Uterine leiomyoma is the most common tumor in women and causes severe morbidity in 15 to 30% of reproductive-age women. Epidemiological studies consistently indicate a correlation between leiomyoma development and exposure to endocrine-disrupting chemical phthalates, especially di-(2-ethylhexyl) phthalate (DEHP); however, the underlying mechanisms are unknown. Here, among the most commonly encountered phthalate metabolites, we found the strongest association between the urine levels of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), the principal DEHP metabolite, and the risk of uterine leiomyoma diagnosis ( n = 712 patients). The treatment of primary leiomyoma and smooth muscle cells ( n = 29) with various mixtures of phthalate metabolites, at concentrations equivalent to those detected in urine samples, significantly increased cell viability and decreased apoptosis. MEHHP had the strongest effects on both cell viability and apoptosis. MEHHP increased cellular tryptophan and kynurenine levels strikingly and induced the expression of the tryptophan transporters SLC7A5 and SLC7A8, as well as, tryptophan 2,3-dioxygenase (TDO2), the key enzyme catalyzing the conversion of tryptophan to kynurenine that is the endogenous ligand of aryl hydrocarbon receptor (AHR). MEHHP stimulated nuclear localization of AHR and up-regulated the expression of CYP1A1 and CYP1B1, two prototype targets of AHR. siRNA knockdown or pharmacological inhibition of SLC7A5/SLC7A8, TDO2, or AHR abolished MEHHP-mediated effects on leiomyoma cell survival. These findings indicate that MEHHP promotes leiomyoma cell survival by activating the tryptophan-kynurenine-AHR pathway. This study pinpoints MEHHP exposure as a high-risk factor for leiomyoma growth, uncovers a mechanism by which exposure to environmental phthalate impacts leiomyoma pathogenesis, and may lead to the development of novel druggable targets.

中文翻译：

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单（2-乙基-5-羟基己基）邻苯二甲酸酯通过激活色氨酸-犬尿氨酸-AHR 通路促进子宫平滑肌瘤细胞存活

子宫肌瘤是女性最常见的肿瘤，导致 15% 至 30% 的育龄妇女出现严重的并发症。流行病学研究一致表明，平滑肌瘤的发展与接触会干扰内分泌的化学邻苯二甲酸盐之间存在相关性，尤其是邻苯二甲酸二（2-乙基己基）酯 (DEHP)；然而，潜在的机制是未知的。在这里，在最常见的邻苯二甲酸酯代谢物中，我们发现主要 DEHP 代谢物单（2-乙基-5-羟基己基）邻苯二甲酸酯 (MEHHP) 的尿液水平与子宫平滑肌瘤诊断风险之间的关联最强（n= 712 名患者）。原发性平滑肌瘤和平滑肌细胞的治疗（n= 29）与邻苯二甲酸酯代谢物的各种混合物，其浓度与尿样中检测到的浓度相当，可显着增加细胞活力并减少细胞凋亡。MEHHP 对细胞活力和细胞凋亡的影响最强。MEHHP 显着增加细胞色氨酸和犬尿氨酸水平，并诱导色氨酸转运蛋白 SLC7A5 和 SLC7A8 以及色氨酸 2,3-双加氧酶 (TDO2) 的表达，TDO2 是催化色氨酸转化为犬尿氨酸的内源性配体芳烃受体 (AHR)。MEHHP 刺激 AHR 的核定位并上调 AHR 的两个原型靶标 CYP1A1 和 CYP1B1 的表达。SLC7A5/SLC7A8、TDO2 或 AHR 的 siRNA 敲低或药理学抑制消除了 MEHHP 介导的对平滑肌瘤细胞存活的影响。这些发现表明 MEHHP 通过激活色氨酸-犬尿氨酸-AHR 通路促进平滑肌瘤细胞存活。这项研究将 MEHHP 暴露确定为平滑肌瘤生长的高危因素，揭示了暴露于环境邻苯二甲酸盐影响平滑肌瘤发病机制的机制，并可能导致开发新的药物靶点。