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

Abstract

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.

• stoichiometry
• perrhenate
• pertechnetate
• milk