Drug transporter, P-glycoprotein (MDR1), is an integrated component of the mammalian blood-testis barrier.
Throughout spermatogenesis, leptotene spermatocytes traverse the blood-testis barrier (BTB) to enter the adluminal compartment of the seminiferous epithelium for continued development. At the same time, the integrity of the BTB, which is constituted by co-existing tight junctions (TJ), basal ectoplasmic specializations (basal ES) and desmosome-like junctions, must be maintained since a breach in barrier function can result in spermatogenic arrest and even infertility. There is evidence to suggest that drug transporters may function at the BTB, but little is known about how they contribute to spermatogenesis. In this study, we investigate the role of P-glycoprotein (P-gp), a drug efflux pump, in BTB dynamics. A survey by RT-PCR revealed several transporter genes to be expressed by the testis, including Mdr1 (gene symbol for P-gp), Mrp1, Abcc5 and Slc15a1. It was also demonstrated that P-gp localizes to the BTB in all stages of the seminiferous epithelial cycle in the adult rat testis, as well as to the Sertoli cell-elongated spermatid interface in stages VII and VIII. We continued our study by examining the levels of several transporters in the testis following oral administration of Adjudin, a compound known to affect Sertoli-germ cell adhesion. In this experiment, the steady-state levels of P-gp, MRP1, ABCG1 and SLC15A1 were all found to increase by several-fold within hours of Adjudin treatment during junction restructuring. More importantly, an increase in P-gp association with TJ proteins (e.g., occludin, claudin-11 and JAM-A) was noted when testis lysates from Adjudin-treated rats were used for co-immunoprecipitation experiments, suggesting that P-gp may enhance BTB function during Sertoli-germ cell junction restructuring.
Su
Linlin
L
Population Council, Center for Biomedical Research, 1230 York Avenue, NY 10065, USA.
Cheng
C Yan
CY
Mruk
Dolores D
DD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001814:Blood-Testis Barrier / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012670:Seminiferous Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012708:Sertoli Cells / Q000166:cytology; D051269:Sodium-Glucose Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D013091:Spermatogenesis; D013093:Spermatogonia / Q000166:cytology; D013737:Testis / Q000166:cytology; D019108:Tight Junctions / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006834:Hydrazines; D007191:Indazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051269:Sodium-Glucose Transporter 1; C432482:1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide; C120809:ABCC5 protein, human; C495674:SLC5A1 protein, human; C421109:multidrug resistance-associated protein 1