Linoleic acid promotes testosterone production by activating Leydig cell GPR120/ ERK pathway and restores BPA-impaired testicular toxicity.

Bisphenol A (BPA) [2,2-bis(4-hydroxyphenyl) propane] has attracted increasing attention over the past few decades as an endocrine-disrupting chemicals that causes low testosterone levels. Linoleic acid (LA) is an essential fatty acid and GPR120 agonist. Herein, we are the first to report that LA induces the expression of GPR120 in mouse Leydig cells to directly promote testosterone production. In addition, we demonstrated that the activated GPR120/ERK signaling pathway was involved in upregulating the expression of 3 beta-HSD and StAR for testosterone production by stimulation of LA. Interestingly, although BPA failed to affect GPR120 expression, LA restored the testosterone levels decreased by BPA in Leydig cells in vitro. Furthermore, the in vivo restoration of testosterone levels and testicular structure was also observed in BPA-impaired mice fed LA. As a result, the sperm functions of BPA-impaired mice returned to normal levels. At the same time, the damaged blood-testis barrier and infertility were also resolved by LA. Our study indicates a novel and safe strategy that utilizes LA to repair reproductive damage caused by low testosterone levels through activating the GPR120/ERK pathway in Leydig cells.