Risk assessment of parabens in a transcriptomics-based in vitro test

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2023
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Seidel, Florian
Kappenberg, Franziska
Fayyaz, Susann
Scholtz-Illigens, Andreas
Cherianidou, Anna
Derksen, Katharina
Nell, Patrick
Marchan, Rosemarie
Hengstler, Jan G.
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Chemico-Biological Interactions. Elsevier. 2023, 384, 110699. ISSN 0009-2797. eISSN 1872-7786. Available under: doi: 10.1016/j.cbi.2023.110699
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Parabens have been used for decades as preservatives in food, drugs and cosmetics. The majority however, were banned in 2009 and 2014 leaving only methyl-, ethyl-, propyl-, and butyl-derivates available for subsequent use. Methyl- and propylparaben have been extensively tested in vivo, with no resulting evidence for developmental and reproductive toxicity (DART). In contrast, ethylparaben has not yet been tested for DART in animal experiments, and it is currently debated if additional animal studies are warranted. In order to perform a comparison of the four currently approved parabens, we used a previously established in vitro test based on human induced pluripotent stem cells (iPSC) that are exposed to test substances during their differentiation to neuroectodermal cells. EC50 values for cytotoxicity were 906 μM, 698 μM, 216 μM and 63 μM for methyl-, ethyl-, propyl- and butylparaben, respectively, demonstrating that cytotoxicity increases with increasing alkyl chain length. Genome-wide analysis demonstrated that FDR-adjusted significant gene expression changes occurred only at cytotoxic or close to cytotoxic concentrations, for example 1720 differentially expressed genes (DEG) at 1000 μM ethylparaben, 1 DEG at 316 μM, and no DEG at 100 μM or lower concentrations. The highest concentration of ethylparaben that did not induce any cytotoxicity nor DEG was 1670-fold above the highest published concentrations reported in biomonitoring studies (60 nM ethylparaben in cord blood). In conclusion, cytotoxicity and gene expression alterations of ethylparaben occurred at concentrations of approximately three orders of magnitude above human blood concentrations; moreover, the substance fitted well into a scenario where toxicity increases with the alkyl chain length, and gene expression changes only occur at cytotoxic or close to cytotoxic concentrations. Therefore, no evidence was obtained suggesting that in vivo DART with ethylparaben would lead to different results as the methyl- or propyl derivates.

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ISO 690SEIDEL, Florian, Franziska KAPPENBERG, Susann FAYYAZ, Andreas SCHOLTZ-ILLIGENS, Anna CHERIANIDOU, Katharina DERKSEN, Patrick NELL, Rosemarie MARCHAN, Marcel LEIST, Jan G. HENGSTLER, 2023. Risk assessment of parabens in a transcriptomics-based in vitro test. In: Chemico-Biological Interactions. Elsevier. 2023, 384, 110699. ISSN 0009-2797. eISSN 1872-7786. Available under: doi: 10.1016/j.cbi.2023.110699
BibTex
@article{Seidel2023-09asses-67766,
  year={2023},
  doi={10.1016/j.cbi.2023.110699},
  title={Risk assessment of parabens in a transcriptomics-based in vitro test},
  volume={384},
  issn={0009-2797},
  journal={Chemico-Biological Interactions},
  author={Seidel, Florian and Kappenberg, Franziska and Fayyaz, Susann and Scholtz-Illigens, Andreas and Cherianidou, Anna and Derksen, Katharina and Nell, Patrick and Marchan, Rosemarie and Leist, Marcel and Hengstler, Jan G.},
  note={Article Number: 110699}
}
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