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Published on: June 2, 2023
The no-observed-adverse-effect level of phthalates promotes proliferation and cell cycle progression in normal human
Fang-Ping Chen1, Mei-Hua Chien2, Chun-Hui Lee3
1Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Keelung 204, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, 259, Taiwan.
Objective:
The data on the association between phthalates and breast cancer risk remains inconsistent. This study aimed to explore the possible mechanism of low-dose exposures of phthalates, including Butyl benzyl phthalate (BBP), di(n-butyl) phthalate (DBP), and di(20ethylhexyl) phthalate (DEHP), on breast tumorigenesis.
Methods And Methods:
MCF-10A normal breast cells were treated with phthalates (10 and 100 nM) and 17β-estradiol (E2, 10 nM), which were co-cultured with fibroblasts from normal mammary tissue. Cell viability, cycle, and apoptosis were detected by MTT assay, flow cytometry, and TUNEL assay respectively. The expression levels of related proteins were determined by Western blot.
Results:
Like E2, both 10 nM and 100 nM phthalates exerted significantly higher cell viability, lower apoptosis, and increased cell numbers in the S and G2/M phases with up-regulation of cyclin D/CDK4, cyclin E/CDK2, cyclin A/CDK2, cyclin A/CDK1, and cyclin B/CDK1, compared with the control group. Significant increase in PDK1, P13K, p-AKT, p-mTOR, and BCL-2 expression and a decrease in Bax protein, cytochrome C, caspase 8, and caspase 3 levels were noted in cells treated with 10 nM and 100 nM phthalates and E2, compared with the control group and MCF-10A cells co-cultured with fibroblasts. The effects of the three phthalates were noted to be dose-dependent.
Conclusions:
The results indicate that phthalates at a level below its no-observed-adverse-effect concentration, as defined by the current standards, still induce cell cycle progression and proliferation as well as inhibit apoptosis of normal breast cells. Thus, the possibility of breast tumorigenesis through chronic phthalate exposure should be considered.
