Maternal Exposure to Di-n-butyl Phthalate Promotes the Formation of Testicular Tight Junctions through Downregulation of NF-κB/COX-2/PGE2/MMP-2 in Mouse Offspring.

Abstract

Previous studies demonstrated that maternal exposure to di-n-butyl phthalate (DBP) resulted in developmental disorder of the male reproductive organ; however, the underlying mechanism has not been thoroughly elucidated to date. The present study was aimed to investigate the effects of maternal exposure to DBP on the formation of the Sertoli cell (SC)-based tight junctions (TJs) in the testes of male offspring mice and the underlying molecular mechanism. By observing the pathological structure and ultrastructure, permeability analysis of the testis of 22 day male offspring in vivo, and transepithelial electrical resistance measurement of inter-SCs in vitro, we found that the formation of TJs between SCs in offspring mice was accelerated, which was paralleled by the accumulation of TJ protein occludin at 50 mg/kg/day DBP exposure in utero and 0.1 mM monobutyl phthalate (MBP, the active metabolite of DBP) in vitro. Our in vitro results demonstrated that 0.1 mM MBP downregulated the expression of matrix metalloproteinase-2 (MMP-2) by inhibiting the activation of nuclear factor-κB (NF-κB)/cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) cascades via attenuated binding of NF-κB to both the MMP-2 promoter and COX-2 promoter. Taken together, the data confirmed that maternal exposure to a relatively low dose of DBP promoted the formation of testicular TJs through downregulation of NF-κB/COX-2/PGE2/MMP-2, which might promote the development of the testis during puberty. Our findings may provide new perspectives for prenatal DBP exposure, which is a potential environmental contributor, leading to earlier puberty in male offspring mice.