Enniatin B1 induces damage to Leydig cells via inhibition of the Nrf2/HO-1 and JAK/STAT3 signaling pathways
Hongping Shen, Yili Cai, Keqi Zhu, Dong Wang, Rui Yu, Xueqin Chen
Abstract
Enniatin B1 (ENN B1) is a mycotoxin that can be found in various foods. However, whether ENN B1 is hazardous to the reproductive system is still elusive. Leydig cells are testosterone-generating cells that reside in the interstitial compartment between seminiferous tubules. Dysfunction of Leydig cells could result in male infertility. This study aimed to examine the toxicological effects of ENN B1 against TM3 Leydig cells. ENN B1 significantly inhibited cell viability in a dose-dependent manner. ENN B1 treatment also decreased the expression of functional genes in Leydig cells. Moreover, ENN B1 induced Leydig cells apoptosis and oxidative stress. Mechanistically, ENN B1 leads to the upregulation of Bax and downregulation of Bcl-2 in Leydig cells. In addition, ENN B1 inhibited the Nrf2/HO-1 pathway, which is critical for the induction of oxidative stress. Additionally, ENN B1 treatment repressed the JAK/STAT3 signaling pathway in Leydig cells. Rescue experiments showed that activation of STAT3 resulted in alleviation of ENN B1-induced damage in Leydig cells. Collectively, our study demonstrated that ENN B1 induced Leydig cell dysfunction via multiple mechanisms. • ENN B1 inhibits the cellular viability and expression of functional genes in Leydig cells. • ENN B1 induces apoptosis of Leydig cells in a caspase-dependent manner. • ENN B1 induces oxidative stress via modulation of Keap1/Nrf2/HO-1 signalling pathway. • ENN B1 regulates SHP1 and the JAK/STAT3 signalling pathway in Leydig cells.