Mono-(2-ethyl-5-hydroxyhexyl) phthalate promotes uterine leiomyoma cell survival through tryptophan-kynurenine-AHR pathway activation

Abstract

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.

Presence of Fibroids on Transvaginal Ultrasonography in a Community-Based, Diverse Cohort of 996 Reproductive-Age Female Participants

“…Prior studies found Black individuals to have higher levels of phthalates compared with White individuals, possibly secondary to differences in use pattern of personal care products . Phthalates may potentiate fibroid growth by delaying apoptosis and promoting leiomyoma cell survival . Higher urinary levels of paraben, an estrogenic preservative, were also observed in Black individuals .…”

“… 37 , 38 Phthalates may potentiate fibroid growth by delaying apoptosis and promoting leiomyoma cell survival. 39 Higher urinary levels of paraben, an estrogenic preservative, were also observed in Black individuals. 40 Limited data also show higher EDC levels in Chinese American female individuals.…”

Association between urinary phthalates and phthalate metabolites and cancer risk: A systematic review and meta-analysis

“…Clinical studies have suggested that MEHHP and MECPP exposure was associated with prostate cancer [ 28 ], thyroid cancer [ 31 ], breast cancer [ 40 ] and urothelial cancer [ 53 ]. In addition, MEHHP was reported to promote the survival of leiomyoma cells by increasing cellular tryptophan uptake, kynurenine production, and activating the aryl hydrocarbon receptor pathway [ 54 ]. All of the above evidence indicated that MEHHP, MECPP and DBP are closely correlated with the development of cancer, which are consistent with our results.…”

The adverse role of endocrine disrupting chemicals in the reproductive system

“…In vitro experiments using human uterine leiomyoma cells demonstrated that DEHP exposure enhanced cell viability, promoted anti-apoptotic protein expression, and induced the expression of HIF-1α and COX-2 ( 32 ). Other epidemiological and in vitro studies have shown that the major DEHP metabolite, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), enhances the survival of leiomyoma cells through activation of the tryptophan-kynurenine-AHR pathway ( 33 ). Additionally, analysis of the TREE cohort data revealed positive associations between certain PAE exposures and the risks of UFs and endometriosis, which may be mediated by oxidatively generated DNA damage ( 34 ).…”