Inhibitory effects of 3,3'-diindolylmethane on epithelial-mesenchymal transition induced by endocrine disrupting chemicals in cellular and xenograft mouse models of breast cancer.
As a phytoestrogen, 3,3'-diindolylmethane (DIM) plays a chemopreventive role by inhibiting cancer progression. In this study, we examined the effects of 17β-estradiol (E2), two endocrine disrupting chemicals (EDCs), triclosan (TCS) and bisphenol A (BPA), and DIM on epithelial-mesenchymal transition (EMT) and metastatic behaviors of estrogen receptor (ER)-positive MCF-7 breast cancer cells. An in vitro assay revealed that E2 (10-9 M), TCS (10-5-10-7 M), and BPA (10-5-10-7 M) induced MCF-7 cell proliferation compared to a control through the ER pathway. In addition, E2, TCS, and BPA changed the cell morphology from the epithelial to the mesenchymal phenotype and increased the migration and invasion capacity of MCF-7 cells via ER; however, co-treatment with DIM (20 μM) effectively suppressed E2, TCS, and BPA-induced cell proliferation, EMT, migration, and invasion of MCF-7 cells. Western blot assay revealed that DIM regulated the protein expression of EMT- and metastasis-related genes toward the inhibition of these processes. Moreover, E2, TCS, and BPA increased the protein expression of CXCR4, which is a receptor of chemokine CXCL12 that is positively involved in breast cancer metastasis via an ER-dependent pathway. Conversely, DIM and a CXCR4 antagonist (AMD3100) decreased CXCR4 protein expression, which led to inhibition of the EMT process, indicating that DIM may suppress E2, TCS or BPA-induced EMT, migration, and invasion of MCF-7 breast cancer cells by suppressing CXCR4 protein expression. These in vitro effects of E2, TCS, BPA, and DIM were also identified in a xenografted mouse model transplanted with MCF-7 breast cancer cells. Taken together, DIM is a potent chemopreventive compound for preventing metastatic behaviors of breast cancer cells induced by EDCs with cancer-related toxicity.
Lee GA
，Hwang KA
，Choi KC
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Long-lasting effects of neonatal bisphenol A exposure on the implantation process.
Successful implantation is the result of complex molecular interactions between the hormonally primed uterus and a mature blastocyst. This very carefully synchronized interplay of hormonal signals and feedback loops is potentially vulnerable to chemicals such as endocrine disruptors that may disrupt endocrine signaling. Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide. This chapter describes the effects of brief postnatal exposure to BPA on female reproductive performance and specifically on the uterine adaptations during the preimplantation period. We propose that an early alteration in Hoxa10 gene expression affects the functional differentiation of the preimplantation uterus as part of an altered endocrine signal transduction pathway. These molecular alterations could explain, at least in part, the adverse effects of BPA on uterine implantation. Exposure to endocrine disruptors, such as BPA, could contribute to the impaired female fertility noted over the past decades.
Varayoud J
，Ramos JG
，Muñoz-de-Toro M
，Luque EH
... -
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Bisphenol A, oocyte maturation, implantation, and IVF outcome: review of animal and human data.
Recent data have raised concerns about the detrimental effect of chronic exposure to environmental chemicals. Some chemicals affect the endocrine system (endocrine disruptors) and have been linked to several diseases, including infertility. One such endocrine disruptor is bisphenol A (BPA), a monomer widely used in the plastic industry, with nearly ubiquitous exposure. In this review, data on the effects of BPA on female fertility are summarized. Specifically, its effect is considered on folliculogenesis, oocyte maturation, embryo quality, and implantation, both in animal and human models. Animal studies have shown that BPA might impair prophase I, follicular growth, and implantation, and may be associated with spindle abnormalities. In humans, while in-vitro studies have suggested an association between BPA exposure and impaired oocyte meiosis, clinical evidence indicate possible adverse effects of BPA exposure on IVF outcomes. As human clinical data are still scarce, larger studies are required to further elucidate the effects of BPA exposure on female fertility.
Machtinger R
，Orvieto R
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