Atrazine binds to the growth hormone-releasing hormone receptor and affects growth hormone gene expression

Abstract

Background: Atrazine (ATR), a commonly used herbicide in the United States, is widely distributed in water and soil because of its mobility through ecosystems and its persistence in the environment. ATR has been associated with defects in sexual development in animals, but studies on mammalian systems have failed to clearly identify a cellular target. Objectives: Our goal in this study was to identify a ligand-binding receptor for ATR in pituitary cells that may explain the mechanism of action at the gene expression level. Methods: We used pituitary cells from postnatal day 7 male rats and pituitary cell lines to study the effect of ATR on gene expression of growth hormone (GH), luteinizing hormone (LH), and prolactin (PRL) at RNA and protein levels. 14C-ATR was used to determine its specific binding to the growth hormone-releasing hormone receptor (GHRHR). The effect of ATR on structural proteins was visualized using immunofluorescent in situ staining. Results: The treatment of rat pituitary cells with ATR, at environmentally relevant concentrations (1 ppb and 1 ppm), resulted in a reduction of GH expression. This effect appeared to result from the inhibition of GH gene transcription due to ATR binding to the GHRHR of the pituitary cells. Conclusions: Identification of GHRHR as the target of ATR is consistent with the myriad effects previously reported for ATR in mammalian systems. These findings may lead to a better understanding of the hazards of environmental ATR contamination and inform efforts to develop guidelines for establishing safe levels in water systems.