The Na+/I- symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate

The Na+/I- symporter (NIS) is a key plasma membrane protein that mediates active I- uptake in the thyroid, lactating breast, and other tissues with an electrogenic stoichiometry of 2 Na+ per I-. In the thyroid, NIS-mediated I- uptake is the first step in the biosynthesis of the iodine-containing thyroid hormones, which are essential early in life for proper CNS development. In the lactating breast, NIS mediates the translocation of I- to the milk, thus supplying this essential anion to the nursing newborn. Perchlorate (ClO4-) is a well known competitive inhibitor of NIS. Exposure to food and water contaminated with ClO4- is common in the U.S. population, and the public health impact of such exposure is currently being debated. To date, it is still uncertain whether ClO4- is a NIS blocker or a transported substrate of NIS. Here we show in vitro and in vivo that NIS actively transports ClO4-, including ClO4- translocation to the milk. A simple mathematical fluxes model accurately predicts the effect of ClO4- transport on the rate and extent of I- accumulation. Strikingly, the Na+/ClO4- transport stoichiometry is electroneutral, uncovering that NIS translocates different substrates with different stoichiometries. That NIS actively concentrates ClO4- in maternal milk suggests that exposure of newborns to high levels of ClO4- may pose a greater health risk than previously acknowledged because ClO4- would thus directly inhibit the newborns' thyroidal I- uptake.