Drug transporters and blood--testis barrier function

Area of Science:

• Reproductive Biology
• Toxicology
• Cell Biology

Background:

• The blood-testis barrier (BTB) is an immunological barrier crucial for male fertility, segregating germ cells.
• Efflux pumps in Sertoli cells and spermatids remove substances from the BTB's apical compartment.
• The role of influx transporters in regulating drug entry into the apical compartment remains unclear.

Purpose of the Study:

• To investigate the role of solute carrier (SLC) transporters, specifically organic anion transporting polypeptide 3 (Oatp3), in regulating drug transport across the BTB.
• To determine if Oatp3 and other Sertoli cell influx pumps are involved in maintaining the BTB's tight junction (TJ) permeability barrier.

Main Methods:

• RNA interference (RNAi) was used to knock down Oatp3 and other major Sertoli cell drug influx pumps (Slc22a5, Slco6b1, Slco6c1).
• The effect of these knockdowns on BTB TJ permeability was assessed.
• The transport of [(3)H]adjudin, a spermatogenesis toxicant, across the BTB was measured following transporter knockdown.

Main Results:

• Oatp3 was found to be integrated into the N-cadherin-based adhesion complex at the BTB.
• Knockdown of Oatp3 alone or with other SLC transporters did not disrupt the Sertoli cell TJ permeability barrier.
• Transport of [(3)H]adjudin across the BTB was significantly reduced upon knockdown of Oatp3 or all four SLC transporters.

Conclusions:

• Drug influx transporters, including Oatp3, are components of the BTB adhesion complex but do not regulate its TJ permeability.
• These transporters play a critical role in the transport of drugs, like adjudin, across the BTB.
• Understanding these transport mechanisms is vital for male contraceptive development and assessing chemical exposure risks.