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

Food Chem Toxicol. 2017 Oct;108(Pt A):30-42. doi: 10.1016/j.fct.2017.07.025. Epub 2017 Jul 12.

Abstract

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 μg/L or 59 μM) 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 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.

Keywords: Breast cancer; Endocrine disrupting effects; Estrogen receptor; Glyphosate; Pesticides.

MeSH terms

  • Benzhydryl Compounds / pharmacology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / metabolism*
  • Gene Expression Regulation / drug effects
  • Glycine / administration & dosage
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Herbicides / pharmacology*
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Phenols / pharmacology
  • Polyethylene Glycols / pharmacology
  • Sequence Analysis, RNA
  • Transcriptome
  • Up-Regulation

Substances

  • Benzhydryl Compounds
  • Estrogen Receptor alpha
  • Herbicides
  • Phenols
  • polyoxyethyleneamine
  • Polyethylene Glycols
  • glyphosate
  • Estradiol
  • bisphenol A
  • Glycine