TY - JOUR
T1 - Benzotriazole UV stabilizers disrupt epidermal growth factor receptor signaling in human cells
AU - Sondermann, Natalie C.
AU - Momin, Afaque A.
AU - Arold, Stefan T.
AU - Haarmann-Stemmann, Thomas
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/8
Y1 - 2024/8
N2 - Phenolic benzotriazole UV stabilizers (BUV) are commonly used additives in synthetic polymeric products, which constantly leak into the environment. They are persistent and bioaccumulative, and have been detected not only in fish, birds, and sea mammals, but also in humans, including breast milk samples. Several authorities including the European Chemical Agency already consider some BUVs as Substances of Very High Concern in need of further information, e.g. mechanistical studies and biomonitoring. In this study, we are addressing this need by investigating the effect of several BUVs on the activity of the human epidermal growth factor receptor (EGFR), an important regulator of cellular processes that has recently been identified as a cell-surface receptor for environmental organic chemicals. By combining in silico docking, mutant analyses, receptor binding and internalization assays, we demonstrate that BUVs, particularly the chlorinated variants, bind to the extracellular domain of EGFR and thereby prevent the binding of growth factors. Accordingly, BUVs can inhibit EGFR downstream events, such as ERK1/2 phosphorylation and DNA synthesis, in human keratinocytes. Our data establish EGFR as a plasma membrane receptor for BUVs, offering novel mechanistic insights into the biological effects induced by these widespread and persistent chemicals. The findings of this study may not only improve hazard assessment for BUVs, but also contribute to the development of novel EGFR-targeting drugs.
AB - Phenolic benzotriazole UV stabilizers (BUV) are commonly used additives in synthetic polymeric products, which constantly leak into the environment. They are persistent and bioaccumulative, and have been detected not only in fish, birds, and sea mammals, but also in humans, including breast milk samples. Several authorities including the European Chemical Agency already consider some BUVs as Substances of Very High Concern in need of further information, e.g. mechanistical studies and biomonitoring. In this study, we are addressing this need by investigating the effect of several BUVs on the activity of the human epidermal growth factor receptor (EGFR), an important regulator of cellular processes that has recently been identified as a cell-surface receptor for environmental organic chemicals. By combining in silico docking, mutant analyses, receptor binding and internalization assays, we demonstrate that BUVs, particularly the chlorinated variants, bind to the extracellular domain of EGFR and thereby prevent the binding of growth factors. Accordingly, BUVs can inhibit EGFR downstream events, such as ERK1/2 phosphorylation and DNA synthesis, in human keratinocytes. Our data establish EGFR as a plasma membrane receptor for BUVs, offering novel mechanistic insights into the biological effects induced by these widespread and persistent chemicals. The findings of this study may not only improve hazard assessment for BUVs, but also contribute to the development of novel EGFR-targeting drugs.
KW - Benzotriazoles
KW - Epidermal growth factor receptor
KW - Human epithelial cells
KW - Persistent organic pollutants
KW - Tyrosine kinase inhibitors
KW - UV absorber
UR - http://www.scopus.com/inward/record.url?scp=85198738531&partnerID=8YFLogxK
U2 - 10.1016/j.envint.2024.108886
DO - 10.1016/j.envint.2024.108886
M3 - Article
C2 - 39024829
AN - SCOPUS:85198738531
SN - 0160-4120
VL - 190
JO - Environment international
JF - Environment international
M1 - 108886
ER -