Transthyretin-Binding Activity of Complex Mixtures Representing the Composition of Thyroid-Hormone Disrupting Contaminants in House Dust and Human Serum

Abstract

Background: House dust contains many organic contaminants that can compete with the thyroid hormone (TH) thyroxine ($T_4$) for binding to transthyretin (TTR). How these contaminants work together at levels found in humans and how displacement from TTR in vitro relates to in vivo $T_4$-TTR binding is unknown.

Objectives: Our aims were to determine the TTR-binding potency for contaminant mixtures as found in house dust, maternal serum, and infant serum; to study whether the TTR-binding potency of the mixtures follows the principle of concentration addition; and to extrapolate the in vitro TTR-binding potency to in vivo inhibition levels of $T_4$-TTR binding in maternal and infant serum.

Methods: Twenty-five contaminants were tested for their in vitro capacity to compete for TTR-binding with a fluorescent FITC-$T_4$ probe. Three mixtures were reconstituted proportionally to median concentrations for these chemicals in house dust, maternal serum, or infant serum from Nordic countries. Measured concentration-response curves were compared with concentration-response curves predicted by concentration addition. For each reconstituted serum mixture, its inhibitor-TTR dissociation constant ($K_i$) was used to estimate inhibition levels of $T_4$-TTR binding in human blood.

Results: The TTR-binding potency of the mixtures was well predicted by concentration addition. The $\sim 20\%$ inhibition in FITC-$T_4$ binding observed for the mixtures reflecting median concentrations in maternal and infant serum was extrapolated to 1.3% inhibition of $T_4$-TTR binding in maternal and 1.5% in infant blood. For nontested mixtures reflecting high-end serum concentrations, these estimates were 6.2% and 4.9%, respectively.

Discussion: The relatively low estimated inhibition levels at median exposure levels may explain why no relationship between exposure to TTR-binding compounds and circulating $T_4$ levels in humans has been reported, so far. We hypothesize, however, that 1.3% inhibition of $T_4$-TTR binding may ultimately be decisive for reaching a status of maternal hypothyroidism or hypothyroxinemia associated with impaired neurodevelopment in children. https://doi.org/10.1289/EHP5911.