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

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.

Prmt7 Downregulation in Mouse Spermatogonia Functions through miR-877-3p/Col6a3

“…Our previous work identified that Prmt7 regulated the proliferation of GC-1 cells (a type of mouse spermatogonial cell line) as the Prmt7 knockdown reduced their proliferation [ 5 ]. However, the underlying molecular mechanisms are still unclear.…”

“…For example, Prmt7 deficiency can lead to the defective proliferation of mouse primordial germ cells during the embryonic stage [ 7 ]. Prmt7 downregulation reduced GC-1 mouse spermatogonial proliferation [ 5 ]. Prmt7 overexpression promotes the malignant progression of nonsmall cell lung cancer cells [ 42 ] and the growth of renal cell carcinoma [ 43 ].…”

“…In our previous study, we found that protein arginine methyltransferase 7 ( Prmt7 ), the only type III PRMT (a type of PRMT that only catalyzes the formation of monomethylarginine of its protein substrates), can replace Sox2 in combination with Oct4 , Nanog , and Klf4 to successfully produce induced pluripotent stem cells [ 4 ]. Our further study revealed that Prmt7 was highly expressed in mouse testes at both mRNA and protein levels and Prmt7 knockdown reduced spermatogonial proliferation [ 5 ]. In addition, Prmt7 is reportedly expressed in male gonocytes and spermatogonia [ 6 ].…”

Alternative Pharmacological Approach to Male Infertility: Anti-Aromatase Compounds: A Systematic Review

“…Apigenin, also known as 4,5,7-trihydroxy flavone, is a potential therapeutic agent with antioxidant, anti-inflammatory, antibacterial, and antiviral properties that has been investigated in the treatment of cancer due to its high anti-tumoral activity. [36][37][38][39] By inhibiting the aromatase enzyme, apigenin can cause changes in semen parameters, androgen levels, and the hypothalamo-pituitarygonadal axis in the male reproductive system. Therefore, it can be used as a therapeutic agent in male infertility alone or in combination therapy.…”

Apigenin supplementation substantially improves rooster sperm freezability and post-thaw function

“…However, it is important to note that the concentration of apigenin used can have different effects. A study on mouse sperm production revealed that certain doses of apigenin interfered with the growth of sperm cells, which could lead to lower sperm count and higher abnormal sperm count 19 .…”