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Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents
Citation:
Mesnage, R., A. Phedonos, M. Biserni, M. Arno, S. Balu, C. Corton, R. Ugarte, AND M. Antoniou. Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. FOOD AND CHEMICAL TOXICOLOGY. Elsevier Science Ltd, New York, NY, 108:30-42, (2017).
Impact/Purpose:
Glyphosate-based herbicides (GBH) are major pesticides used worldwide. There is a debate currently focused on the estrogenic effects of their constituent components. In three human breast cancer cell lines we examined the estrogenic effects of glyphosate, two forms of the polyethoxylated tallowamine co-formulant, and 4 commercial formulations containing different ratios of co-formulants and compared these effects to those induced by estradiol and bisphenol A. Cell proliferation was assessed using the E-screen assay. Estrogen receptor (ER) activity was assessed by trans-activation of an Estrogen Responsive Element (ERE)-luciferase reporter in T47D-KBluc cells. Gene expression was measured in hormone dependent MCF-7 human breast cancer cells using the Affymetrix microarray platform and by RNA-seq. Quantum mechanical behaviour of glyphosate ion interactions within the ligand binding domain (LBD) of ERα was assessed using molecular dynamics simulations.
Description:
The safety, including the endocrine disruptive capability, of glyphosate-based herbicides (GBHs) is a matter of intense debate. We evaluated the estrogenic potential of glyphosate, commercial GBHs and polyethoxylated tallowamine adjuvants present as co-formulants in GBHs. Glyphosate (?10,000 mg/L or 59 mM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased the expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47DKBluc cells, which was blocked by the estrogen antagonist ICI 182,780. Commercial GBH formulations or their adjuvants alone did not exhibit estrogenic effects in either assay. Transcriptomics analysis of MCF-7 cells treated with glyphosate revealed changes in gene expression reflective of hormone-induced cell proliferation but did not overlap with an ERa gene expression biomarker. Calculation of glyphosate binding energy to ERa predicts a weak and unstable interaction (?4.10 kcal mol?1) compared to estradiol (?25.79 kcal mol?1), which suggests that activation of this receptor by glyphosate is via a ligandindependent mechanism. Induction of ERE-luc expression by the PKA signalling activator IBMX shows that ERE-luc is responsive to ligand-independent activation, suggesting a possible mechanism of glyphosate-mediated activation. Our study reveals that glyphosate, but not other components present in GBHs, can activate ERa in vitro, albeit at relatively high concentrations.
