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Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide ingredients
Citation:
Mesnage, R., A. Phedonos, M. Arno, S. Balu, C. Corton, R. Ugarte, AND M. Antoniou. Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide ingredients. SOT, Baltimore, Maryland, March 13 - 16, 2017.
Impact/Purpose:
Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. There is a debate on the estrogenic effects of their ingredients. We examined in three human breast cancer cell lines the estrogenic effects of glyphosate, two forms of the polyethoxylated tallowamine co-formulant (technical grade and agricultural spray adjuvant), and 4 commercial formulations containing different ratios of co-formulants and compared these effects to those induced by estradiol and bisphenol A.
Description:
Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. There is a debate on the estrogenic effects of their ingredients. We examined in three human breast cancer cell lines the estrogenic effects of glyphosate, two forms of the polyethoxylated tallowamine co-formulant (technical grade and agricultural spray adjuvant), 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 MCF7 human breast cancer cells using the Affymetrix microarray platform and by RNA-seq. Quantum mechanical behavior of glyphosate ion interactions within the ligand binding domain (LBD) of ERα was performed using molecular dynamics simulations. Glyphosate (>10 mg/L) promoted proliferation of hormone dependent MCF-7 cells and increased expression of luciferase in the T47D-KBluc reporter assay. Addition of the anti-estrogen ICI 182,780 antagonized the activation of ER demonstrating dependence on ER for activation. Adjuvants and commercial formulations did not exhibit estrogenic effects. Although gene expression profiles of glyphosate-exposed MCF-7 cells were reflective of hormone-induced proliferative effects, the gene expression pattern did not significantly overlap with that of an ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα by molecular dynamics simulations followed by ONIOM calculations revealed that the interaction between glyphosate and the ERα LBD is weak (−4.10 kcal mol-1) and unstable, compared to estradiol (-25.79 kcal mol-1). Thus, we hypothesize that glyphosate is not likely to bind to ERα and that gene activation by this compound may be through a ligand-independent mechanism. However, further investigation is needed to confirm this hypothesis. In conclusion, our study reveals that glyphosate but not other chemicals in 4 major commercial formulations activate ERα. (This abstract does not reflect EPA policy.)