TCDD对甲状腺的影响中的作用。事实上，早期（从E0.5到PND30）和低剂量（0.001 μg/kg/天）TCDD暴露降低了循环fT4并改变了甲状腺特异性转录物的表达。通过监测Pax8+/ -和Nkx2-1+/ -小鼠中相同的标记物，估计遗传成分的作用，这些小鼠易患甲状腺功能障碍，从E15.5到PND60暴露于0.1 μg/kg/天的TCDD。Pax8或Nkx2-1基因的单倍不足以性别依赖的方式加剧了暴露损害甲状腺富集mrna的影响。这种作用在体内外均通过Nkx2-1/p53/p65/IĸBα通路介导。胎儿暴露于TCDD对甲状腺功能和基因表达均有影响，但对甲状腺发育和分化没有明显影响。在小鼠中，较强的效应与早期暴露或特定的遗传背景有关，如Pax8或Nkx2-1单倍不全，两者都与人类甲状腺功能减退有关。此外，我们的数据强调，需要长时间的暴露来模拟体外和体内的结果。
Genetic and environmental factors contribute to thyroid diseases. Although still debated, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is thought to induce thyroid dysfunction in humans and rodents. The data here reported point out the contribution of the exposure window and genetic background in mediating the low-dose TCDD effects on thyroid. Indeed, early (from E0.5 to PND30) and low-dose (0,001 μg/kg/day) TCDD exposure reduced the circulating fT4 and altered the expression of thyroid specific transcripts. The role of genetic components was estimated monitoring the same markers in Pax8+/− and Nkx2-1+/− mice, susceptible to thyroid dysfunction, exposed to 0, 1 μg/kg/day TCDD from E15.5 to PND60. Haploinsufficiency of either Pax8 or Nkx2-1 genes exacerbated the effects of the exposure impairing the thyroid enriched mRNAs in sex dependent manner. Such effect was mediated by mechanisms involving the Nkx2-1/p53/p65/IĸBα pathway in vitro and in vivo. Foetal exposure to TCDD impaired both thyroid function and genes expression while thyroid development and differentiation did not appear significantly affected. In mouse, stronger effects were related to earlier exposure or specific genetic background such as either Pax8 or Nkx2-1 haploinsufficiency, both associated to hypothyroidism in humans. Furthermore, our data underline that long exposure time are needed to model in vitro and in vivo results.
登录
查看更多内容
影响因子：
5.5
作者：
Mulero-Navarro S;Fernandez-Salguero PM
通讯作者：
Fernandez-Salguero PM
影响因子：
4.4
作者：
Lee J;Prokopec SD;Watson JD;Sun RX;Pohjanvirta R;Boutros PC
通讯作者：
Boutros PC
影响因子：
--
作者：
Hutt KJ;Shi Z;Albertini DF;Petroff BK
通讯作者：
Petroff BK
影响因子：
--
作者：
Chen PM;Wu TC;Cheng YW;Chen CY;Lee H
通讯作者：
Lee H
影响因子：
15.8
作者：
Baccarelli A;Giacomini SM;Corbetta C;Landi MT;Bonzini M;Consonni D;Grillo P;Patterson DG;Pesatori AC;Bertazzi PA
通讯作者：
Bertazzi PA