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

The Na super(+)/I super(-) symporter (NIS) is a key plasma membrane protein that mediates active I super(-) uptake in the thyroid, lactating breast, and other tissues with an electrogenic stoichiometry of 2 Na super(+) per I super(-). In the thyroid, NIS-mediated I super(-) 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 super(-) to the milk, thus supplying this essential anion to the nursing newborn. Perchlorate (ClO[Formula: see text]) is a well known competitive inhibitor of NIS. Exposure to food and water contaminated with ClO[Formula: see text] 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 ClO[Formula: see text] is a NIS blocker or a transported substrate of NIS. Here we show in vitro and in vivo that NIS actively transports ClO[Formula: see text], including ClO[Formula: see text] translocation to the milk. A simple mathematical fluxes model accurately predicts the effect of ClO[Formula: see text] transport on the rate and extent of I super(-) accumulation. Strikingly, the Na super(+)/ ClO[Formula: see text] transport stoichiometry is electroneutral, uncovering that NIS translocates different substrates with different stoichiometries. That NIS actively concentrates ClO[Formula: see text] in maternal milk suggests that exposure of newborns to high levels of ClO[Formula: see text] may pose a greater health risk than previously acknowledged because ClO[Formula: see text] would thus directly inhibit the newborns' thyroidal I super(-) uptake.