Differential effects of genistein and 8-prenylgenistein on reproductive tissues in immature female mice

Xiao-Li Li,Li Sui,Fu-Hui Lin,Yin Lian,Lian-Zhong Ai,Yan Zhang

doi:10.1080/13880209.2019.1590422

Abstract

Context: We identified an active prenylated derivative of genistein, 8-prenylgenistein (8PG) from Erythrina variegata L. (Leguminosae) and found that 8PG increased osteoprotective effects of genistein in oestrogen-deficient mice.Objective: This study investigated and compared the oestrogenic effects of genistein and 8PG on uterus and vagina of immature mice.Materials and methods: Immature female CD-1 mice were orally treated with vehicle (Control, n = 10) or genistein (75 mg/kg, n = 10) or 8PG with low (8PG-L, 75 mg/kg, n = 10) and high dose (8PG-H, 150 mg/kg, n = 10) for 7 consecutive days by intragastric gavage. The uterus and vagina were harvested for histological and molecular measurements.Results: Treatment with genistein and 8PG-H significantly increased uterus index (1.98 ± 0.21 & 1.49 ± 0.16 mg/g) and vagina index (3.83 ± 0.11 & 3.13 ± 0.25 mg/g) as compared to untreated control (uterus, 1.12 ± 0.13 mg/g; vagina, 2.32 ± 0.18 mg/g). Accordingly, both genistein and 8PG-H made vaginal cells keratinized and induced uterine and vaginal hypertrophy associated with the endometrial proliferation. 8PG-L did not affect oestrus cycle and histology of uterus and vagina. Treatment of immature mice with genistein or 8PG-H upregulated protein expression of oestrogen receptor-α (ER-α) and proliferating cell nuclear antigen (PCNA), but 8PG-L did not alter ER-α and PCNA expression in uterus and vagina.Conclusion: This study indicated that 8-prenylgenistein exerted oestrogenic effects in immature female mice. The efficacy and safety of 8-prenylgenistein when applied in improving oestrogen deficiency-induced syndrome requires further elucidation.

Highlights

Prenylated flavanones are a unique class of naturally occurring flavonoids characterized by the presence of a prenylated side chain in the flavonoid skeleton (Stulıkova et al 2018)
The phytoestrogen-free diet supplemented with 8PG (300 ppm) protected against oestrogen deficiency-induced osteoporosis in mice and 8PG (300 & 600 ppm) did not produce the uterotrophic effect that was shown in genistein-treated ovariectomized mice (Zhang et al 2018)
The present study investigates the effects of 8PG on oestrogen-targeting tissues, such as uterus and vagina, in immature female mice after short-term oral administration and evaluates the in vivo safety and the oestrogenic activity of 8PG

Summary

Introduction

Prenylated flavanones are a unique class of naturally occurring flavonoids characterized by the presence of a prenylated side chain in the flavonoid skeleton (Stulıkova et al 2018). We previously reported that EV exhibited osteopreserve effects in ovariectomized rats (Zhang et al 2007) and mice (Zhang et al.2010) and identified types of prenylated isoflavones with soy isoflavone genistein as the backbone from EV (Li et al 2006). Among these prenylated genistein derivatives, using in vitro biological measurements, we revealed that 8-prenylgenistein (8PG) could increase the ability in stimulating osteoblastic function in comparison to genistein (Zhang et al 2008). The phytoestrogen-free diet supplemented with 8PG (300 ppm) protected against oestrogen deficiency-induced osteoporosis in mice and 8PG (300 & 600 ppm) did not produce the uterotrophic effect that was shown in genistein-treated ovariectomized mice (Zhang et al 2018)

Objectives

Methods

Results