Widespread phthalate appears to trigger cell growth and delay cell death
Exposure to a chemical found in a wide variety of consumer products may trigger the growth of uterine fibroid cells and delay the rate at which they die, suggests a study funded by the National Institutes of Health. The study provides a potential explanation for why women exposed to industrial chemicals known as phthalates—found in personal care products, food packaging, and medical products—have higher rates of fibroid tumors than other women. The findings may also inform future strategies to prevent or treat fibroids.
The study was conducted by Serdar E. Bulun, M.D., of Northwestern University, and colleagues. It appears in Proceedings of the National Academy of Sciences. It was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institute of Environmental Health Sciences.
Once in the body, di-(2-ethylhexyl) phthalate (DEHP) is broken down or metabolized into several related chemicals, among them mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). The researchers found that levels of MEHHP corresponding to those in the urine of women with fibroids fostered the growth of fibroid cells in laboratory cultures while inhibiting their rate of cell death. In a series of experiments, they found that MEHHP caused the cells to take in higher amounts of the amino acid tryptophan and convert it to a compound that stimulated a receptor known to promote the growth of tumor cells and inhibit their death rate.
Background
Uterine fibroids, or leiomyomas, are tumors that grow in or on the wall of the uterus. By age 50, almost 80% of reproductive age women will develop at least one fibroid. Fibroids may cause difficulty in achieving or maintaining a pregnancy. Roughly 200,000 hysterectomies are performed each year to treat the complications of fibroids, which include heavy or painful periods, bleeding between periods, and pain.
According to the U.S. Centers for Disease and Prevention, phthalates are a group of chemicals used to make plastics more durable. DEHP is commonly used in such products as tablecloths, floor tiles, furniture upholstery, shower curtains, garden hoses, swimming pool liners, rainwear, some toys, shoes, automobile upholstery, packaging film and sheets, medical tubing, and blood storage bags. People are exposed to DEHP by eating food, drinking liquids, or breathing in dust containing DEHP.
For the current study, researchers investigated the potential effects of MEHHP on cultures of fibroid cells derived from five patients with fibroids.
Results
Researchers found that fibroid cells treated with MEHHP grew faster than cells treated with other DEHP metabolites. Similarly, MEHHP-treated cells had a reduced rate of apoptosis—cell death—compared to cells treated with other metabolites. In contrast, MEHHP did not appear to influence the growth or death of myometrial (uterine muscle) cells from participants without fibroids. Fibroids are thought to originate from myometrial cells.
Cells treated with MEHHP also had higher numbers of the aryl hydrocarbon receptor. Previous studies have shown higher activation of the receptor in many kinds of tumors. The MEHPP-treated cells also had higher levels of the amino acid tryptophan and its metabolite, kynurenine, which activates the kynurenine receptor. Similarly, they had higher levels of the enzyme tryptophan 2,3-dioxygenase, which converts tryptophan to kynurenine. They also had higher levels of two proteins that transport tryptophan into the cells, SLC7A5 and SLC7A8.
Halting production of the enzyme, the proteins, or the aryl hydrocarbon receptor prevented the runaway growth of the fibroid cells exposed to MEHPP.
Significance
The authors said their study provides strong evidence that exposure to MEHHP increases the growth of fibroids by stimulating intake of tryptophan, its conversion to kynurenine, and subsequent activation of the aryl hydrocarbon receptor. They concluded that their findings could inform new strategies to treat or prevent fibroids.
Reference
Iizuka, DR, et al. Mono-(2-ethyl-5-hydroxyhexyl) phthalate promotes uterine leiomyoma cell survival through tryptophan-kynurenine-AHR pathway activation. Proceedings of the National Academy of Sciences. 2022. https://doi.org/10.1073/pnas.2208886119 
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