The sodium/iodide transporter (NIS) mediates active I− uptake in thyroid, lactating breast, salivary gland, and stomach epithelial cells. NIS-mediated I− transport is electrogenic with a 2:1 Na+:I− stoichiometry, i.e. when NIS activity is measured electrophysiologically in NIS-expressing oocytes, inward positive currents are recorded upon addition of I− or other anions that are NIS substrates. However, no currents are detected when perchlorate (ClO4−), a competitive inhibitor of NIS is used. This suggests that ClO4− either blocks NIS function without being transported, is translocated with a 1:1 stochiometry, or is transported at an extremely slow rate. ClO4−, which is used in military industry as a component of jet fuel, is a well known environmental contaminant of water supplies. The possible impact of environmental ClO4− exposure on the thyroid function of adults and nursing newborns is widely debated.
We report a thorough analysis of NIS-mediated ClO4− transport in vivo and in vitro. When lactating rats received ClO4−, both mothers and suckling pups exhibited a ∼50% decrease in thyroidal I− uptake relative to controls. For in vitro studies, we used a polarized MDCK epithelial monolayer setup in which NIS is expressed on only one side. Simultaneous addition of I− and perchlorate markedly slowed NIS translocation of I− to the opposite side, as compared to the control with I− alone, because perchlorate was translocated first.
Hill plot analysis of NIS-mediated Na+-dependent perrhenate transport revealed that perrhenate, an analogue of ClO4−, is transported with a 1:1 stoichiometry, explaining the absence of electrical currents observed with perrhenate also. Taken together, these observations provide novel mechanistic information on NIS, i.e. that NIS catalyzes substrate transport with different coupling ratios. In addition, that perchlorate is unequivocally transported by NIS and therefore actively concentrated in the milk, suggests that ClO4− water contamination may be more serious than previously thought, particularly for the most susceptible population, pregnant and lactating women and nursing newborns.