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Advancing an Understanding of the Occurrence of Glucocorticoid Pharmaceuticals and Associated Hazards in Aquatic Systems
Citation:
Cole, Alex, B. Blackwell, J. Cavallin, L. Langan, Dan Villeneuve, AND B. Brooks. Advancing an Understanding of the Occurrence of Glucocorticoid Pharmaceuticals and Associated Hazards in Aquatic Systems. American Chemical Society Fall 2024 Global Virtual Symposium, Denver, CO, August 18 - 22, 2024. https://doi.org/10.23645/epacomptox.27103651
Impact/Purpose:
The glucocorticoid receptor is a key mediator of stress responses in vertebrates. Activation of the glucocorticoid receptor by natural stress hormones evokes a physiological "fight or flight" response that both promotes release of blood glucose and anti-inflammatory and immune suppressive responses. As a result, the glucocorticoid receptor is a target for a wide variety of over the counter and prescribed medications include topical creams, allergy medications, etc. Production and human use of these compounds results in their release to aquatic systems, primarily through wastewater. Monitoring efforts for these compounds is inconsistent compared to other chemicals of emerging concern. Additionally, despite an abundance of mammalian data, the structural conservation of the glucocorticoid receptor and cross-species susceptibility, particularly for aquatic species, has not been well defined. The present examined the global occurrence of synthetic glucocorticoids and their respective agonistic activity; employed in silico and in vitro methods to elucidate a greater understanding of receptor-mediated effects of synthetic glucocorticoid exposure in teleost fish; and utilized in vivo exposure to examine an adverse outcome associated with exposure to these compounds. Comprehensive literature review showed ubiquitous occurrence of synthetic glucocorticoids in surface waters and wastewater effluent. In silico analyses confirm high levels of evolutionary conservation. Subsequent in vitro and in vivo experiments provided evidence of cross-species susceptibility to two synthetic glucocorticoids, while providing evidence for key events and key event relationships within an adverse outcome pathway. These findings support the use of new approach methodologies – reducing the need for multi-species in vivo experimentation – and provide empirical evidence that synthetic glucocorticoids can cause physiological responses in fish through their actions on the vertebrate glucocorticoid receptor agonism. Results highlight the need to both develop relevant adverse outcome pathways to better understand potential ecological hazards of synthetic glucocorticoid agonists, and to develop additional data to support ecological risk assessment of these compounds which are pollutants relevant to the Office of Water, States, and Tribes.
Description:
Though estrogenic and androgenic contaminants have received extensive attention as endocrine disrupting and modulating chemicals causing water quality concerns, glucocorticoid agonism has been receiving increasing attention in aquatic systems. Of particular interest are synthetic glucocorticoids, which are pharmaceutical compounds that mimic cortisol, the endogenous ligand ubiquitous to vertebrates, that bind to the glucocorticoid receptor (GR) within the cytoplasm. We initially performed a critical literature review examining the occurrence of pharmaceutical glucocorticoids and GR agonism in aquatic systems and conducted probabilistic environmental hazard assessments to consider water quality hazards around the world. Discrepancies among contaminant specific water quality hazards, geographic regions and monitoring efforts were identified. Standardized and receptor-mediated predicted no-effect concentrations were exceeded at a higher rate than therapeutic hazard values and AC50 values from in vitro testing. We then analyzed the evolutionary conservation of the GR receptor using in silico and in vitro methodologies. Using SeqAPASS, we identified the structural conservation of the GR while cellular bioassays containing human and zebrafish GR were employed to confirm functional conservation. Lastly, we examined whether glucocorticoid receptor agonism induced by fluticasone propionate elicited inhibition of fin regeneration in juvenile fathead minnow (Pimephales promelas). We observed fluticasone propionate and dexamethasone to significantly inhibit fin regeneration at 2 µg/L and 4mg/L respectively (n = 20) compared to controls. Analysis of mRNA using RT-PCR resulted in elucidation of potential mechanisms of inhibition through the restriction of intracellular communication. This research provides weight of evidence to further development of adverse outcome pathway 334 (AOP:334) – Glucocorticoid Receptor Activation Leads to Impaired Fin Regeneration – and elucidates a quantitative relationship between fluticasone propionate and glucocorticoid receptor agonism. The contents of this abstract neither constitute nor necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Advancing an Understanding of the Occurrence of Glucocorticoid Pharmaceuticals and Associated Hazards in Aquatic Systems
ADVANCING AN UNDERSTANDING OF THE OCCURRENCE OF GLUCOCORTICOID PHARMACEUTICALS AND ASSOCIATED HAZARDS IN AQUATIC SYSTEMS- 508.PDF (PDF, NA pp, 8132.995 KB, about PDF)