Mono-(2-ethyl-5-hydroxyhexyl) phthalate promotes uterine leiomyoma cell survival through tryptophan-kynurenine-AHR pathway activation.
Mono-(2-ethyl-5-hydroxyhexyl) phthalate promotes uterine leiomyoma cell survival through tryptophan-kynurenine-AHR pathway activation.
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DOI：
10.1073/pnas.2208886119
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发表时间：
2022-11-22
影响因子：
11.1
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中科院分区：
文献类型：
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子宫平滑肌瘤（或纤维瘤）是最常见的肿瘤，影响多达80%的育龄妇女。流行病学研究一致表明，暴露于内分泌干扰邻苯二甲酸酯和平滑肌瘤风险之间存在正相关性;然而，其潜在机制仍不清楚。在这里，我们证明了普遍存在的环境污染物邻苯二甲酸单（2-乙基-5-羟己基）酯[MEHHP，邻苯二甲酸二（2-乙基己基）酯的主要代谢产物]通过增加细胞色氨酸摄取、犬尿氨酸产生和芳烃受体途径激活来促进平滑肌瘤细胞存活。从流行病学和机理上，我们的研究确定MEHHP暴露是平滑肌瘤生长的高危因素。这些发现有望在平滑肌瘤研究领域开辟新的途径，并促进开发新的干预策略，用于治疗或预防该疾病。子宫平滑肌瘤是女性最常见的肿瘤，在15%至30%的育龄妇女中引起严重的发病率。流行病学研究一致表明，平滑肌瘤的发生与内分泌干扰化学品邻苯二甲酸酯（尤其是邻苯二甲酸二（2-乙基己基）酯（DEHP））的暴露之间存在相关性;然而，其潜在机制尚不清楚。在这里，在最常见的邻苯二甲酸酯代谢物中，我们发现尿液中邻苯二甲酸单（2-乙基-5-羟己基）酯（MEHHP）（主要DEHP代谢物）水平与子宫平滑肌瘤诊断风险之间的关联最强（n = 712例患者）。用邻苯二甲酸酯代谢物的各种混合物（浓度相当于尿样中检测到的浓度）治疗原发性平滑肌瘤和平滑肌细胞（n = 29），显著增加细胞活力并降低细胞凋亡。MEHHP对细胞活力和凋亡的影响最强。MEHHP显著增加细胞色氨酸和犬尿氨酸水平，并诱导色氨酸转运蛋白SLC 7A 5和SLC 7A 8以及色氨酸2，3-双加氧酶（TDO 2）的表达，TDO 2是催化色氨酸转化为犬尿氨酸的关键酶，犬尿氨酸是芳烃受体（AHR）的内源性配体。MEHHP刺激AHR的核定位，并上调AHR的两个原型靶标CYP 1A 1和CYP 1B 1的表达。SLC 7A 5/SLC 7A 8、TDO 2或AHR的siRNA敲除或药理学抑制消除了MEHHP介导的对平滑肌瘤细胞存活的作用。这些发现表明，MEHHP通过激活Dahan-kynurenine-AHR途径促进平滑肌瘤细胞存活。这项研究指出MEHHP暴露是平滑肌瘤生长的一个高危因素，揭示了暴露于环境邻苯二甲酸酯影响平滑肌瘤发病机制的机制，并可能导致新的可药用靶点的开发。
Uterine leiomyomas (or fibroids) represent the most common tumor affecting up to 80% of reproductive-age women. Epidemiological studies consistently indicate a positive association between exposure to endocrine-disrupting phthalates and leiomyoma risk; however, the underlying mechanisms remain unclear. Here, we demonstrate that the ubiquitous environmental pollutant mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP, the major metabolite of di-(2-ethylhexyl) phthalate] promotes leiomyoma cell survival through increasing cellular tryptophan uptake, kynurenine production, and aryl hydrocarbon receptor pathway activation. Both epidemiologically and mechanistically, our study identified MEHHP exposure as a high-risk factor for leiomyoma growth. These findings are expected to open new avenues in the leiomyoma research field and facilitate the development of novel intervention strategies for the treatment or prevention of the disease. 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.
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DOI：
10.1073/pnas.88.21.9543
发表时间：
1991-11-01
影响因子：
11.1
作者：
BJELDANES, LF;KIM, JY;BRADFIELD, CA
通讯作者：
BRADFIELD, CA
影响因子：
3.2
作者：
Choi, Kyoungju;Joo, Hyun;Clewell, Harvey J., III
通讯作者：
Clewell, Harvey J., III
影响因子：
4
作者：
Ernst, Jana;Jann, Johann-Christoph;Fischer, Bernd
通讯作者：
Fischer, Bernd
DOI：
10.1089/jwh.2021.0280
发表时间：
2021-08
期刊：
Journal of women's health (2002)
影响因子：
--
作者：
Aninye IO;Laitner MH
通讯作者：
Laitner MH
影响因子：
4.6
作者：
Amenya HZ;Tohyama C;Ohsako S
通讯作者：
Ohsako S