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Persistent, mobile, and toxic compounds released to the environment are likely to pollute drinking water sources due to their slow environmental degradation (persistency) and high water solubility (mobility). The aim of the present study was to create in vitro hazard profiles for 16 triazoles, 9 triazines, and 11 poly- and perfluoroalkyl substances (PFAS) based on their agonistic and antagonistic effects in estrogen receptor (ER), androgen receptor (AR), and thyroid hormone receptor (TR) reporter gene assays, their ability to bind human transthyretin (TTR), and their effects on steroidogenesis. The triazole fungicides tetraconazole, bitertanol, fenbuconazole, tebuconazole, cyproconazole, difenoconazole, propiconazole, paclobutrazol, and triadimenol had agonistic or antagonistic effects on the ER and AR. Difenoconazole, propiconazole, and triadimenol were also found to be TR antagonists. The triazine herbicide ametryn was an ER, AR, and TR antagonist. The same 9 triazole fungicides and the triazines atrazine, deethyl-atrazine, and ametryn affected the secretion of steroid hormones. Furthermore, PFAS compounds PFBS, PFHxS, PFHxA, PFOS, PFOA, and GenX and the triazoles bitertanol, difenoconazole, and 4-methyl benzotriazole were found to displace T4 from TTR. These results are in line with earlier in vitro and in vivo studies on the endocrine-disrupting properties of triazines, triazoles, and PFAS. The present study demonstrates that this battery of in vitro bioassays can be used to profile compounds from different classes based on their endocrine-disrupting properties as a first step to prioritize them for further research, emission reduction, environmental remediation, and regulatory purposes. [ABSTRACT FROM AUTHOR]

Only a fraction of the total number of per‐ and polyfluoroalkyl substances (PFAS) are monitored on a routine basis using targeted chemical analyses. We report on an approach toward identifying bioactive substances in environmental samples using effect‐directed analysis by combining toxicity testing, targeted chemical analyses, and suspect screening. PFAS compete with the thyroid hormone thyroxin (T4) for binding to its distributor protein transthyretin (TTR). Therefore, a TTR‐binding bioassay was used to prioritize unknown features for chemical identification in a PFAS‐contaminated sediment sample collected downstream of a factory producing PFAS‐coated paper. First, the TTR‐binding potencies of 31 analytical PFAS standards were determined. Potencies varied between PFAS depending on carbon chain length, functional group, and, for precursors to perfluoroalkyl sulfonic acids (PFSA), the size or number of atoms in the group(s) attached to the nitrogen. The most potent PFAS were the seven‐ and eight‐carbon PFSA, perfluoroheptane sulfonic acid (PFHpS) and perfluorooctane sulfonic acid (PFOS), and the eight‐carbon perfluoroalkyl carboxylic acid (PFCA), perfluorooctanoic acid (PFOA), which showed approximately four‐ and five‐times weaker potencies, respectively, compared with the native ligand T4. For some of the other PFAS tested, TTR‐binding potencies were weak or not observed at all. For the environmental sediment sample, not all of the bioactivity observed in the TTR‐binding assay could be assigned to the PFAS quantified using targeted chemical analyses. Therefore, suspect screening was applied to the retention times corresponding to observed TTR binding, and five candidates were identified. Targeted analyses showed that the sediment was dominated by the di‐substituted phosphate ester of N‐ethyl perfluorooctane sulfonamido ethanol (SAmPAP diester), whereas it was not bioactive in the assay. SAmPAP diester has the potential for (bio)transformation into smaller PFAS, including PFOS. Therefore, when it comes to TTR binding, the hazard associated with this substance is likely through (bio)transformation into more potent transformation products. Environ Toxicol Chem 2024;43:245–258. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Introduction Over the past decade, awareness has increased that house dust is a matrix containing complex mixtures of contaminants. Most of these contaminants originate from the use and wear of [...], Background: House dust contains many organic contaminants that can compete with the thyroid hormone (TH) thyroxine ([T.sub.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.sub.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 [pounds sterling]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.sub.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 (Ki) was used to estimate inhibition levels of [T.sub.4]-TTR binding in human blood. Results: The TTR-binding potency of the mixtures was well predicted by concentration addition. The ~ 20% inhibition in FITC-[T.sub.4] binding observed for the mixtures reflecting median concentrations in maternal and infant serum was extrapolated to 1.3% inhibition of [T.sub.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.sub.4] levels in humans has been reported, so far. We hypothesize, however, that 1.3% inhibition of [T.sub.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

Abstract Background Metallothionein (mt) transcription is elevated in heavy metal tolerant field populations of Orchesella cincta (Collembola). This suggests that natural selection acts on transcriptional regulation of mt in springtails at sites where cadmium (Cd) levels in soil reach toxic values This study investigates the nature and the evolutionary origin of polymorphisms in the metallothionein promoter (pmt) and their functional significance for mt expression. Results We sequenced approximately 1600 bp upstream the mt coding region by genome walking. Nine pmt alleles were discovered in NW-European populations. They differ in the number of some indels, consensus transcription factor binding sites and core promoter elements. Extensive recombination events between some of the alleles can be inferred from the alignment. A deviation from neutral expectations was detected in a cadmium tolerant population, pointing towards balancing selection on some promoter stretches. Luciferase constructs were made from the most abundant alleles, and responses to Cd, paraquat (oxidative stress inducer) and moulting hormone were studied in cell lines. By using paraquat we were able to dissect the effect of oxidative stress from the Cd specific effect, and extensive differences in mt induction levels between these two stressors were observed. Conclusion The pmt alleles evolved by a number of recombination events, and exhibited differential inducibilities by Cd, paraquat and molting hormone. In a tolerant population from a metal contaminated site, promoter allele frequencies differed significantly from a reference site and nucleotide polymorphisms in some promoter stretches deviated from neutral expectations, revealing a signature of balancing selection. Our results suggest that the structural differences in the Orchesella cincta metallothionein promoter alleles contribute to the metallothionein -over-expresser phenotype in cadmium tolerant populations.