| 1. |
- Hamers, Timo, et al.
(författare)
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Biotransformation of brominated flame retardants into potentially endocrine-disrupting metabolites, with special attention to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47).
- 2008
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Ingår i: Mol Nutr Food Res. - 1613-4125. ; 52:2, s. 284-298
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Tidskriftsartikel (refereegranskat)abstract
- In this study, the endocrine-disrupting (ED) potency of metabolites from brominated flame retardants (BFRs) was determined. Metabolites were obtained by incubating single-parent compound BFRs with phenobarbital-induced rat liver microsomes. Incubation extracts were tested in seven in vitro bioassays for their potency to compete with thyroxine for binding to transthyretin (TTR), to inhibit estradiol-sulfotransferase (E2SULT), to interact with thyroid hormone-mediated cell proliferation, and to (in-)activate the androgen, progesterone, estrogen, or aryl hydrocarbon receptor. For most BFRs, TTR-binding potencies, and to a lesser extent E2SULT-inhibiting potencies, significantly increased after biotransformation. Microsomal incubation had less pronounced effects on other ED modes of action, due to low biotransformation efficiency and background activities determined in control incubations without BFRs. Moreover, cell-based bioassays suffered from cytotoxicity from metabolites of lower-brominated polybrominated diphenyl ethers. For the environmentally relevant 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), six hydroxylated metabolites were identified. Individual metabolites had TTR-binding and E2SULT-inhibiting potencies 160-1600 and 2.2-220 times higher than BDE-47 itself, whereas their combined potencies in a realistic mixture were well predicted via concentration addition. In combination with other environmentally relevant hydroxylated organohalogens acting on TTR-binding and E2SULT inhibition, internal exposure to BFR metabolites may significantly contribute to the overall risk of endocrine disruption.
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| 2. |
- Visser, W Edward, et al.
(författare)
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Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations
- 2009
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 30:1, s. 29-38
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Tidskriftsartikel (refereegranskat)abstract
- Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 arc associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501 del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3 responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501 del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations.
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| 3. |
- Jansen, Jurgen, et al.
(författare)
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Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:6, s. 2378-2381
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Tidskriftsartikel (refereegranskat)abstract
- Context: T-3 action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T-3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T-3 levels. Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T-3. Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T-3 uptake, 2) T-3 metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T-3 levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T-3 in central neurons.
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