Endocrine-disrupting chemicals (EDCs) are considered to cause testicular toxicity primarily via interference with
steroid hormone function. Alternatively, EDCs could possibly exert their effects by interaction with
ATP-binding cassette (
ABC) transporters that are expressed in the blood-testis barrier. In this study, we investigated the effects of
bisphenol A (BPA),
tetrabromobisphenol A (TBBPA), bis(2-ethylhexyl)
phthalate, mono(2-ethylhexyl)
phthalate,
perfluorooctanoic acid (PFOA), and
perfluorooctanesulfonic acid (PFOS) on
breast cancer resistance
protein (BCRP),
multidrug resistance proteins 1 and 4 (
MRP1 and MRP4), and
P-glycoprotein (P-gp) using membrane vesicles overexpressing these transporters. BPA solely inhibited BCRP activity, whereas TBBPA, PFOA, and PFOS inhibited all transporters tested. No effect was observed for the phthalates. Using transporter-overexpressing Madin-Darby canine kidney cells, we show that BPA and PFOA, but not TBBPA, are transported by BCRP, whereas none of the compounds were transported by P-gp. To investigate the toxicological implications of these findings,
testosterone secretion and expression of steroidogenic genes were determined in murine Leydig (MA-10) cells upon exposure to the selected EDCs. Only BPA and TBBPA concentration dependently increased
testosterone secretion by MA-10 cells to 6- and 46-fold of control levels, respectively. Inhibition of the Mrp's by
MK-571 completely blocked
testosterone secretion elicited by TBBPA, which could not be explained by coinciding changes in expression of steroidogenic genes. Therefore, we hypothesize that transporter-mediated efflux of
testosterone precursors out of MA-10 cells is inhibited by TBBPA resulting in higher availability for
testosterone production. Our data show the toxicological and clinical relevance of
ABC transporters in EDC risk assessment related to testicular toxicity.