High-throughput screening of estrogen receptor activity in personalized mixtures of persistent organic pollutants detected in the blood of Swedish adults.

Reis L, Strand D, Höglund A, Lundgren B, Bergdahl IA, Martin JW, Karlsson O

Environ. Res. 290 (-) 123388 [2026-02-01; online 2025-11-20]

Toxicological studies of single chemicals overlook the real-world complexity of human exposure, where multiple compounds may interact to disrupt biological processes such as endocrine signaling. Moreover, the chemical exposome, the sum of an individual's chemical burden, varies markedly between people, yet its biological implications remain unclear. To address this gap, we reconstructed individualized human chemical exposomes to assess their effects on estrogen receptor (ER) activity. Sixteen exposomes comprising 24 persistent organic pollutant (POP) were derived from blood profiles of participants in the Swedish Västerbotten Intervention Programme. Using automated, non-contact acoustic liquid dispensing, we reconstructed 14 personalized mixtures (PMs) reflecting individual blood compositions and two formulated mixtures (FM) representing the cohort's median and maximum population exposure levels. ER activity was assessed in VM7Luc4E2 cells using a high-throughput 384-well adaption of the OECD No. 455 assay at 1×, 10× and 100× blood concentrations. While most individual POPs showed no or weak ER activity, three mixtures induced ER agonism. The PM-High, corresponding to the individual with the highest total POP levels, and the FM-Median activated the ER at 100×, while the FM-Maximum induced activation at 10× and 100×. Removing β-HCH and trans-nonachlor from the active mixtures abolished or reduced ER activity. Co-treatment with physiological estradiol levels increased ER responses in six mixtures, PM#1 (1× and 10×), PM#4 (100×), PM#8 (10×), PM#9 (100×), PM#10 (1×) and the FM-Median (1×), indicating potentiation of endogenous hormonal signaling. Overall, this study reveals endocrine activity in real-world POP mixtures and advances high-throughput screening as a scalable approach for individualized exposome-based health risk evaluation.

PubMed 41274449

DOI 10.1016/j.envres.2025.123388

Crossref 10.1016/j.envres.2025.123388

pii: S0013-9351(25)02641-6