Stress is a potential catalyst for thyroid dysregulation through cross-communication of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid (HPT) axes. Stress and stressors exposure motivates molecular mechanisms affecting compound feedback loops of the HPT axis. While there is evidence of connection between stress and thyroid dysregulation, the question whether this connection is implicated in the development of thyroid cancer (TC) remains unanswered. In view of the rising incidence of TC in both adults and children alongside the increasing stress in our modern society, there is a need to understand possible interrelations between stress, thyroid dysregulation, and TC. Prolonged glucocorticoid secretion due to stress interferes with immune system response by altering the cytokines, inducing low-grade chronic inflammation, and suppressing function of immune-protective cells. Chronic inflammation is a risk factor linked to TC. The role of autoimmunity has been a matter of controversy. However, there is epidemiological connection between autoimmune thyroid disease (AITD) and TC; patients with AITD show increased incidence in papillary thyroid carcinoma (PTC), and those with TC show a high prevalence of intrathyroidal lymphocyte infiltration and thyroid autoantibodies. Timing and duration-dependent exposure to specific endocrine disrupting chemicals (EDCs) has an impact on thyroid development, function, and proliferation, leading to thyroid disease and potentially cancer. Thyroid hormone imbalance, chronic inflammation, and EDCs are potential risk factors for oxidative stress. Oxygen free radicals are capable of causing DNA damage via stimulation of the mitogen-activating protein kinase or phosphatidylinositol-3-kinase and/or nuclear factor kB pathways, resulting in TC-associated gene mutations such as RET/PTC, AKAP9-BRAF, NTRK1, RAASF, PIK3CA, and PTEN. Stressful events during the critical periods of prenatal and early life can influence neuroendocrine regulation and induce epigenetic changes. Aberrant methylation of tumor suppressor genes such as P16INK4A, RASSF, and PTEN is associated with PTC; histone H3 acetylation is shown to be higher in TC, and thyroid-specific noncoding RNAs are downregulated in PTC. This review focuses on the above proposed mechanisms that potentially lead to thyroid tumorigenesis with the aim to help in the development of novel prognostic and therapeutic strategies for TC.

中文翻译：

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儿童和青少年的压力、甲状腺失调和甲状腺癌：拟议的即将发生的机制。

通过下丘脑-垂体-肾上腺和下丘脑-垂体-甲状腺 (HPT) 轴的交叉通讯，压力是甲状腺失调的潜在催化剂。压力和压力源暴露激发了影响 HPT 轴复合反馈回路的分子机制。虽然有证据表明压力与甲状腺失调之间存在联系，但这种联系是否与甲状腺癌 (TC) 的发展有关的问题仍未得到解答。鉴于 TC 在成人和儿童中的发病率上升以及现代社会压力的增加，有必要了解压力、甲状腺功能失调和 TC 之间可能存在的相互关系。应激导致的糖皮质激素分泌延长会通过改变细胞因子、诱发低度慢性炎症来干扰免疫系统反应，和抑制免疫保护细胞的功能。慢性炎症是与 TC 相关的危险因素。自身免疫的作用一直存在争议。然而，自身免疫性甲状腺疾病（AITD）与TC之间存在流行病学联系；AITD 患者甲状腺乳头状癌 (PTC) 的发病率增加，而 TC 患者甲状腺内淋巴细胞浸润和甲状腺自身抗体的发生率较高。暴露于特定内分泌干扰化学物质 (EDC) 的时间和持续时间依赖性会影响甲状腺的发育、功能和增殖，从而导致甲状腺疾病和潜在的癌症。甲状腺激素失衡、慢性炎症和内分泌干扰物是氧化应激的潜在危险因素。氧自由基能够通过刺激有丝分裂原活化蛋白激酶或磷脂酰肌醇-3-激酶和/或核因子 kB 通路造成 DNA 损伤，导致 TC 相关基因突变，如 RET/PTC、AKAP9-BRAF、NTRK1 、RAASF、PIK3CA 和 PTEN。产前和生命早期关键时期的压力事件会影响神经内分泌调节并诱发表观遗传变化。P16INK4A、RASSF 和 PTEN 等抑癌基因的异常甲基化与 PTC 相关；组蛋白 H3 乙酰化在 TC 中更高，甲状腺特异性非编码 RNA 在 PTC 中下调。本综述侧重于上述可能导致甲状腺肿瘤发生的机制，旨在帮助开发新的 TC 预后和治疗策略。