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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.

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Title: Evaluating the Endocrine-Disrupting and Oxidative Stress Potential of a 50-Component Human-Relevant Complex Chemical Mixture Using In Vitro Tests.
Authors: 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.
Source: Journal of applied toxicology : JAT [J Appl Toxicol] 2026 Jun; Vol. 46 (6), pp. 2003-2018. Date of Electronic Publication: 2025 Nov 29.
Publication Type: Journal Article; Research Support, Non-U.S. Gov't
Language: English
Journal Info: 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-
MeSH Terms: 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
Abstract: 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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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
Database: MEDLINE
Description
ISSN:1099-1263
DOI:10.1002/jat.70011