Endocrine Abstracts

Efflux transporters in the blood–testis barrier (BTB) prevent entry and accumulation of xenobiotics in testis but are also involved in local transport of steroid hormones. Among these are the ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp/ABCB1) and multidrug resistance proteins 1 (MRP1/ABCC1) and 4 (MRP4/ABCC4). Here, we studied the interaction of suggested endocrine disruptors (EDCs) bisphenol A (BPA), tetrabromobisphenol A (TBBPA), bis(2-ethylhexyl) phthalate (DEHP), mono(2-ethylhexyl) phthalate (MEHP), perfluorooctanoic acid (PFOA), and perfluorooctanesulfonic acid (PFOS) with human P-gp, MRP1 and MRP4-mediated transport using membrane vesicles of human embryonic kidney (HEK293) cells overexpressing these transporters. Our data show that BPA, DEHP and MEHP, did not significantly alter P-gp, MRP1 and/or MRP4 activity. Both PFOA and PFOS inhibited the MRPs by 50% and P-gp up to 25% at 100 μM. TBBPA showed complete inhibition of the three transporters at the highest concentration (100 μM) tested. To investigate the toxicological implications of transporter inhibition further, testosterone secretion and expression of steroidogenic genes were determined in mouse Leydig MA-10 cells upon exposure to EDCs. Only, BPA and TBBPA concentration-dependently induced testosterone secretion by MA-10 cells to 350 and 1000% of control at 10 μM, respectively. Blocking P-gp, using PSC833, further increased testosterone secretion after BPA and TBBPA exposure to 475 and 2000%, respectively. In contrast, the MRP inhibitor MK571 partly blocked testosterone secretion elicited by BPA (till 300%) and completely by TBBPA. Furthermore, expression of testis-specific steroidogenic genes StAR and CYP11A1 increased when exposed to EDCs in combination with transporter inhibitors. No effects on androgen receptor (AR) activation were found using an AR luciferase reporter assay. These data suggest that EDCs might affect male fertility by locally acting on the BTB and steroidogenesis. We propose that EDCs might disrupt local androgen production and transport from Leydig into Sertoli cells, thus potentially affecting normal germ cell development.