Phenylphenols, biphenols, bisphenol-A and 4-tert-octylphenol exhibit α and β estrogen activities and antiandrogen activity in reporter cell lines

Paris, Florentin; Balaguer, Patrick; Térouanne, Béatrice; Servant, Nadège; Lacoste, Caroline; Cravedi, Jean‐Pierre; Nicolas, Jean‐Claude; Sultan, Charles

doi:10.1016/s0303-7207(02)00094-1

Cited by 179 publications

(103 citation statements)

References 17 publications

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“…Our results indicate that the chemical compounds, BPA, OP, BBP, and DEHP, and the pesticide dieldrin have estrogenic activity in these two mammary cell lines. These results are consistent with previous results using MELN or HELN ERa (Balaguer et al 1999, Paris et al 2002. In addition, as observed for E 2 activity, the estrogenic activity of xenoestrogens is higher in the MELN than in the MELP cell line, as deduced from results expressed in fold induction.…”

Section: Resultssupporting

confidence: 93%

“…Our results show that BPA and OP at 10 K6 M increase VEGF secretion in MCF-7 and MELN cells. This increase is correlated to their estrogenic activity in MELN, consistent with previous studies performed in MCF-7 and MELN (Soto et al 1995, Andersen et al 1999, Paris et al 2002. various kinase signaling inhibitors (20 mM PD98059, 10 mM SB203580, 25 mM LY294002, or 0 .…”

Section: Discussionsupporting

confidence: 89%

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Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

Buteau-Lozano¹,

Velasco²,

Cristofari³

et al. 2007

Journal of Endocrinology

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120

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Environmental chemicals may affect human health by disrupting endocrine function. Their possible role in the mammary gland and breast tumors is still unknown. Previous studies have demonstrated that vascular endothelial growth factor (VEGF), a key factor in angiogenesis and tumor progression, is an estrogenregulated gene. We analyzed whether VEGF expression is regulated by different xenoestrogens in several breast cancer cells, MELN (derived from MCF-7) and MELP (derived from MDA-MB-231) and stably expressing estrogen receptor a (ERa); these cell lines stably express estrogen response element (b-globin)-luciferase. Genistein, bisphenol A (BPA), 4-(tert-octyl)phenol (OP), dieldrin, and several phthalates, including benzyl butyl phthalate (BBP) and di-ethyl-2-hexyle phthalate (DEHP), were first shown to be estrogenic. These compounds induced a dosedependent increase of VEGF secretion in MELN and MCF-7 cells; maximal effect was observed at 1-10 mM non-cytotoxic concentrations and was inhibited by the antiestrogen ICI 182 780. VEGF increase was not observed in ERa-negative MDA-MB-231 cells. Most substances increased VEGF transcript levels in MELN cells. In contrast, g-hexachlorocyclohexane, vinclozolin, and the phthalates (mono-n-butyl ester phthalic acid, di-isononyle phthalate, and di-isodecyle phthalate) were ineffective on both VEGF secretion and estrogenic luciferase induction in these cell lines. Specific kinase inhibitors PD98059, SB203580, or LY294002 suppressed the xenoestrogen-induced VEGF response, suggesting activation of MEK, p38 kinase, and phosphatidylinositol-3-kinase pathways. Our in vitro results show for the first time that genistein and xenoestrogens (BPA, OP, dieldrin, BBP, and DEHP at high concentrations) up-regulate VEGF expression in MELN cells by an ER-dependent mechanism. Since VEGF increases capillary permeability and breast tumor angiogenesis in vivo, the physiological relevance of these findings is discussed.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 89%

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

Buteau-Lozano¹,

Velasco²,

Cristofari³

et al. 2007

Journal of Endocrinology

Self Cite

120

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“…S12 B-D). Interestingly, all studied bisphenols appeared to bind to AR exclusively in the antagonist BPC-like orientation, in agreement with the observation that these compounds act as AR antagonists (20) (SI Appendix, Fig. S14).…”

Section: Resultssupporting

confidence: 87%

“…Although the two estrogen receptors (ERs), ERα and ERβ, are considered as the main targets of BPA (13,14), several other cellular targets have been proposed for this compound. We and others have previously demonstrated that BPA or its halogenated derivatives also activate the pregnane X receptor (15,16), the estrogen-related receptor γ (ERRγ) (17), or the peroxisome proliferator activated receptor γ (18,19), and inhibit the androgen receptor (AR) (20) or the thyroid hormone receptor (21,22). BPA has also been reported to interact with the G proteincoupled ER (23), so that the net effect of BPA could be caused by synergistic actions through different pathways.…”

mentioning

confidence: 99%

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes

Delfosse

Grimaldi

Pons

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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326

268

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Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) α and β differ from that used by 17β-estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17β-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor γ and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment.crystal structure | endocrine disruptor | nuclear receptor | virtual screening

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“…Non-genomic actions are mediated by a plasma membrane estrogen or androgen receptor. Xenoestrogens have both M a n u s c r i p t estrogenic and antiandrogenic actions and compete with natural androgens for the ligandbinding domain (LBD) of the AR gene [87]. They also induce more potent estrogenic metabolites.…”

Section: Iii-1 Types Of Action Of Environmental Pollutantsmentioning

confidence: 99%

Hypospadias: Interactions between environment and genetics

Kalfa

Philibert

Baskin

et al. 2011

Molecular and Cellular Endocrinology

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Phenylphenols, biphenols, bisphenol-A and 4-tert-octylphenol exhibit α and β estrogen activities and antiandrogen activity in reporter cell lines

Cited by 179 publications

References 17 publications

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes

Hypospadias: Interactions between environment and genetics

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