Perfluorooctanoic acid disrupts the blood–testis barrier and activates the TNFα/p38 MAPK signaling pathway in vivo and in vitro

Perfluorooctanoic acid (PFOA) is correlated with male reproductive dysfunction in animals and humans, but the underlying mechanisms for this remain unknown. To explore the potential reproductive toxicity of PFOA, we studied blood-testis barrier (BTB) damage using in vivo and in vitro models. Male mice were gavage-administered PFOA (0-20 mg/kg/d) for 28 consecutive days, and breeding capacity and permeability of the Sertoli cell-based BTB were estimated. Primary Sertoli cells (SCs) were exposed to PFOA (0-500 μM) for 48 h, and transepithelial electrical resistance (TER) was assessed. Furthermore, BTB-associated protein expression, TNFα content, and phosphorylation and protein levels of the mitogen-activated protein kinase (MAPK) pathway were detected. An apparent decrease in mated and pregnant females per male mouse as well as litter weight was observed. Marked BTB damage was evidenced by increased red biotin fluorescence in the lumen tubular of the testes and the decrease in TER in SCs in vitro. The protein levels of claudin-11, connexin-43, N-cadherin, β-catenin, and occludin were significantly decreased in the testes and also in the SCs in vitro except for N-cadherin and β-catenin. TNFα content showed a dose-dependent increase in the testes and a dose- and time-dependent increase in the SCs, with the p-p38/p38 MAPK ratio also increasing in testes and SCs after PFOA exposure. Moreover, PFOA altered expressions of claudin-11, connexin-43, TNFα, and p-p38 MAPK were recovered 48 h after PFOA removal in the SCs. The SCs appeared to be target to PFOA, and the disruption of the BTB may be crucial to PFOA-induced reproductive dysfunction in mice.