Bisphenol A drives di(2-ethylhexyl) phthalate promoting thyroid tumorigenesis via regulating HDAC6/PTEN and c-MYC signaling

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.