Organophosphate ester tri-o-cresyl phosphate interacts with estrogen receptor α in MCF-7 breast cancer cells promoting cancer growth.

Abstract

Plastic in the ocean degrades to microplastic, thereby enhancing the leaching of incorporated plasticizers due to the increased particle surface. The uptake of microplastic-derived plasticizers by marine animals and the subsequent entry in the food chain raises concerns for adverse health effects in human beings. Frequently used plasticizers as the organophosphate ester tri-o-cresyl phosphate (TOCP) are known to affect the male reproductive system. However, the overall endocrine potential of TOCP and the underlying molecular mechanisms remain elusive as yet. In this study, we investigated the molecular effects of TOCP on estrogen receptor α (ERα)-transfected HEK-ESR1 cells and the human breast cancer cell line MCF-7. Applying virtual screening and molecular docking, we identified TOCP as potent ligand of ERα in silico. Microscale thermophoresis confirmed the binding in vitro with similar intensity as the natural ligand 17-β-estradiol. To identify the molecular mechanisms of TOCP-mediated effects, we used next-generation sequencing to analyze the gene expression pattern of TOCP-treated MCF-7 cells. RNA-sequencing revealed 22 differently expressed genes associated with ESR1 as upstream regulator: CYP1A1, SLC7A11, RUNX2, DDIT4, STC2, KLHL24, CCNG2, CEACAM5, SLC7A2, MAP1B, SLC7A5, IGF1R, CD55, FOSL2, VEGFA, and HSPA13 were upregulated and PRKCD, CCNE1, CEBPA, SFPQ, TNFAIP2, KRT19 were downregulated. The affected genes promote tumor growth by increasing angiogenesis and nutritional supply, favor invasion and metastasis, and interfere with the cell cycle. Based on the gene expression pattern, we conclude TOCP to mediate endocrine effects on MCF-7 cells by interacting with ERα.

• Authors: Madeleine Böckers, Norbert W Paul, Thomas Efferth
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 395 Pg. 114977 (05 15 2020) ISSN: 1096-0333 [Electronic] United States
• PMID: 32234386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• ESR1 protein, human
• Endocrine Disruptors
• Estrogen Receptor alpha
• Plasticizers
• Tritolyl Phosphates
• RNA
• tri-o-cresyl phosphate

Topics

• Breast Neoplasms (genetics, pathology)
• Cell Cycle (genetics)
• Endocrine Disruptors
• Estrogen Receptor alpha (drug effects, genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• High-Throughput Nucleotide Sequencing
• Humans
• MCF-7 Cells
• Male
• Models, Molecular
• Molecular Docking Simulation
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis (genetics)
• Neovascularization, Pathologic (genetics)
• Plasticizers (toxicity)
• RNA (chemistry)
• Transfection
• Tritolyl Phosphates (metabolism, toxicity)