Bisphenol A (BPA) and di-(2-ethylhcxyl) phthalate (DEHP) are exist widespread in the environment and produce adverse effect to human as environmental disruptors (EDCs). Epidemiological studies have found that the exposure of DEHP and BPA could increase the susceptibility to thyroid diseases including thyroid cancer and benign thyroid nodules. Due to the existence of multiple pollutants in our daily life, the mixed toxic effects of exposure and their interrelationships may distinguish from the exposure to a single chemical, so it is of great significance to explore the mixed toxic effect of DEHP and BPA co-exposure. Thyroid, as one of the target organs of EDCs, is prone to tumor occurrence, however, whether the mixture of BPA and DEHP will affect the occurrence of thyroid cancer is still obscure. We aim to investigate the effect of single or combined exposure to BPA and DEHP on the occurrence of thyroid cancer. An animal model of exposure to BPA and DEHP was firstly established to evaluate their effect on DMD-induced thyroid cancer. Additionally, human thyroid cancer cells BCPAP and thyroid cells Nthy-ori3–1 were used to further clarify some possible mechanisms of BPA and MEHP, the main metabolite of DEHP. Consequently, we found that BPA alone could increase the incidence of thyroid tumors in female rats compared with DEHP, and DEHP enhanced the effect of BPA on cancer promotion. BPA alone and in combination with DEHP mainly induced the expression of HDAC6, inhibited tumor suppressor gene PTEN upregulated the expression of oncogene c-MYC, and eventually elevate the susceptibility to thyroid tumors. Mechanistically, BPA alone and in combination with MEHP could significantly induce the proliferation of BCPAP cells depending on HDAC6, which could modulate H3K9ac to inhibit PTEN, activate AKT signaling pathway, and simultaneously upregulate the expression of c-MYC. Interestingly, we found that BPA alone and in combination with MEHP could significantly induce the proliferation of Nthy-ori3–1 cells independent on HDAC6 via activating ERK signaling pathway. Taken together, these findings not only provide new evidence of the promoting effect of BPA and DEHP on thyroid cancer but also discusses some possible mechanisms underlying these effects.

双酚 A (BPA) 和邻苯二甲酸二 (2-乙基) 酯 (DEHP) 广泛存在于环境中，并作为环境干扰物 (EDC) 对人类产生不利影响。流行病学研究发现，接触 DEHP 和 BPA 会增加甲状腺疾病的易感性，包括甲状腺癌和良性甲状腺结节。由于我们日常生活中存在多种污染物，暴露的混合毒性效应及其相互关系可能与单一化学物质的暴露区分开来，因此探索DEHP和BPA共同暴露的混合毒性效应具有重要意义. 甲状腺作为EDCs的靶器官之一，易发生肿瘤，但BPA与DEHP的混合是否会影响甲状腺癌的发生尚不清楚。我们旨在研究单次或联合暴露于 BPA 和 DEHP 对甲状腺癌发生的影响。首次建立了暴露于 BPA 和 DEHP 的动物模型，以评估它们对 DMD 诱导的甲状腺癌的影响。此外，人类甲状腺癌细胞 BCPAP 和甲状腺细胞 Nthy-ori3-1 用于进一步阐明 BPA 和 DEHP 的主要代谢物 MEHP 的一些可能机制。因此，我们发现与 DEHP 相比，单独的 BPA 可以增加雌性大鼠甲状腺肿瘤的发病率，并且 DEHP 增强了 BPA 的促癌作用。BPA单独和与DEHP联合主要诱导HDAC6的表达，抑制抑癌基因PTEN上调癌基因c-MYC的表达，最终提高甲状腺肿瘤的易感性。机械地，BPA 单独和与 MEHP 联合使用可显着诱导依赖于 HDAC6 的 BCPAP 细胞增殖，其可调节 H3K9ac 抑制 PTEN，激活 AKT 信号通路，同时上调 c-MYC 的表达。有趣的是，我们发现单独的 BPA 和与 MEHP 联合使用可以通过激活 ERK 信号通路显着诱导不依赖于 HDAC6 的 Nthy-ori3-1 细胞的增殖。总之，这些发现不仅为 BPA 和 DEHP 对甲状腺癌的促进作用提供了新的证据，而且还讨论了这些作用背后的一些可能机制。有趣的是，我们发现单独的 BPA 和与 MEHP 联合使用可以通过激活 ERK 信号通路显着诱导不依赖于 HDAC6 的 Nthy-ori3-1 细胞的增殖。总之，这些发现不仅为 BPA 和 DEHP 对甲状腺癌的促进作用提供了新的证据，而且还讨论了这些作用背后的一些可能机制。有趣的是，我们发现单独的 BPA 和与 MEHP 联合使用可以通过激活 ERK 信号通路显着诱导不依赖于 HDAC6 的 Nthy-ori3-1 细胞的增殖。总之，这些发现不仅为 BPA 和 DEHP 对甲状腺癌的促进作用提供了新的证据，而且还讨论了这些作用背后的一些可能机制。