Ghrelin alleviates endoplasmic reticulum stress and inflammation-mediated reproductive dysfunction induced by stress

Psychological stress exists widely in modern society and results in the disruption of testicular tight junctions, germ cell apoptosis, and the disorder of fertility hormones and even causes infertility. Ghrelin (GHRL), a 28-amino acid peptide secreted mainly by the stomach and pancreas, has been reported to alleviate male reproductive injury through inhibiting apoptosis. However, whether GHRL has a beneficial effect on psychological stress-induced testicular injury and the possible mechanisms remain poorly understood.

Male mice were immobilized in Decapicone bags for 3 h daily for 14 days treated with or without GHRL (i.p. 100 mg/kg body weight). Body weight and testicular weight were measured. Histological alterations and apoptosis were examined by H.E. staining and TUNEL staining, respectively. The expression of endoplasmic reticulum (ER) stress markers, inflammatory cytokines, Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB) in the testes was investigated.

Exposure to stress caused testicular histological alterations, an elevation of the Johnsen score, and germ cell apoptosis, while GHRL partially alleviated the adverse effects. The expression of ER stress marker proteins, including GRP78, CHOP, ATF6, p-JNK, and XBP-1, was upregulated in the stress group; however, GHRL treatment significantly suppressed the activation of ER stress in the testes. GHRL also inhibited the expression of TNF-α, IL-1β, IL-6, IL-10, TLR4, and NF-κB.

GHRL alleviated testicular injury induced by ER stress and inflammation which is associated with the TLR4/NF-κB signaling pathway, and these findings may provide a novel strategy for preventing and treating reproductive dysfunction.