Glucocorticoid mixtures of fluticasone propionate, triamcinolone acetonide and clobetasol propionate induce additive effects in zebrafish embryos.

Raffael Alois Willi,Karl Fent,Noelia Salgueiro-González,Giulia Carcaiso

doi:10.1016/j.jhazmat.2019.04.023

Abstract

Many synthetic glucocorticoids from medical applications occur in the aquatic environment. Whether they pose a risk for fish health is poorly known. Here we investigate effects of glucocorticoids fluticasone propionate (FLU) and triamcinolone acetonide (TRI) as single steroids and as ternary mixtures with clobetasol propionate (CLO) in zebrafish embryos. Exposure to FLU and TRI in a range of concentrations between 0.099 and 120.08 μg/L led to concentration-related decrease in muscle contractions and increase in heart rate at 0.98 and 1.05 μg/L, respectively, and higher. Genes encoding for proteins related to glucose metabolism (g6pca, pepck1), immune system regulation (fkbp5, irg1l, socs3, gilz) and matrix metalloproteinases mmp-9 and mmp-13 showed expressional alterations, as well as genes encoding for the progestin receptor (pgr) and corticosteroid dehydrogenase (hsd11b2). FLU accelerated hatching and led to embryotoxicity (immobilization and edema). Ternary mixtures (FLU + TRI + CLO) induced the same physiological and toxicological effects at concentrations of individual glucocorticoids of 11.1-16.37 μg/L and higher. Heart rate was increased in the mixture at concentrations as low as 0.0885-0.11 μg/L of each steroid. Glucocorticoids in mixtures showed additive activity; the fold-changes of transcripts of 19 target genes were additive. Together, our data show that glucocorticoids act additively and their joint activity may be of concern for developing fish in contaminated environments.

Highlights

Synthetic glucocorticoids are frequently prescribed in medicine due to their anti-inflammatory, anti-allergic and immunosuppressive properties
We showed that binary mixtures of cortisol and clobetasol propionate (CLO) showed mainly similar activities as CLO alone in zebrafish embryos due to the much higher activity of CLO [1]
Fluticasone propionate (FLU), triamcinolone acetonide (TRI), clobetasol propionate (CLO), dimethyl sulfoxide (DMSO) and medroxyprogesterone (CAS-number: 520-85-4), which was used as internal standard for chemical analysis, were purchased from Sigma Aldrich, Fluka AG, Buchs, Switzerland

Summary

Introduction

Synthetic glucocorticoids are frequently prescribed in medicine due to their anti-inflammatory, anti-allergic and immunosuppressive properties. Synthetic glucocorticoids are often halogenated, including fluticasone propionate (FLU) and triamcinolone acetonide (TRI); they were designed to increase the half-life in the human body and to increase receptor binding, and to enhance potency. Endogenous glucocorticoids are synthesized in the inter-renal tissue of the head kidney in teleost fish. They play a significant role in carbohydrate, protein and lipid metabolism and in the immune response involved in the reaction to stress and anti-inflammatory action. They have an osmoregulatory function in fish [5]. Glucocorticoids interact with other steroid hormone receptors, including the mineralocorticoid receptor, at lower potency [8]

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