Speaker
Description
Background: The estrogen axis is regulated through coordinated control of steroid hormone biosynthesis and receptor-mediated transcription. Disruption at either level can alter reproductive, developmental, metabolic, and oncogenic processes.
We developed and applied an integrated approach to identify compounds that target both levels of estrogen regulation: human aromatase (CYP19A1) and estrogen receptor α (ERα).
Methods: We first established and validated biochemical assays capable of detecting chemicals that directly interfere with human aromatase activity and used them in combination with an ERα gene-reporter assay. A series of environmental contaminants were then tested, including pesticides.
Results: Some compounds showed no significant interference with aromatase activity, while glyphosate exerted an inhibitory effect through a mixed inhibition mechanism when applied at low micromolar concentrations. A carbamate insecticide (methiocarb) and neonicotinoids including thiacloprid exhibited ERα-mediated weak estrogenic activity.
Extending the work to persistent pesticides detected in European waters, imazamox and metolachlor bind aromatase with micromolar affinity and act as partial inhibitors. Spectroscopic and isothermal titration calorimetry analyses revealed dissociation constants and IC50 values in the micromolar range.
At the receptor level, ERα reporter assays showed that quinclorac and terbuthylazine-desethyl induced ERα-dependent transcription with EC50 values of 9.02 x 10⁻⁴ and 1.83 x 10⁻⁵ M, respectively.
Conclusions: The data provide evidence of the potential toxic effects of persistent pesticides on two key targets of the estrogen endocrine axis, demonstrating that these compounds can perturb hormonal homeostasis, thereby raising concerns about their contribution to endocrine-related disorders under conditions of chronic exposure, mixture effects, and environmental accumulation.
Acknowledgments:
Supported by PRIN 2022 – grant No. 2022H24A2A.
