Coexposure to Phytoestrogens and Bisphenol A Mimics Estrogenic Effects in an Additive Manner

Abstract

Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.

Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat

“…These results indicate that BPA and estradiol may be signaling through similar pathways to cause exacerbated migraine-like behaviors. Studies have demonstrated that BPA has the ability to interact with and activate ERalpha, ERβ, and GPR30 (Katchy, et al, 2014, Montes-Grajales and Olivero-Verbel, 2013). Interestingly, a recently published study demonstrated BPA-mediated activation of ERK in a cell model, and the use of a GPR30 antagonist in conjunction with BPA exposure led to suppression of ERK activation (Ge, et al, 2014).…”

Gestational bisphenol A exposure and testis development

“…We found that identical genes were regulated by BPA, phytoestrogens, and 17β-estradiol. 29 Although MCF-7 cells also express the AR, PPARα/β/γ, TRα/β, GPER1, and AHR, 30–32 we found that the expression of all genes regulated at 24 h BPA treatment were inhibited by co-treatment with the ERα antagonist ICI. 29 This suggests that the transcriptional activity elicited by BPA in these cells was mediated through ERα, and that there were no unique BPA target genes that estrogen did not activate.…”

“…We also demonstrated that BPA and phytoestrogens acted in an additive manner. 29 The additive effect of BPA and phytoestrogens raises concerns that the feeding of phytoestrogen-rich soy-based formula to infants may enhance the effect of BPA exposure.…”

“…19,29 Thus, in theory, BPA should have negligible human health effects at the current exposure levels. Multiple studies have, however, shown that low level BPA exposure can alter many physiological processes, and epidemiologic evidence supports that BPA is related to altered neuronal and brain development, immune, ovarian, and metabolic diseases (for a recent review, see ref.…”

Endocrine disruption of the epigenome: a breast cancer link

“…BPA acts as an estrogen mimetic and can interact with the ligand-binding domain of ERα (Sengupta et al 2013), increasing cellular proliferation, potentially via reducing the rate of apoptosis (Mlynarcikova et al 2013), and inducing a gene expression profile that clusters with poor breast cancer prognosis (Katchy et al 2014). BPA also interacts with the orphan nuclear receptor, estrogen-related receptor γ (ERRγ; Takayanagi et al 2006), and may also signal via the G-protein-coupled receptor GPER/GPR30 (Pupo et al 2012).…”