Suppression of Thyroid Hormone Receptor-Mediated Transcription by Methamidophos

Abstract

Methamidophos is a cholinesterase inhibitor organophosphate (OP) used commonly as a pesticide. Its use is currently a global concern due to widespread occurrence, persistence, bioaccumulation and neurotoxic potential. We therefore examined the effect of methamidophos on thyroid hormone receptor (TR)-mediated gene expression using transient transfection-based reporter gene assay. Our results shows that methamidophos (10^-6 M) suppressed thyroid hormone (TH)-induced TR-mediated transcription. We further examined the effects of methamidophos on TR-thyroid hormone response element (TRE) binding using the liquid chemiluminescent DNA pull-down assay (LCDPA), and found no dissociation of TR from TRE. Using mammalian two hybrid assay, we showed that methamidophos did not recruit co-activator (steroid receptor co-activator 1; SRC-1) to TR in the presence of TH. Also, it did not recruit co-repressors (nuclear co-repressor; NCoR) to TR in the absence of TH at all concentrations examined. The effects of methamidophos on cerebellar Purkinje cell dendritogenesis, granule cell neurite morphology and synaptic plasticity are currently under investigation. Taken together, our results show that methamidophos can potentially disrupt TR–mediated gene expression, suggesting that methamidophos may interfere with thyroid hormone-mediated activities in various target organs including the developing brain.

Keywords: Methamidophos, Thyroid hormones, Purkinje cell,