| 1. |
- Delaine, Tamara, 1981, et al.
(författare)
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A structure activity relationship study of geranial derivatives
- 2012
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Ingår i: Contact Dermatitis 11th congress of the European society of contact dermatitis (ESCD) 13-16 june 2012, Malmö, Sweden. - : Wiley. ; 66:Suppl. 2
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Konferensbidrag (refereegranskat)abstract
- Background: Fragrances are common causes of contact allergy. Skin exposure to geranial is frequent since citral (mixture of geranial and neral) is commonly used in fragrances and flavors and is considered as a moderate allergen. Previous studies according to the local lymphnodeassay (LLNA)in micehaverevealed large variations in the sensitizing capacity of different geranial derivatives. Objectives: For a better understanding of these variations, a structure-activity relationship (SAR) study on a series of derivatives of geranial was carried out. Methods: The chemical reactivity of the compounds towards a model peptide was investigated using LC-MS. The adduct formation and the non-reacted peptide depletion were monitored. Adducts formed with model amino acids were investigated and structural determination was performed. Additional derivatives were synthesized and their sensitization potencies were evaluated in relation to their physicochemical and reactivity properties. Results: Most of the derivatives were shown to bind covalently to the cysteine residue of the model peptide. The percentage of depletion of the non-reacted peptide ranged from 0% to 100% after 24 hr, constant rate of depletion revealed a large difference between the fastest and lowest reacting derivatives. These resultswere congruent with the skin sensitization potencies obtained with the LLNA. Conclusions: A good correlation between the reactivity and the sensitizing potency was observed. Small changes in the chemical structure of geranial result in significant differences in sensitizing capacity and chemical reactivity. Conflicts of interest: The authors have declared no conflicts.
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| 2. |
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| 3. |
- Delaine, Tamara, 1981, et al.
(författare)
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Epoxyalcohols: bioactivation and conjugation required for skin sensitization.
- 2014
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 27:10, s. 1860-70
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Tidskriftsartikel (refereegranskat)abstract
- Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated, nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential.
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| 4. |
- Delaine, Tamara, 1981, et al.
(författare)
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Skin Sensitization of Epoxyaldehydes: Importance of Conjugation.
- 2013
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 26:5, s. 674-684
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Tidskriftsartikel (refereegranskat)abstract
- Structure-activity relationship (SAR) models are important tools for predicting the skin sensitization potential of new compounds without animal testing. In compounds possessing a structural alert (aldehyde) and an activation alert (double bond), it is important to consider bioactivation/autoxidation (e.g., epoxidation). In the present study, we have explored a series of aldehydes with regard to contact allergy. The chemical reactivity of these 6 aldehydes toward a model hexapeptide was investigated, and their skin sensitization potencies were evaluated using the local lymph node assay (LLNA). Overall, we observed a similar trend for the in vitro reactivity and the in vivo sensitization potency for the structural analogues in this study. The highly reactive conjugated aldehydes (α,β-unsaturated aldehydes and 2,3-epoxyaldehydes) are sensitizing moieties, while nonconjugated aldehydes and nonterminal aliphatic epoxides show low reactivity and low sensitization potency. Our data show the importance of not only double bond conjugation to aldehyde but also epoxide-aldehyde conjugation. The observations indicate that the formation of nonconjugated epoxides by bioactivation or autoxidation is not sufficient to significantly increase the sensitization potency of weakly sensitizing parent compounds.
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| 5. |
- Delaine, Tamara, 1981, et al.
(författare)
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Structure-Activity Relationship between the in Vivo Skin Sensitizing Potency of Analogues of Phenyl Glycidyl Ether and the Induction of Nrf2-Dependent Luciferase Activity in the KeratinoSens in Vitro Assay.
- 2011
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 24:8, s. 1312-8
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Tidskriftsartikel (refereegranskat)abstract
- Because of regulatory constraints and ethical considerations, research on alternatives to animal testing to predict the skin sensitization potential of novel chemicals has become a high priority. Ideally, these alternatives should not only predict the hazard of novel chemicals but also rate the potency of skin sensitizers. Currently, no alternative method gives reliable potency estimations for a wide range of chemicals in differing structural classes. Performing potency estimations within specific structural classes has thus been proposed. Detailed structure-activity studies for the in vivo sensitization capacity of a series of analogues of phenyl glycidyl ether (PGE) were recently published. These studies are part of an investigation regarding the allergenic activity of epoxy-resin monomers. Here we report data on the same chemicals in the KeratinoSens in vitro assay, which is based on a stable transgenic keratinocyte cell line with a luciferase gene under the control of an antioxidant response element. A strong correlation between the EC3 values in the local lymph node assay (LLNA) and both the luciferase-inducing concentrations and the cytotoxicity in the cell-based assay was established for six analogues of PGE. This correlation allowed the potency in the LLNA of two novel structurally closely related derivatives to be predicted by read-across with errors of 1.4- and 2.6-fold. However, the LLNA EC3 values of two structurally different bifunctional monomers were overpredicted on the basis of this data set, indicating that accurate potency estimation by read-across based on in vitro data might be restricted to a relatively narrow applicability domain.
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| 6. |
- Niklasson, Ida B, 1982, et al.
(författare)
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Cinnamyl alcohol oxidizes rapidly upon air exposure
- 2013
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 68:3, s. 129-138
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Tidskriftsartikel (refereegranskat)abstract
- Background. Cinnamyl alcohol and cinnamal are frequent fragrance contact allergens. Both are included in the European baseline fragrance mix I, which is used for screening of contact allergy in dermatitis patients. Objectives. The aim of this study was to investigate the autoxidation of cinnamyl alcoholandtoidentifytheoxidationproductsformedonairexposure.Wealsowantedto evaluate the effect of autoxidation on the sensitization potency of cinnamyl alcohol. Methods. Samples of commercially available cinnamyl alcohol with and without purificationwereexposedtoair,andtheautoxidationwasfollowedbychemicalanalysis. Theanalysiswasperformedwithmassspectrometry(LC/MS/MS).Sensitizationpotencies ofcompoundsweredeterminedwiththemurinelocallymphnodeassay(LLNA)inmice. Results. Chemical analysis showed that the concentration of cinnamyl alcohol in the air-exposed samples decreased rapidly over time, and that autoxidation products were formed. Cinnamal, epoxy cinnamyl alcohol and cinnamic acid were identified as oxidation products. According to our study, cinnamal and epoxy cinnamyl alcohol were thefirstautoxidation productsformed. Theepoxy cinnamyl alcohol wasshowntobethe oxidation product with the highest sensitization potency. The analysis of our samples of commercially available cinnamyl alcohol showed that there was already a content of 1.5% cinnamal at the start of the autoxidation experiments. Conclusion. Cinnamylalcoholreadilyautoxidizesuponairexposure,andformsstrong sensitizers as determined by the LLNA. Cinnamal was formed in the largest amounts, showingthatcinnamalisnotonlyformedviabioactivation,ashaspreviouslybeenshown. A highly sensitizing epoxide was also identified and quantified in the oxidation mixture.
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| 7. |
- Niklasson, Ida B, 1982, et al.
(författare)
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Impact of a Heteroatom in a Structure-Activity Relationship Study on Analogues of Phenyl Glycidyl Ether (PGE) from Epoxy Resin Systems.
- 2011
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 24:4, s. 542-8
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Tidskriftsartikel (refereegranskat)abstract
- Epoxy resins are among the most common causes of occupational contact dermatitis. They are normally used in so-called epoxy resin systems (ERS). These commercial products are combinations of epoxy resins, curing agents, modifiers, and reactive diluents. The most frequently used resins are diglycidyl ethers based on bisphenol A (DGEBA) and bisphenol F (DGEBF). In this study, we have investigated the contact allergenic properties of a series of analogues to the reactive diluent phenyl glycidyl ether (PGE), all with similar basic structures but with varying heteroatoms or with no heteroatom present. The chemical reactivity of the compounds in the test series toward the hexapeptide H-Pro-His-Cys-Lys-Arg-Met-OH was investigated. All epoxides were shown to bind covalently to both cysteine and proline residues. The percent depletion of nonreacted peptide was also studied resulting in ca. 60% depletion when using either PGE, phenyl 2,3-epoxypropyl sulfide (2), or N-(2,3-epoxypropyl)aniline (3), and only 15% when using 1,2-epoxy-4-phenylbutane (4) at the same time point. The skin sensitization potencies of the epoxides using the murine local lymph node assay (LLNA) were evaluated in relation to the observed physicochemical and reactivity properties. To enable determination of statistical significance between structurally closely related compounds, a nonpooled LLNA was performed. It was found that all investigated compounds containing a heteroatom in the α-position to the epoxide were strong sensitizers, congruent with the reactivity data, indicating that the impact of a heteroatom is crucial for the sensitizing capacity for this type of epoxides.
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| 8. |
- O'Boyle, Niamh M, et al.
(författare)
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Analogues of the epoxy resin monomer diglycidyl ether of Bisphenol F: effects on contact allergenic potency and cytotoxicity
- 2012
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 25:11, s. 2469-2478
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Tidskriftsartikel (refereegranskat)abstract
- Diglycidyl ethers of bisphenol A (DGEBA) and bisphenol F (DGEBF) are widely used as components in epoxy resin thermosetting products. They are known to cause occupational and nonoccupational allergic contact dermatitis. The aim of this study is to investigate analogues of DGEBF with regard to contact allergy and cytotoxicity. A comprehensive knowledge of the structural features that contribute to the allergenic and cytotoxic effects of DGEBF will guide the development of future novel epoxy resin systems with reduced health hazards for those coming into contact with them. It was found that the allergenic effects of DGEBF were dependent on its terminal epoxide groups. In contrast, it was found that the cytotoxicity in monolayer cell culture was dependent not only on the presence of epoxide groups but also on other structural features.
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| 9. |
- O'Boyle, Niamh M, et al.
(författare)
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Epoxy Resin Monomers with Reduced Skin Sensitizing Potency
- 2014
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:6, s. 1002-1010
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Tidskriftsartikel (refereegranskat)abstract
- Epoxy resin monomers (ERMs), especially diglycidyl ethers of bisphenol A and F (DGEBA and DGEBF), are extensively used as building blocks for thermosetting polymers. However, they are known to commonly cause skin allergy. This research describes a number of alternative ERMs, designed with the aim of reducing the skin sensitizing potency while maintaining the ability to form thermosetting polymers. The compounds were designed, synthesized, and assessed for sensitizing potency using the in vivo murine local lymph node assay (LLNA). All six epoxy resin monomers had decreased sensitizing potencies compared to those of DGEBA and DGEBF. With respect to the LLNA EC3 value, the best of the alternative monomers had a value approximately 2.5 times higher than those of DGEBA and DGEBF. The diepoxides were reacted with triethylenetetramine, and the polymers formed were tested for technical applicability using thermogravimetric analysis and differential scanning calorimetry. Four out of the six alternative ERMs gave polymers with a thermal stability comparable to that obtained with DGEBA and DGEBF. The use of improved epoxy resin monomers with less skin sensitizing effects is a direct way to tackle the problem of contact allergy to epoxy resin systems, particularly in occupational settings, resulting in a reduction in the incidence of allergic contact dermatitis.
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| 10. |
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