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Evaluating the Endocrine-Disrupting and Oxidative Stress Potential of a 50-Component Human-Relevant Complex Chemical Mixture Using In Vitro Tests.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Evaluating the Endocrine-Disrupting and Oxidative Stress Potential of a 50-Component Human-Relevant Complex Chemical Mixture Using In Vitro Tests.
Συγγραφείς: Engelhardt J; Department of Environmental Science, Stockholm University, Stockholm, Sweden., Struwe N; School of Science and Technology, Örebro University, Örebro, Sweden., Jansson A; Department of Environmental Science, Stockholm University, Stockholm, Sweden.; Department of Chemical Engineering, Royal Institute of Technology (KTH), Stockholm, Sweden.; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Kos VM; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Larsson M; School of Science and Technology, Örebro University, Örebro, Sweden., Weiss JM; Department of Environmental Science, Stockholm University, Stockholm, Sweden.
Πηγή: Journal of applied toxicology : JAT [J Appl Toxicol] 2026 Jun; Vol. 46 (6), pp. 2003-2018. Date of Electronic Publication: 2025 Nov 29.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: John Wiley And Sons Country of Publication: England NLM ID: 8109495 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1099-1263 (Electronic) Linking ISSN: 0260437X NLM ISO Abbreviation: J Appl Toxicol Subsets: MEDLINE
Imprint Name(s): Publication: : Chichester : John Wiley And Sons
Original Publication: [Philadelphia, Pa. : Heyden & Son, c1981-
Ιατρικοί όροι (MeSH): Endocrine Disruptors*/toxicity , Oxidative Stress*/drug effects , Complex Mixtures*/toxicity , Environmental Pollutants*/toxicity, Flame Retardants/toxicity ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Polychlorinated Biphenyls/toxicity ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Humans ; Cell Line
Περίληψη: Humans are chronically exposed to mixtures of environmental contaminants. Exposure to endocrine-disrupting chemicals (EDCs) contributes to increased health impairment observed globally. This study aimed to evaluate the endocrine-disruptive and oxidative stress potential of a human-relevant, complex chemical mixture in vitro. By testing chemical class subgroup mixtures, the identity of toxicological drivers and mixture additivity could be investigated. A 50-component mixture was compiled based on Swedish human blood concentrations (xHBC), consisting of six subgroup mixtures: polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (PCB mixture), brominated flame retardants (BFR mixture), per- and polyfluoroalkyl substances (PFAS mixture), pesticide mixture, synthetic phenolic contaminants (phenol mixture), and phthalate mixture. These were tested in four chemically activated luciferase gene expression (CALUX) assays: dioxin responsive (DR-), estrogen receptor α (ERα-), androgen receptor. (AR-), and nuclear factor erythroid 2-related factor 2 (Nrf2)-CALUX, along with an adipocyte cell assay. The total mixture caused significant agonistic activity in DR- and ER-, and antagonistic activity in AR-CALUX at 0.1-15 xHBC, depending on the assay. Mixture additivity was assessed in ERα-, DR-, and anti-AR-CALUX using subgroup mixtures and the concentration addition (CA) model. The total mixture followed the CA model in ERα-, anti-AR- and DR-CALUX. The toxicological drivers of these activities were mainly the PCB and phenol mixture. A significant increase in differentiated adipocytes was observed at 100 xHBC. These results raise concerns regarding potential health effects on the endocrine system. The additive effects at human-relevant concentrations observed in this study motivate considering mixtures in regulatory contexts to protect the well-being of future generations.
(© 2025 The Author(s). Journal of Applied Toxicology published by John Wiley & Sons Ltd.)
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Chemosphere. 2022 Jul;298:134362. (PMID: 35307388)
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Environ Int. 2021 Jan;146:106206. (PMID: 33120228)
Diabetes. 2011 Jul;60(7):1838-48. (PMID: 21709279)
Toxicol In Vitro. 2010 Feb;24(1):201-7. (PMID: 19765641)
Toxicol In Vitro. 2016 Apr;32:269-77. (PMID: 26812027)
Healthcare (Basel). 2021 May 18;9(5):. (PMID: 34069956)
Environ Health Perspect. 2014 Aug;122(8):769-74. (PMID: 24659601)
PLoS One. 2014 Feb 12;9(2):e88808. (PMID: 24533151)
J Theor Biol. 1985 Jun 7;114(3):413-31. (PMID: 4021503)
Ecotoxicol Environ Saf. 2012 Dec;86:93-100. (PMID: 23084651)
Environ Health Perspect. 2020 Jan;128(1):17015. (PMID: 32003587)
Environ Int. 2020 Jan;134:105295. (PMID: 31726357)
Environ Sci Pollut Res Int. 2016 Feb;23(3):2099-107. (PMID: 26077315)
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Food Chem. 2021 Aug 15;353:129488. (PMID: 33714793)
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Environ Health Perspect. 2005 Nov;113(11):1549-54. (PMID: 16263510)
Ecotoxicol Environ Saf. 2025 Jul 1;299:118401. (PMID: 40412253)
Int J Hyg Environ Health. 2023 Jun;251:114196. (PMID: 37279611)
Toxicol Sci. 2005 Apr;84(2):249-59. (PMID: 15635150)
Ecotoxicol Environ Saf. 1980 Dec;4(4):415-21. (PMID: 7472245)
Environ Toxicol Chem. 2021 Mar;40(3):606-630. (PMID: 33017053)
J Appl Toxicol. 2026 Jun;46(6):2003-2018. (PMID: 41317044)
Environ Int. 2024 Oct;192:108991. (PMID: 39299052)
J Hazard Mater. 2022 Feb 15;424(Pt A):127306. (PMID: 34879546)
Chemosphere. 2015 Jun;129:239-45. (PMID: 25455676)
Interdiscip Toxicol. 2016 Dec;9(3-4):90-100. (PMID: 28652852)
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Grant Information: 2018-02264 Swedish Research Council FORMAS; 2019-00375 Swedish Research Council FORMAS; August Emil Wilhelm Smitts stipendie- och understödsstiftelse; 20190098 KK Foundation
Contributed Indexing: Keywords: CALUX; chemical mixtures; concentration additivity; endocrine‐disrupting chemicals; environmental contaminants; human blood concentrations; in vitro; oxidative stress
Substance Nomenclature: 0 (Endocrine Disruptors)
0 (Complex Mixtures)
0 (Environmental Pollutants)
0 (Flame Retardants)
0 (Receptors, Androgen)
DFC2HB4I0K (Polychlorinated Biphenyls)
0 (NF-E2-Related Factor 2)
0 (Estrogen Receptor alpha)
Entry Date(s): Date Created: 20251129 Date Completed: 20260503 Latest Revision: 20260909
Update Code: 20260909
PubMed Central ID: PMC13136407
DOI: 10.1002/jat.70011
PMID: 41317044
Βάση Δεδομένων: MEDLINE
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  Data: Evaluating the Endocrine-Disrupting and Oxidative Stress Potential of a 50-Component Human-Relevant Complex Chemical Mixture Using In Vitro Tests.
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  Data: <searchLink fieldCode="AU" term="%22Engelhardt+J%22">Engelhardt J</searchLink>; Department of Environmental Science, Stockholm University, Stockholm, Sweden.<br /><searchLink fieldCode="AU" term="%22Struwe+N%22">Struwe N</searchLink>; School of Science and Technology, Örebro University, Örebro, Sweden.<br /><searchLink fieldCode="AU" term="%22Jansson+A%22">Jansson A</searchLink>; Department of Environmental Science, Stockholm University, Stockholm, Sweden.; Department of Chemical Engineering, Royal Institute of Technology (KTH), Stockholm, Sweden.; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.<br /><searchLink fieldCode="AU" term="%22Kos+VM%22">Kos VM</searchLink>; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.<br /><searchLink fieldCode="AU" term="%22Larsson+M%22">Larsson M</searchLink>; School of Science and Technology, Örebro University, Örebro, Sweden.<br /><searchLink fieldCode="AU" term="%22Weiss+JM%22">Weiss JM</searchLink>; Department of Environmental Science, Stockholm University, Stockholm, Sweden.
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  Data: <searchLink fieldCode="JN" term="%228109495%22">Journal of applied toxicology : JAT</searchLink> [J Appl Toxicol] 2026 Jun; Vol. 46 (6), pp. 2003-2018. <i>Date of Electronic Publication: </i>2025 Nov 29.
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  Data: <searchLink fieldCode="MM" term="%22Endocrine+Disruptors%22">Endocrine Disruptors*</searchLink>/<searchLink fieldCode="MM" term="%22Endocrine+Disruptors+toxicity%22">toxicity</searchLink> <br /><searchLink fieldCode="MM" term="%22Oxidative+Stress%22">Oxidative Stress*</searchLink>/<searchLink fieldCode="MM" term="%22Oxidative+Stress+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Complex+Mixtures%22">Complex Mixtures*</searchLink>/<searchLink fieldCode="MM" term="%22Complex+Mixtures+toxicity%22">toxicity</searchLink> <br /><searchLink fieldCode="MM" term="%22Environmental+Pollutants%22">Environmental Pollutants*</searchLink>/<searchLink fieldCode="MM" term="%22Environmental+Pollutants+toxicity%22">toxicity</searchLink><br /><searchLink fieldCode="MH" term="%22Flame+Retardants%22">Flame Retardants</searchLink>/<searchLink fieldCode="MH" term="%22Flame+Retardants+toxicity%22">toxicity</searchLink> ; <searchLink fieldCode="MH" term="%22Receptors%2C+Androgen%22">Receptors, Androgen</searchLink>/<searchLink fieldCode="MH" term="%22Receptors%2C+Androgen+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Receptors%2C+Androgen%22">Receptors, Androgen</searchLink>/<searchLink fieldCode="MH" term="%22Receptors%2C+Androgen+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Polychlorinated+Biphenyls%22">Polychlorinated Biphenyls</searchLink>/<searchLink fieldCode="MH" term="%22Polychlorinated+Biphenyls+toxicity%22">toxicity</searchLink> ; <searchLink fieldCode="MH" term="%22NF-E2-Related+Factor+2%22">NF-E2-Related Factor 2</searchLink>/<searchLink fieldCode="MH" term="%22NF-E2-Related+Factor+2+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22NF-E2-Related+Factor+2%22">NF-E2-Related Factor 2</searchLink>/<searchLink fieldCode="MH" term="%22NF-E2-Related+Factor+2+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Estrogen+Receptor+alpha%22">Estrogen Receptor alpha</searchLink>/<searchLink fieldCode="MH" term="%22Estrogen+Receptor+alpha+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Estrogen+Receptor+alpha%22">Estrogen Receptor alpha</searchLink>/<searchLink fieldCode="MH" term="%22Estrogen+Receptor+alpha+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Cell+Line%22">Cell Line</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Humans are chronically exposed to mixtures of environmental contaminants. Exposure to endocrine-disrupting chemicals (EDCs) contributes to increased health impairment observed globally. This study aimed to evaluate the endocrine-disruptive and oxidative stress potential of a human-relevant, complex chemical mixture in vitro. By testing chemical class subgroup mixtures, the identity of toxicological drivers and mixture additivity could be investigated. A 50-component mixture was compiled based on Swedish human blood concentrations (xHBC), consisting of six subgroup mixtures: polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (PCB mixture), brominated flame retardants (BFR mixture), per- and polyfluoroalkyl substances (PFAS mixture), pesticide mixture, synthetic phenolic contaminants (phenol mixture), and phthalate mixture. These were tested in four chemically activated luciferase gene expression (CALUX) assays: dioxin responsive (DR-), estrogen receptor α (ERα-), androgen receptor. (AR-), and nuclear factor erythroid 2-related factor 2 (Nrf2)-CALUX, along with an adipocyte cell assay. The total mixture caused significant agonistic activity in DR- and ER-, and antagonistic activity in AR-CALUX at 0.1-15 xHBC, depending on the assay. Mixture additivity was assessed in ERα-, DR-, and anti-AR-CALUX using subgroup mixtures and the concentration addition (CA) model. The total mixture followed the CA model in ERα-, anti-AR- and DR-CALUX. The toxicological drivers of these activities were mainly the PCB and phenol mixture. A significant increase in differentiated adipocytes was observed at 100 xHBC. These results raise concerns regarding potential health effects on the endocrine system. The additive effects at human-relevant concentrations observed in this study motivate considering mixtures in regulatory contexts to protect the well-being of future generations.<br /> (© 2025 The Author(s). Journal of Applied Toxicology published by John Wiley & Sons Ltd.)
– Name: Ref
  Label: References
  Group: RefInfo
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– Name: GrantInfo
  Label: Grant Information
  Group: Grant
  Data: 2018-02264 Swedish Research Council FORMAS; 2019-00375 Swedish Research Council FORMAS; August Emil Wilhelm Smitts stipendie- och understödsstiftelse; 20190098 KK Foundation
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  Data: <i>Keywords: </i>CALUX; chemical mixtures; concentration additivity; endocrine‐disrupting chemicals; environmental contaminants; human blood concentrations; in vitro; oxidative stress
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  Data: 0 (Endocrine Disruptors)<br />0 (Complex Mixtures)<br />0 (Environmental Pollutants)<br />0 (Flame Retardants)<br />0 (Receptors, Androgen)<br />DFC2HB4I0K (Polychlorinated Biphenyls)<br />0 (NF-E2-Related Factor 2)<br />0 (Estrogen Receptor alpha)
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  Data: <i>Date Created: </i>20251129 <i>Date Completed: </i>20260503 <i>Latest Revision: </i>20260909
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        Value: 10.1002/jat.70011
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        StartPage: 2003
    Subjects:
      – SubjectFull: Flame Retardants toxicity
        Type: general
      – SubjectFull: Receptors, Androgen genetics
        Type: general
      – SubjectFull: Receptors, Androgen metabolism
        Type: general
      – SubjectFull: Polychlorinated Biphenyls toxicity
        Type: general
      – SubjectFull: NF-E2-Related Factor 2 genetics
        Type: general
      – SubjectFull: NF-E2-Related Factor 2 metabolism
        Type: general
      – SubjectFull: Estrogen Receptor alpha genetics
        Type: general
      – SubjectFull: Estrogen Receptor alpha metabolism
        Type: general
      – SubjectFull: Humans
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      – SubjectFull: Cell Line
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      – SubjectFull: Endocrine Disruptors toxicity
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      – SubjectFull: Complex Mixtures toxicity
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      – SubjectFull: Environmental Pollutants toxicity
        Type: general
    Titles:
      – TitleFull: Evaluating the Endocrine-Disrupting and Oxidative Stress Potential of a 50-Component Human-Relevant Complex Chemical Mixture Using In Vitro Tests.
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            – D: 01
              M: 06
              Text: 2026 Jun
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 1099-1263
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              Value: 46
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