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Chemical Mixtures Isolated from House Dust Disrupt Thyroid Receptor ? Signaling.

ABSTRACT: House dust is a source of exposure to chemicals that can impact hormone regulation. This study was designed to evaluate the potential of house dust mixtures ( n = 137) to disrupt thyroid hormone nuclear receptor signaling in a cell-based reporter assay and to examine associations with thyroid hormones (TH) measured in residents of the homes. Approximately 41% of the extracts (ranging from 10.5 to 4.097 ?g of dust/mL) significantly antagonized thyroid receptor ? (TR?) signaling by 20-67% relative to the hormone control. The concentrations of 12 flame retardants (FRs) quantified in the mixtures were significantly correlated with TR? antagonism; however, they were inactive when tested individually. We hypothesize that the observed antagonism is due to mixture effects or unidentified compounds that co-occur with FRs. Dust extract potency was significantly associated with free thyroxine (FT4, rs = -0.64, p < 0.001), suggesting that more potent dust samples are associated with higher FT4 levels in residents. Overall, these results suggest that house dust is a significant source of exposure to TH-disrupting chemicals, and TR? may have a role in mediating effects of exposure on TH levels. Additional studies are needed to identify the chemical(s) driving the observed effects on TR? and to determine if these changes lead to any adverse outcomes.

SUBMITTER: Kollitz EM

PROVIDER: S-EPMC6433547 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Chemical Mixtures Isolated from House Dust Disrupt Thyroid Receptor β Signaling.

Kollitz Erin M EM Kassotis Christopher D CD Hoffman Kate K Ferguson P Lee PL Sosa Julie Ann JA Stapleton Heather M HM

Environmental science & technology 20180925 20

House dust is a source of exposure to chemicals that can impact hormone regulation. This study was designed to evaluate the potential of house dust mixtures ( n = 137) to disrupt thyroid hormone nuclear receptor signaling in a cell-based reporter assay and to examine associations with thyroid hormones (TH) measured in residents of the homes. Approximately 41% of the extracts (ranging from 10.5 to 4.097 μg of dust/mL) significantly antagonized thyroid receptor β (TRβ) signaling by 20-67% relative ...[more]

PMID: 30212187

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Project description:Background: House dust contains many organic contaminants that can compete with the thyroid hormone (TH) thyroxine (T4) 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 T4-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 T4-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-T4 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 (Ki) was used to estimate inhibition levels of T4-TTR binding in human blood.Results: The TTR-binding potency of the mixtures was well predicted by concentration addition. The ?20% inhibition in FITC-T4 binding observed for the mixtures reflecting median concentrations in maternal and infant serum was extrapolated to 1.3% inhibition of T4-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 T4 levels in humans has been reported, so far. We hypothesize, however, that 1.3% inhibition of T4-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.

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Chemical Mixtures Isolated from House Dust Disrupt Thyroid Receptor ? Signaling.

Publications

Chemical Mixtures Isolated from House Dust Disrupt Thyroid Receptor β Signaling.

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