Toxicity and enantiospecific differences of two β-blockers, propranolol and metoprolol, in the embryos and larvae of zebrafish (Danio rerio)

Abstract

The risk presented by β-blockers on aquatic organisms remains uncertain, particularly given the enantiospecific differences in toxicity of chiral β-blockers. In this study, the toxicity of two β-blockers, propranolol and metoprolol, was determined. The 96-h LC50 of propranolol in the zebrafish larvae was 2.48 mg/L, whereas 50 mg/L metoprolol did not result in death. Both β-blockers decreased the heart rate and hatching rate and increased the mortality of the zebrafish embryos. Among these indicators, the heart rate was the most sensitive. However, the acute larval and embryo toxicity results displayed no enantioselectivity. Additionally, the transcriptional response of the genes encoding the β-adrenergic receptors and those involved in other physiological processes, including the antioxidant response, detoxification, and apoptosis, in zebrafish larvae exposed to the β-blockers was examined. Although the changes in gene transcription were fairly minor, significant enantioselectivity was observed for β-blockers, suggesting that the transcriptional response was more sensitive for the evaluation of enantiospecific toxicity. Based on these results, the pharmaceutical drugs were not expected to pose a risk to fish; however, this conclusion should not be considered final. These results also demonstrated that the enantiospecific toxicity of chiral β-blockers should be investigated when performing an ecological risk assessment.

Overlapping and Opposing Functions of G Protein-coupled Receptor Kinase 2 (GRK2) and GRK5 during Heart Development

“…To test this, we treated zebrafish embryos from the tailbud stage onward with either propranolol or, as a control, the adrenergic agonist isoproterenol. In earlier studies, it was shown that propranolol has a mild effect on the heart rate starting from 44 hpf onward (48,49). Consistent with this, MO-mediated KD of ␤1AR in zebrafish resulted in lower heart rates at 4 days postfertilization (50).…”

Evaluation of ecotoxicological effects of drugs on Daphnia magna using different enzymatic biomarkers

“…This finding, in conjugation with the lack of effects in terms of catalase activity, suggests that GPx induction may not be related to an increase of hydrogen peroxide levels, and to an increase in oxidative stress. As previously stated, these two enzymes play similar roles in reducing hydrogen peroxide levels, but Sun et al (2014) observed that their transcription processes exhibited opposite patterns when exposed to β-blockers, such as propranolol and metoprolol in zebrafish larvae (Danio rerio).…”

Transcriptional Responses in Adult Zebrafish (Danio rerio) Exposed to Propranolol and Metoprolol

“…Similarly, transcriptional changes in genes involved in the antioxidant response and detoxification process were found. Considering the concentrations of b-blockers found in the aquatic environment, the results of the present study, our previous studies (Sun et al 2014) and those of other researchers (Giltrow et al 2009;Owen et al 2009), these pharmaceuticals seem unlikely to pose a risk to the well-being of fish. However, more specific consequences of adrenoceptor blockade should be assessed before a definitive answer can be given.…”

“…Following a 48-h exposure to propranolol, an LC50 value of 24.3 mg/L was obtained for 3 to 4-day-old Japanese medaka; however, acute exposure to metoprolol did not affect the survival of the fish even at concentrations greater than 100 mg/L (Huggett et al 2002). Our previous work has shown that the 96-h LC50 value for propranolol in zebrafish larvae was 2.48 mg/L, but exposure to 50 mg/L of metoprolol did not increase mortality (Sun et al 2014). Exposure to propranolol ranging from 4 to 32 mg/L also affected the hatching and mortality rate, decreased spontaneous movement and caused morphological abnormalities of the zebrafish embryos (Fraysse et al 2006).…”