Copper Exposure Destroys the Integrity of the Blood-Testis Barrier (BTB) Through p38 MAPK-Meditated Autophagy Pathways.

Abstract

Copper (Cu) is an essential trace element for living organisms. However, excessive exposure to Cu is harmful to male fertility. But the precise mechanisms are still unknown. The blood-testis barrier (BTB), an important testicular structure composed of connections between Sertoli cells, is the target of reproductive toxicity induced by various environmental contaminants. In this study, we found an increase in sperm malformation rates as well as testicular histopathology abnormalities after exposure to Cu. The BTB integrity assay findings showed that Cu induced BTB degradation. Also, the expression of BTB-related proteins such as the gap junction (GJ) and tight junction (TJ) in the mouse testis and Sertoli cells (TM4) decreased after intake of high Cu. Next, to study the involvement of the p38 MAPK signaling pathway in Cu-mediated BTB degradation, the p38 inhibitor (SB203580) was co-treated with Cu in TM4 cells; the results showed that the p38 inhibitor blocked autophagy and alleviated Cu-induced BTB impairment. Furthermore, we treated the cells with an autophagy inhibitor in combination with Cu, and it was discovered that inhibiting autophagy also prevented Cu-induced BTB impairment. These results suggest that Cu destroys the BTB instruction and is dependent on the p38 MAPK signaling pathway.