TY - JOUR
T1 - Excessive levels of diverse phytoestrogens can modulate steroidogenesis and cell migration of KGN human granulosa-derived tumor cells
AU - Solak, Kamila A.
AU - Wijnolts, Fiona M.J.
AU - Nijmeijer, Sandra M.
AU - Blaauboer, Bas J.
AU - van den Berg, Martin
AU - van Duursen, Majorie B.M.
PY - 2014
Y1 - 2014
N2 - Abstract Phytoestrogens are plant-derived estrogen-like compounds that are increasingly used for their suggested health promoting properties, even by healthy, young women. However, scientific concerns exist regarding potential adverse effects on female reproduction. In this study, naringenin (NAR), 8-prenylnaringenin (8-PN), genistein (GEN), coumestrol (COU), quercetin (QUE) and resveratrol (RSV) up-regulated steroidogenic acute regulatory protein (StaR) mRNA levels in KGN human granulosa-like tumor cells. Most of the phytoestrogens tested also increased CYP19A1 (aromatase) mRNA levels via activation of ovary-specific I.3 and II promoters. Yet, only NAR (3 and 10 μM), COU (10 and 30 μM) and QUE (10 μM) also statistically significantly induced aromatase activity in KGN cells after 24 h. 8-PN, aromatase inhibitor letrozole and estrogen receptor antagonist ICI 182,780 concentration-dependently inhibited aromatase activity with IC50 values of 8 nM, 10 nM and 72 nM, respectively. Co-exposure with ICI 182,780 (0.1 μM) statistically significantly attenuated the induction of aromatase activity by QUE and COU, but not NAR. Cell cycle status and proliferation of KGN cells were not affected by any of the phytoestrogens tested. Nonetheless, the migration of KGN cells was significantly reduced with approximately 30% by COU, RSV and QUE and 46% by GEN at 10 μM, but not NAR and 8-PN. Our results indicate that phytoestrogens can affect various pathways in granulosa-like cells in vitro at concentrations that can be found in plasma upon supplement intake. This implies that phytoestrogens may interfere with ovarian function and caution is in place regarding the use of supplements with high contents of phytoestrogens.
AB - Abstract Phytoestrogens are plant-derived estrogen-like compounds that are increasingly used for their suggested health promoting properties, even by healthy, young women. However, scientific concerns exist regarding potential adverse effects on female reproduction. In this study, naringenin (NAR), 8-prenylnaringenin (8-PN), genistein (GEN), coumestrol (COU), quercetin (QUE) and resveratrol (RSV) up-regulated steroidogenic acute regulatory protein (StaR) mRNA levels in KGN human granulosa-like tumor cells. Most of the phytoestrogens tested also increased CYP19A1 (aromatase) mRNA levels via activation of ovary-specific I.3 and II promoters. Yet, only NAR (3 and 10 μM), COU (10 and 30 μM) and QUE (10 μM) also statistically significantly induced aromatase activity in KGN cells after 24 h. 8-PN, aromatase inhibitor letrozole and estrogen receptor antagonist ICI 182,780 concentration-dependently inhibited aromatase activity with IC50 values of 8 nM, 10 nM and 72 nM, respectively. Co-exposure with ICI 182,780 (0.1 μM) statistically significantly attenuated the induction of aromatase activity by QUE and COU, but not NAR. Cell cycle status and proliferation of KGN cells were not affected by any of the phytoestrogens tested. Nonetheless, the migration of KGN cells was significantly reduced with approximately 30% by COU, RSV and QUE and 46% by GEN at 10 μM, but not NAR and 8-PN. Our results indicate that phytoestrogens can affect various pathways in granulosa-like cells in vitro at concentrations that can be found in plasma upon supplement intake. This implies that phytoestrogens may interfere with ovarian function and caution is in place regarding the use of supplements with high contents of phytoestrogens.
KW - Phytoestrogens
KW - KGN cells
KW - Ovarian-specific CYP19A1 promoters
KW - CYP19
KW - Cell migration
KW - Tumor progression
U2 - 10.1016/j.toxrep.2014.06.006
DO - 10.1016/j.toxrep.2014.06.006
M3 - Article
SN - 2214-7500
VL - 1
SP - 360
EP - 372
JO - Toxicology Reports
JF - Toxicology Reports
ER -
