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通讯作者:

陈欢欢,E-mail:drchenhuanhuan@njmu.edu.cn

中图分类号:R581

文献标识码:A

文章编号:1007-4368(2023)03-427-05

DOI:10.7655/NYDXBNS20230320

参考文献 1
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KYRIACOU A,TZIAFERI V,TOUMBA M.Stress,thy⁃ roid dysregulation and thyroid cancer in children and ado⁃ lescents.proposed impending mechanisms[J/OL].Horm Res Paediatr,2022[2022 ⁃ 09 ⁃ 11].DOI:10.1159/000524477
参考文献 5
ALSEN M,SINCLAIR C,COOKE P,et al.Endocrine dis⁃ rupting chemicals and Thyroid cancer:an overview[J].Toxics,2021,9(1):14
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参考文献 7
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参考文献 8
PANCHANATHAN R,LIU H,CHOUBEY D.Expression of murine Unc93b1 is up ⁃ regulated by interferon and es⁃ trogen signaling:implications for sex bias in the develop⁃ ment of autoimmunity[J].Int Immunol,2013,25(9):521-529
参考文献 9
MAGLIONE A,ROLLA S,MERCANTI S F,et al.The adaptive immune system in multiple sclerosis:an estrogen ⁃mediated point of view[J].Cells,2019,8(10):1280
参考文献 10
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参考文献 11
PANCHANATHAN R,CHOUBEY D.Murine BAFF ex⁃ pression is up ⁃ regulated by estrogen and interferons:im⁃ plications for sex bias in the development of autoimmunity [J].Mol Immunol,2013,53(1/2):15-23
参考文献 12
CHAILURKIT L O,AEKPLAKORN W,ONGPHIPHAD⁃ HANAKUL B.The association of serum bisphenol a with thyroid autoimmunity[J].Int J Environ Res Public Health,2016,13(11):1153
参考文献 13
KIM M J,PARK Y J.Bisphenols and thyroid hormone[J].Endocrinol Metab(Seoul),2019,34(4):340-348
参考文献 14
ZHANG Y,YAN M,KUANG S,et al.Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO ⁃Y4:involvement of ROS ⁃mediated mTOR/ULK1 pathway[J].Ecotoxicol Environ Saf,2021,230:113119
参考文献 15
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参考文献 16
LINA B,JUSTIN J,ELISABETH J,et al.Thyroid furc⁃ tion and immune status in perch(Perca fluviatilis)from lakes contaminated with PFASs of PCBs[J].Ecotoxicol Environ Sat,2021,222:112495
参考文献 17
WANG C,PETRIELLO M C,ZHU B,et al.PCB 126 in⁃ duces monocyte/macrophage polarization and inflamma⁃ tion through AhR and NF ⁃ kappaB pathways[J].Toxicol Appl Pharmacol,2019,367:71-81
参考文献 18
SOKAL A,JARMAKIEWICZ ⁃ CZAJA S,TABARKIE⁃ WICZ J,et al.Dietary intake of endocrine disrupting sub⁃ stances presents in environment and their impact on thy⁃ roid function[J].Nutrients,2021,13(3):867
参考文献 19
LERRO C C,JONES R R,LANGSETH H,et al.A nested case ⁃ control study of polychlorinated biphenyls,organo⁃ chlorine pesticides,and thyroid cancer in the Janus Se⁃ rum Bank cohort[J].Environ Res,2018,165:125-132
参考文献 20
VIGNERI R,MALANDRINO P,GIANI F,et al.Heavy metals in the volcanic environment and thyroid cancer [J].Mol Cell Endocrinol,2017,457:73-80
参考文献 21
SUR U,ERKEKOGLU P,BULUS A D,et al.Oxidative stress markers,trace elements,and endocrine disrupting chemicals in children with Hashimoto’s thyroiditis[J].Toxicol Mech Methods,2019,29(9):633-643
参考文献 22
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参考文献 23
ZENG F,LERRO C,LAVOUE J,et al.Occupational expo⁃ sure to pesticides and other biocides and risk of thyroid cancer[J].Occup Environ Med,2017,74(7):502-510
参考文献 24
FERRARI S M,FALLAHI P,ELIA G,et al.Thyroid auto⁃ immune disorders and cancer[J].Semin Cancer Biol,2020,64:135-146
目录contents

    摘要

    环境内分泌干扰物广泛存在于人们的生产生活环境中,其种类繁多,不仅干扰人体的生殖、神经、免疫等系统,更是对体内最大的内分泌器官——甲状腺产生不可忽视的影响。然而,以往研究多从甲状腺激素和甲状腺的组织病理学入手,很少从自身免疫性甲状腺疾病和甲状腺癌的角度切入。本文通过系统回顾,阐述了几种常见的环境内分泌干扰物在自身免疫性甲状腺疾病和甲状腺癌发生发展过程中的作用,包括诱导抗甲状腺自身抗体产生和影响T细胞分化等,为研究自身免疫性甲状腺疾病和甲状腺癌的潜在环境暴露危险因素提供依据,对该类疾病的防治有积极意义。

    Abstract

    Environmental endocrine disrupting chemicals(EDC)are widespread in people’s production and living environment. Due to a wide variety of endocrine disruptors,they not only interfere with human reproductive system,nervous system and immune system,but also exert a non-negligible influence on the thyroid,which is the largest endocrine organ in the body. The previous studies mostly focused on thyroid hormone and histopathology,and few reports were available on the associations between autoimmune thyroid diseases(AITD)or thyroid cancer(TC)and EDC. Therefore,the current review elucidates the potential adverse effects of EDC on thyroid,especially in autoimmune thyroid diseases and thyroid cancer,including induction of thyroid autoantibodies and the effect on T cell differentiation,etc.,which may provide a basis for the study of the potential environmental exposure risk factors of autoimmune thyroid diseases and thyroid cancer,and has positive significance on prevention and treatment of these diseases.

  • 环境内分泌干扰物(endocrine disrupting chemi⁃ cal,EDC)因其对内分泌系统具有显著的干扰作用,近年来得到国内外的广泛关注。

  • 甲状腺激素在维持人体生长发育、促进新陈代谢、提高神经系统兴奋性以及增强心肌收缩力方面发挥关键作用。甲状腺是人体最大的内分泌器官,容易受到EDC的影响。

  • 然而,既往研究和综述多关注于EDC对甲状腺功能和甲状腺激素水平的影响,鲜有专注EDC对自身免疫性甲状腺疾病(autoimmune thyroid disease, AITD)或甲状腺癌(thyroid cancer,TC)的影响。因此,本文通过PubMed和知网搜索“分泌干扰物和甲状腺”,筛选涉及AITD和TC的研究,针对几类常见的 EDC 对甲状腺自身免疫的影响及可能作用机制进行综述,从而为更好地开展这一领域的研究工作提供方向或思路。

  • 1 EDC

  • 美国环境保护署将EDC定义为“干扰负责人体稳态、生殖和发育过程的重要天然血源性激素的合成、分泌、运输、代谢、结合或清除的外源性物质”[1]。常见的EDC如多氯联苯、烷基酚类、溴化阻燃剂、农药类、重金属类等可通过污染水源、食物或经皮肤吸收等多途经进入机体,影响体内激素的动态平衡,从而对内分泌产生各种干扰作用。

  • 2 AITD和TC

  • AITD 是主要由 T 细胞介导的器官特异性自身免疫性疾病。患者血清中存在针对甲状腺的自身抗体,如促甲状腺激素受体抗体(thyrotropin recep⁃ tor antibody,TRAb)、抗甲状腺过氧化物酶抗体(anti⁃ thyroid peroxidase antibody,TPOAb)、甲状腺球蛋白抗体(thyroglobulin antibody,TgAb)等,其主要临床表现为以甲状腺功能减退为特征的桥本甲状腺炎 (Hashimoto thyroiditis,HT)或以甲状腺功能亢进为特征的弥漫性毒性甲状腺肿(diffuse toxic goiter; Graves disease,GD)以及其他少见类型,如萎缩性甲状腺炎、无痛性甲状腺炎、产后甲状腺炎、药物性甲状腺炎和桥本甲状腺毒症等。

  • TC是内分泌系统中最常见的癌症之一,其发病率不断增加,国际癌症中心统计数据显示,2020年全球 TC 发病率排名第 9 位,全球女性 TC 发病率为 10.1/10万,比男性高约3倍。在中国,2020年TC发病率高达第7位。在中国女性中,TC发病率则迅速跃升至第 4 位[2]。大多数 TC 为分化型甲状腺癌 (differentiated thyroid cancer,DTC),根据组织病理学标准分为乳头状甲状腺癌(papillary thyroid cancer, PTC)和滤泡状甲状腺癌(follicular thyroid cancer, FTC)。对于未分化型甲状腺癌(anaplastic thyroid carcinoma,ATC)和出现广泛全身转移或碘抵抗的DTC患者,生存期会大大缩短[3]

  • 既往研究显示AITD与TC之间存在流行病学联系,AITD患者的PTC发病率增加,TC患者的甲状腺内淋巴细胞浸润和甲状腺自身抗体的发生率较高。文献显示,这两种甲状腺疾病发病率的上升趋势与某些环境因素有关,尤其是EDC。暴露于某些 EDC的特定节点和持续时间对甲状腺细胞增生、分化和功能均有影响,导致甲状腺疾病[4]。如生活在被有机氯农药或多氯联苯污染地区的居民的HT患病率均较高[1]。长期接触多氯联苯、邻苯二甲酸盐以及某些杀虫剂可能会增加患TC的风险[5]

  • 3 EDC诱发AITD的机制

  • AITD典型病理表现为甲状腺组织内淋巴细胞 (尤其是 T 细胞)浸润,CD8+ T 细胞数量减少,CD4/ CD8 比例增加。从 T 细胞亚群来看,Th1 细胞分泌白介素(interleukin,IL)⁃1β、IL⁃2、肿瘤环死因子(tu⁃ mor necrosis factor,TNF)⁃α、干扰素(interferon,IFN)⁃γ 等细胞因子,主要介导细胞免疫;Th2细胞分泌IL⁃4、 IL⁃5和IL⁃10,刺激B细胞活化,产生自身抗体,参与体液免疫。当Th1细胞亚群占优势时,患者常表现为HT;反之,当Th2细胞亚群占优势时,患者以GD 多见[6]。值得注意的是,CD4+ CD25+ Foxp3+ Treg具有免疫抑制作用,而 HT 患者体内 CD4 + CD25 + Foxp3 + Treg数量下降和功能紊乱,提示其过强的自身免疫不能被抑制[7]

  • EDC 能显著影响甲状腺功能,干扰激素稳态,但机制尚不完全清楚。研究显示,EDC可能通过影响免疫细胞群的数量和功能、干扰碘的转运、诱导氧化应激等方式引发 AITD,且具有剂量及时间效应。基于EDC复杂的内分泌干扰效应,本文重点阐述常见 EDC 诱发 AITD 的免疫机制及对 AITD 患者的影响。

  • 3.1 烷基酚(alkylphenols,Aps)类

  • Aps是一类非离子表面活性剂,广泛应用于塑料、纺织加工、农业化学品等产品的生产。其中,双酚 A(bisphenol A,BPA)是烷基酚的代表物之一。 BPA暴露可触发自身免疫的多种机制,包括其模拟雌激素信号传导、表达细胞因子和活化巨噬细胞、模拟三碘甲状腺原氨酸分子(triiodothyronine,T3)等 (图1)。

  • BPA具有显著的拟雌激素活性,参与免疫反应的许多过程。网状跨膜蛋白UNC93B1对于从内质网中运输 Toll 样受体(Toll like receptor,TLR)至关重要,雌激素可上调UNC93B1的数量,诱发自身免疫[8]。BPA的拟雌激素效应可促进T细胞活化,影响巨噬细胞产生TNF⁃α,影响树突状细胞分化和分泌 INF 及调节人外周血单核细胞(human peripheral blood mononuclear cell,PBMC)的增殖和分化[9]。BPA 还可能在多种辅助T细胞的平衡中诱导极性,即随着 BPA 暴露水平的增加,辅助 T 细胞的极化由 Th1 偏倚转向Th2偏倚[10]。BPA可通过刺激活化T细胞结合位点的Ca2+ /钙调神经磷酸酶依赖性核因子(NF ⁃AT)来增加CD4+ T细胞中IL⁃4和血清中抗原特异性 IgE的水平,B细胞产生自身抗体增加[11],因此,推测 AITD患者也可能通过以上途径产生针对甲状腺的自身抗体,从而增加 AITD 的严重程度。Chailurkit 等[12] 对泰国 2 361 例老年人血清样本进行检测,发现随着 BPA 浓度的增加,血清 TgAb 和 TPOAb 浓度也增加;而HT的血清学特征即为TgAb和TPOAb浓度增加。因此,该项研究认为暴露于BPA可能导致 HT的发病率增加。

  • BPA和T3的分子结构十分相似,因而BPA可能作为 T3受体位点的拮抗剂,抑制 T3与受体结合,还可能导致抗原⁃抗体复合物的自身免疫交叉反应,阻止其发挥正常功能[13]。这也可能是AITD发病的原因之一。

  • 此外,BPA能够剂量依赖性地触发体内活性氧(reactive oxygen species,ROS)的生成,导致氧化应激,参与细胞凋亡、抗原递呈细胞活化及诱导自身免疫反应[14]

  • 迄今为止,尚不清楚 BPA 是否在 TC 的发病机制中起作用。近期国内进行的一项病例对照研究中,甲状腺结节或 TC 患者尿液中的 BPA 浓度显著高于对照组,并且在 TgAb 和 TPOAb 阳性的受试者中观察到 BPA 浓度与多发性甲状腺结节之间存在显著的近线性关联[15]。综上所述,BPA与甲状腺结节或 TC 之间可能存在联系,但缺乏证据表明 BPA 可诱导甲状腺结节或TC。

  • 3.2 多氯联苯(polychlorinated biphenyl,PCB)

  • PCB 存在于各种树脂、橡胶、涂料等工业化合物中。PCB能以甲磺基多氯联苯形式长期蓄积在肝脏、肺等器官的脂肪组织和脑组织中,从而造成机体损伤。

  • 因其结构与甲状腺激素相似,PCB可破坏甲状腺激素信号传导并导致甲状腺疾病,特别是破坏雌激素受体(estrogen receptor,ER),芳香烃受体(aro⁃ matic hydrocarbon receptor,AhR)或甲状腺激素受体 (thyroid hormone receptor,TR)[16]。PCB可通过上调 AhR的mRNA表达参与调节免疫反应和Th17细胞的分化而加强自身免疫[17]。在分子水平上,PCB 可能通过抑制钠/碘转运体(sodium/iodine symporter,NIS)造成甲状腺细胞功能障碍。此外,它可以降低脱碘酶2(deiodinase2,DIO2)和脱碘酶3(deiodinase3,DIO3)的表达及增强肝脏代谢,加速甲状腺激素的清除[18]

  • 图1 BPA诱导自身免疫的机制

  • Figure1 Mechanism of BPA⁃induced autoimmunity

  • PCB引起TC可能有两种机制,即关键致癌转录因子的激活和甲状腺稳态的破坏[5]。Lerro 等[19] 研究表明,儿童时期接触PCB可能会增加成年时期患 TC的风险,他们指出年龄可能是重要的危险因素,在生命早期接触PCB可能会增加患TC的风险。

  • 3.3 重金属

  • 许多重金属可以通过食物链富集或弥散在空气中,再经过皮肤、呼吸道或消化道进入人体,作为 EDS影响内分泌系统的正常功能。推测重金属类物质既干扰内分泌系统,影响甲状腺相关激素的合成、释放和代谢,又对免疫系统产生影响,诱导T细胞向Th1或Th2分化,二者共同作用诱发AITD。

  • 重金属也可以作为致癌物,促进肿瘤生成。在西西里岛埃特纳火山地区存在严重的重金属污染,与生活在邻近非火山地区的居民相比,该地区居民尿液和头皮毛发中检测到高水平重金属,且TC发病率远高于对照区,这表明火山污染物中的重金属具有致癌作用[20]

  • 3.4 邻苯二甲酸酯(phthalate ester,PAE)

  • PAE普遍应用于玩具、食品包装材料以及许多个人护理产品中。与酚类类似,PAE在人和动物体内发挥拟雌激素效应[21]。然而,现有的研究仅证明了PAE对甲状腺相关激素产生的影响,未表明PAE 与自身免疫有关。

  • Liu等[3] 进行的一项研究调查了PAE对肿瘤发生的影响,发现尿中邻苯二甲酸甲酯、2⁃乙基⁃5⁃羟基己基邻苯二甲酸酯和 2⁃乙基己基邻苯二甲酸酯与TC和甲状腺结节的发展有关。

  • 3.5 溴化阻燃剂

  • 溴化阻燃剂常用于电子设备、塑料、涂料和合成纺织品等多种产品中。溴化阻燃剂可结合TR与甲状腺球蛋白(thyroglobulin,Tg),干扰肝脏清除甲状腺激素,从而在多个水平上干扰甲状腺功能。体外细胞研究显示,多溴联苯醚能浓度依赖性抑制 Tg、甲状腺过氧化物酶(thyroid peroxidase,TPO)和促甲状腺激素受体(thyrotropin receptor,TSHR) mRNA的表达,进而抑制甲状腺细胞功能[22]

  • 3.6 农药类

  • 农药包括杀虫剂、除草剂和杀菌剂,它们能通过多种机制破坏甲状腺功能,如抑制碘摄取,结合转运蛋白或TR,影响脱碘酶活性,增加甲状腺激素清除等,导致甲状腺疾病。

  • 此外,某些杀虫剂还是潜在的致癌因子。Zeng 等[23] 调查发现与从未接触过农药的人相比,职业暴露于农药(包括杀虫剂、消毒剂和除草剂)的工人患 TC的风险显著增加。

  • 4 预防与管理

  • 越来越多的研究提示,EDC不仅影响甲状腺功能,且可能导致AITD 和TC。EDC 不仅对甲状腺细胞具有直接毒性作用,还可能导致体内产生抗甲状腺自身抗体,诱发 AITD。因此,预防 EDC 造成的 AITD和TC尤为重要,可以从针对EDC和疾病自身两方面进行干预。

  • 首先,采取有效措施减少 EDC 的暴露,尽量避免使用过多家用化学品及各种化学制剂;其次,建立并完善有关甲状腺内分泌干扰物的筛查和检查体系;再次,对污染地区定期检测EDC含量,严格治理污染;最后,加强对民众的健康宣传教育工作。

  • 生活在污染较重地区或职业暴露较严重的居民,应当定期进行甲状腺彩超及甲状腺功能检查,做到早干预、早治疗。已确诊患者,可适当补充硒和肌醇,研究显示AITD患者经过肌醇和硒代蛋氨酸联合治疗后,体内甲状腺自身抗体水平显著下降[24]

  • 5 总结与展望

  • 综上所述,EDC可从多方面造成甲状腺功能紊乱。本文系统回顾了既往有关AITD、TC与EDC 的相关研究,发现EDC在AITD和TC的发生发展中产生不可忽视的影响,为AITD和TC的治疗和预防提供了新思路。与既往综述论证EDC对甲状腺激素的影响比较,本文重点阐述了EDC与AITD的关联,补充了在 EDC 与甲状腺自身免疫方面研究的不足,为 EDC所致甲状腺疾病的研究提供了多方面的依据。

  • 本文也存在着一定的局限性。首先,基于相关研究数量和规模的限制,有关 EDC 诱发 AITD 的机制仍需进一步论证和补充。其次,AITD包括HT在内的多种类型,然而除HT外其他类型的AITD,未查阅到相关研究,导致本文着重于 HT 而对其他类型 AITD 的描述不足。因此,未来需要更多有关 EDC 影响各种 AITD 的研究以供学习和参考。最后,能否根据以上机制寻找治疗靶点,针对性地阻断或削弱EDC对AITD和TC的影响,进而缓解病情或改善预后,仍需进一步研究。

  • 参考文献

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    • [4] KYRIACOU A,TZIAFERI V,TOUMBA M.Stress,thy⁃ roid dysregulation and thyroid cancer in children and ado⁃ lescents.proposed impending mechanisms[J/OL].Horm Res Paediatr,2022[2022 ⁃ 09 ⁃ 11].DOI:10.1159/000524477

    • [5] ALSEN M,SINCLAIR C,COOKE P,et al.Endocrine dis⁃ rupting chemicals and Thyroid cancer:an overview[J].Toxics,2021,9(1):14

    • [6] RAGUSA F,FALLAHI P,ELIA G,et al.Hashimotos’ thyroiditis:epidemiology,pathogenesis,clinic and therapy [J].Best Pract Res Clin Endocrinol Metab,2019,33(6):101367

    • [7] TOOR S M,SALEH R,SASIDHARAN N V,et al.T⁃cell responses and therapies against SARS ⁃ CoV ⁃ 2 infection [J].Immunology,2021,162(1):30-43

    • [8] PANCHANATHAN R,LIU H,CHOUBEY D.Expression of murine Unc93b1 is up ⁃ regulated by interferon and es⁃ trogen signaling:implications for sex bias in the develop⁃ ment of autoimmunity[J].Int Immunol,2013,25(9):521-529

    • [9] MAGLIONE A,ROLLA S,MERCANTI S F,et al.The adaptive immune system in multiple sclerosis:an estrogen ⁃mediated point of view[J].Cells,2019,8(10):1280

    • [10] CUNNINGHAM M,GILKESON G.Estrogen receptors in immunity and autoimmunity[J].Clin Rev Allergy Immu⁃ nol,2011,40(1):66-73

    • [11] PANCHANATHAN R,CHOUBEY D.Murine BAFF ex⁃ pression is up ⁃ regulated by estrogen and interferons:im⁃ plications for sex bias in the development of autoimmunity [J].Mol Immunol,2013,53(1/2):15-23

    • [12] CHAILURKIT L O,AEKPLAKORN W,ONGPHIPHAD⁃ HANAKUL B.The association of serum bisphenol a with thyroid autoimmunity[J].Int J Environ Res Public Health,2016,13(11):1153

    • [13] KIM M J,PARK Y J.Bisphenols and thyroid hormone[J].Endocrinol Metab(Seoul),2019,34(4):340-348

    • [14] ZHANG Y,YAN M,KUANG S,et al.Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO ⁃Y4:involvement of ROS ⁃mediated mTOR/ULK1 pathway[J].Ecotoxicol Environ Saf,2021,230:113119

    • [15] LI L,YING Y,ZHANG C,et al.Bisphenol A exposure and risk of thyroid nodules in Chinese women:A case ⁃ control study[J].Environ Int,2019,126:321-328

    • [16] LINA B,JUSTIN J,ELISABETH J,et al.Thyroid furc⁃ tion and immune status in perch(Perca fluviatilis)from lakes contaminated with PFASs of PCBs[J].Ecotoxicol Environ Sat,2021,222:112495

    • [17] WANG C,PETRIELLO M C,ZHU B,et al.PCB 126 in⁃ duces monocyte/macrophage polarization and inflamma⁃ tion through AhR and NF ⁃ kappaB pathways[J].Toxicol Appl Pharmacol,2019,367:71-81

    • [18] SOKAL A,JARMAKIEWICZ ⁃ CZAJA S,TABARKIE⁃ WICZ J,et al.Dietary intake of endocrine disrupting sub⁃ stances presents in environment and their impact on thy⁃ roid function[J].Nutrients,2021,13(3):867

    • [19] LERRO C C,JONES R R,LANGSETH H,et al.A nested case ⁃ control study of polychlorinated biphenyls,organo⁃ chlorine pesticides,and thyroid cancer in the Janus Se⁃ rum Bank cohort[J].Environ Res,2018,165:125-132

    • [20] VIGNERI R,MALANDRINO P,GIANI F,et al.Heavy metals in the volcanic environment and thyroid cancer [J].Mol Cell Endocrinol,2017,457:73-80

    • [21] SUR U,ERKEKOGLU P,BULUS A D,et al.Oxidative stress markers,trace elements,and endocrine disrupting chemicals in children with Hashimoto’s thyroiditis[J].Toxicol Mech Methods,2019,29(9):633-643

    • [22] WANG Y,CHEN L,WANG C,et al.Association between organophosphate pesticide exposure and thyroid hor⁃ mones in pregnant women[J].Epidemiology,2017,28(Suppl 1):S35-S40

    • [23] ZENG F,LERRO C,LAVOUE J,et al.Occupational expo⁃ sure to pesticides and other biocides and risk of thyroid cancer[J].Occup Environ Med,2017,74(7):502-510

    • [24] FERRARI S M,FALLAHI P,ELIA G,et al.Thyroid auto⁃ immune disorders and cancer[J].Semin Cancer Biol,2020,64:135-146

  • 参考文献

    • [1] BENVENGA S,ELIA G,RAGUSA F,et al.Endocrine dis⁃ ruptors and thyroid autoimmunity[J].Best Pract Res Clin Endocrinol Metab,2020,34(1):101377

    • [2] SUNG H,FERLAY J,SIEGEL R L,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2021,71(3):209-249

    • [3] LIU C,DENG Y L,ZHENG T Z,et al.Urinary biomarkers of phthalates exposure and risks of thyroid cancer and be⁃ nign nodule[J].J Hazard Mater,2020,383:121189

    • [4] KYRIACOU A,TZIAFERI V,TOUMBA M.Stress,thy⁃ roid dysregulation and thyroid cancer in children and ado⁃ lescents.proposed impending mechanisms[J/OL].Horm Res Paediatr,2022[2022 ⁃ 09 ⁃ 11].DOI:10.1159/000524477

    • [5] ALSEN M,SINCLAIR C,COOKE P,et al.Endocrine dis⁃ rupting chemicals and Thyroid cancer:an overview[J].Toxics,2021,9(1):14

    • [6] RAGUSA F,FALLAHI P,ELIA G,et al.Hashimotos’ thyroiditis:epidemiology,pathogenesis,clinic and therapy [J].Best Pract Res Clin Endocrinol Metab,2019,33(6):101367

    • [7] TOOR S M,SALEH R,SASIDHARAN N V,et al.T⁃cell responses and therapies against SARS ⁃ CoV ⁃ 2 infection [J].Immunology,2021,162(1):30-43

    • [8] PANCHANATHAN R,LIU H,CHOUBEY D.Expression of murine Unc93b1 is up ⁃ regulated by interferon and es⁃ trogen signaling:implications for sex bias in the develop⁃ ment of autoimmunity[J].Int Immunol,2013,25(9):521-529

    • [9] MAGLIONE A,ROLLA S,MERCANTI S F,et al.The adaptive immune system in multiple sclerosis:an estrogen ⁃mediated point of view[J].Cells,2019,8(10):1280

    • [10] CUNNINGHAM M,GILKESON G.Estrogen receptors in immunity and autoimmunity[J].Clin Rev Allergy Immu⁃ nol,2011,40(1):66-73

    • [11] PANCHANATHAN R,CHOUBEY D.Murine BAFF ex⁃ pression is up ⁃ regulated by estrogen and interferons:im⁃ plications for sex bias in the development of autoimmunity [J].Mol Immunol,2013,53(1/2):15-23

    • [12] CHAILURKIT L O,AEKPLAKORN W,ONGPHIPHAD⁃ HANAKUL B.The association of serum bisphenol a with thyroid autoimmunity[J].Int J Environ Res Public Health,2016,13(11):1153

    • [13] KIM M J,PARK Y J.Bisphenols and thyroid hormone[J].Endocrinol Metab(Seoul),2019,34(4):340-348

    • [14] ZHANG Y,YAN M,KUANG S,et al.Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO ⁃Y4:involvement of ROS ⁃mediated mTOR/ULK1 pathway[J].Ecotoxicol Environ Saf,2021,230:113119

    • [15] LI L,YING Y,ZHANG C,et al.Bisphenol A exposure and risk of thyroid nodules in Chinese women:A case ⁃ control study[J].Environ Int,2019,126:321-328

    • [16] LINA B,JUSTIN J,ELISABETH J,et al.Thyroid furc⁃ tion and immune status in perch(Perca fluviatilis)from lakes contaminated with PFASs of PCBs[J].Ecotoxicol Environ Sat,2021,222:112495

    • [17] WANG C,PETRIELLO M C,ZHU B,et al.PCB 126 in⁃ duces monocyte/macrophage polarization and inflamma⁃ tion through AhR and NF ⁃ kappaB pathways[J].Toxicol Appl Pharmacol,2019,367:71-81

    • [18] SOKAL A,JARMAKIEWICZ ⁃ CZAJA S,TABARKIE⁃ WICZ J,et al.Dietary intake of endocrine disrupting sub⁃ stances presents in environment and their impact on thy⁃ roid function[J].Nutrients,2021,13(3):867

    • [19] LERRO C C,JONES R R,LANGSETH H,et al.A nested case ⁃ control study of polychlorinated biphenyls,organo⁃ chlorine pesticides,and thyroid cancer in the Janus Se⁃ rum Bank cohort[J].Environ Res,2018,165:125-132

    • [20] VIGNERI R,MALANDRINO P,GIANI F,et al.Heavy metals in the volcanic environment and thyroid cancer [J].Mol Cell Endocrinol,2017,457:73-80

    • [21] SUR U,ERKEKOGLU P,BULUS A D,et al.Oxidative stress markers,trace elements,and endocrine disrupting chemicals in children with Hashimoto’s thyroiditis[J].Toxicol Mech Methods,2019,29(9):633-643

    • [22] WANG Y,CHEN L,WANG C,et al.Association between organophosphate pesticide exposure and thyroid hor⁃ mones in pregnant women[J].Epidemiology,2017,28(Suppl 1):S35-S40

    • [23] ZENG F,LERRO C,LAVOUE J,et al.Occupational expo⁃ sure to pesticides and other biocides and risk of thyroid cancer[J].Occup Environ Med,2017,74(7):502-510

    • [24] FERRARI S M,FALLAHI P,ELIA G,et al.Thyroid auto⁃ immune disorders and cancer[J].Semin Cancer Biol,2020,64:135-146

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