The Effects of Flavonoid Apigenin on Male Reproductive Health: Inhibition of Spermatogonial Proliferation through Downregulation of Prmt7/Akt3 Pathway.

Bingyuan Wang,Zhiguo Liu,Fei Guo,Kui Li,Jiankang Guo,Yulian Mu,Mingrui Zhang,Rong Zhou

doi:10.3390/ijms222212209

Abstract

Apigenin, a common dietary flavonoid abundantly present in a variety of fruits and vegetables, has promising anticancer properties. As an effector of apigenin in myoblasts, protein arginine methyltransferase 7 (Prmt7) is required for male germ cell development. However, whether apigenin may influence male reproductive health through Prmt7 is still unclear. To this end, mouse spermatogonia were treated with different concentrations (2.5 to 50 μM) of apigenin for 48 h, which showed that apigenin could cause reduced cell proliferation in conjunction with longer S phase and G2/M phase (with concentrations of 10 and 20 μM, respectively), and increased apoptosis of spermatogonia (with concentration of 20 μM). Reduced Prmt7 expression was found in 20 μM apigenin-treated spermatogonia. Moreover, siRNA-induced Prmt7 knockdown exhibited similar influence on spermatogonia as that of apigenin treatment. In mechanistic terms, transcriptome analysis revealed 287 differentially expressed genes between Prmt7-downregulated and control spermatogonia. Furthermore, rescue experiments suggested that the effects of apigenin on spermatogonia might be mediated through the Prmt7/Akt3 pathway. Overall, our study supports that apigenin can interfere with mouse spermatogonial proliferation by way of the downregulated Prmt7/Akt3 pathway, which demonstrates that the concentration should be taken into account in future applications of apigenin for cancer therapy of men.

Highlights

Infertility is a global public health issue and a major clinical concern
Our results revealed that certain concentrations of apigenin interfere with mouse spermatogonial proliferation by way of the downregulated protein arginine methyltransferase 7 (Prmt7)/Akt3 pathway, which provides information useful for the dietary application as well as male cancer therapy of apigenin
To the inhibitory effect of apigenin on the proliferation of spermatogonia, we examined its effect on apoptosis, using Annexin V-PI staining followed by flow cytometry analysis

Summary

Introduction

Infertility is a global public health issue and a major clinical concern. It is estimated that 8–12% of couples in reproductive age experience infertility worldwide and half of infertility cases are reportedly due to a male factor [1]. A meta-analysis discovered that sperm counts declined by 50–60% within four decades in industrialized countries. Further systematic review as well as meta-regression analysis showed that both sperm concentration and total sperm count exhibited declined trends within four decades [2,3,4]. The causes of infertility are multifactorial, among which nutrition has a significant impact on men’s reproductive health. Several dietary components and nutrients have been considered as possible determinants of sperm function, fertility, or normal function of the reproductive system [6,7]. Identifying the dietary components or nutrients that influence male fertility is of great importance for the preservation of fertility, and this is even more so in those cases where fertility is threatened by, e.g., cancer treatment

Objectives

Methods

Results