Nickel induces blood-testis barrier damage through ROS-mediated p38 MAPK pathways in mice

Abstract

Nickel (Ni) is an essential common environmental contaminant, it is hazardous to male reproduction, but the precise mechanisms are still unknown. Blood-testis barrier (BTB), an important testicular structure consisting of connections between sertoli cells, is the target of reproductive toxicity caused by many environmental toxins. In this study, ultrastructure observation and BTB integrity assay results indicated that NiCl₂ induced BTB damage. Meanwhile, BTB-related proteins including the tight junction (TJ), adhesion junction (AJ) and the gap junction (GJ) protein expression in mouse testes as well as in sertoli cells (TM4) were significantly decreased after NiCl₂ treatment. Next, the antioxidant N-acetylcysteine (NAC) was co-treated with NiCl₂ to study the function of oxidative stress in NiCl₂-mediated BTB deterioration. The results showed that NAC attenuated testicular histopathological damage, and the expression of BTB-related proteins were markedly reversed by NAC co-treatment in vitro and vivo. Otherwise, NiCl₂ activated the p38 MAPK signaling pathway. And, NAC co-treatment could significantly inhibit p38 activation induced by NiCl₂ in TM4 cells. Furthermore, in order to confirm the role of the p38 MAPK signaling pathway in NiCl₂-induced BTB impairment, a p38 inhibitor (SB203580) was co-treated with NiCl₂ in TM4 cells, and p38 MAPK signaling inhibition significantly restored BTB damage induced by NiCl₂ in TM4 cells. These results suggest that NiCl₂ treatment destroys the BTB, in which the oxidative stress-mediated p38 MAPK signaling pathway plays a vital role.

Keywords: Blood-testis barrier; Nickel; Oxidative stress; TM4 cells; p38 MAPK.