Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents

TY - JOUR

T1 - Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents

AU - Mesnage, Robin

AU - Phedonos, Alexia

AU - Biserni, Martina

AU - Arno, Matthew

AU - Balu, Sucharitha

AU - Corton, J. Christopher

AU - Ugarte, Ricardo

AU - Antoniou, Michael N.

PY - 2017/10

Y1 - 2017/10

N2 - The safety, including 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 μg/L or 59 μM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47D-KBluc 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 ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα 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 ligand-independent 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 ERα in vitro, albeit at relatively high concentrations.

AB - The safety, including 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 μg/L or 59 μM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47D-KBluc 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 ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα 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 ligand-independent 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 ERα in vitro, albeit at relatively high concentrations.

KW - Endocrine disrupting effects

KW - Pesticides

KW - Glyphosate

KW - Breast cancer

KW - Estrogen receptor

UR - https://www.scopus.com/pages/publications/85025630331

U2 - 10.1016/j.fct.2017.07.025

DO - 10.1016/j.fct.2017.07.025

M3 - Article

SN - 0278-6915

VL - 108

SP - 30

EP - 42

JO - Food and Chemical Toxicology

JF - Food and Chemical Toxicology

ER -