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.