Environmental impacts of COVID-19 treatment: Toxicological evaluation of azithromycin and hydroxychloroquine in adult zebrafish

Abstract

One of the most impact issues in recent years refers to the COVID-19 pandemic, the consequences of which thousands of deaths recorded worldwide, are still inferior understood. Its impacts on the environment and aquatic biota constitute a fertile field of investigation. Thus, to predict the impact of the indiscriminate use of azithromycin (AZT) and hydroxychloroquine (HCQ) in this pandemic context, we aim to assess their toxicological risks when isolated or in combination, using zebrafish ( Danio rerio ) as a model system. In summary, we observed that 72 h of exposure to AZT and HCQ (alone or in binary combination, both at 2.5 μg/L) induced the reduction of total protein levels, accompanied by increased levels of thiobarbituric acid reactive substances, hydrogen peroxide, reactive oxygen species and nitrite, suggesting a REDOX imbalance and possible oxidative stress. Molecular docking analysis further supported this data by demonstrating a strong affinity of AZT and HCQ with their potential antioxidant targets (catalase and superoxide dismutase). In the protein-protein interaction network analysis, AZT showed a putative interaction with different cytochrome P450 molecules, while HCQ demonstrated interaction with caspase-3. The functional enrichment analysis also demonstrated diverse biological processes and molecular mechanisms related to the maintenance of REDOX homeostasis. Moreover, we also demonstrated an increase in the AChE activity followed by a reduction in the neuromasts of the head when zebrafish were exposed to the mixture AZT+HCQ. These data suggest a neurotoxic effect of the drugs. Altogether, our study demonstrated that short exposure to AZT, HCQ or their mixture induced physiological alterations in adult zebrafish. These effects can compromise the health of these animals, suggesting that the increase of AZT and HCQ due to COVID-19 pandemic can negatively impact freshwater ecosystems.

Toxicology evaluation of overdose hydroxychloroquine on zebrafish (Danio rerio) embryos

“…6 and Supplementary Table 5 ). A previous study demonstrated enhancement of the oxidative stress processes in zebrafish because of HCQ exposure 13 . We found two genes, namely nfe2 and pxdn, that are involved in the oxidative stress process.…”

Environmental and ecotoxicological effects of drugs used for the treatment of COVID 19

“…Hydroxychloroquine, approved by the Food and Drug Administration (FDA) as an antimalarial drug, was reused to treat COVID-19 patients (da Luz et al, 2021;Mendonça-Gomes et al, 2021). Cell culture experiments have shown solid antiviral action of hydroxychloroquine against a variety of viruses, including HIV-1, dengue, Zika and West Nile viruses, Venezuelan equine encephalitis virus, Chikungunya, pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19) (Gautret et al, 2021;Jans and Wagstaff 2021), in dermatology and rheumatology and emerging roles in oncology (Yusuf et al, 2017).…”

“…The presence of azithromycin and hydroxychloroquine at 12.5 μg/L affects wild aquatic life, such as neotropical tadpoles of Physalaemus cuvieri species. In fishes like Zebrafish (Danio rerio), azithromycin and hydroxychloroquine at 2.5 μg/L induce protein reduction, redox imbalance, and possible oxidative stress (Mendonça-Gomes et al, 2021). In the European Sea, Bass (Dicentrarchus labrax) azithromycin causes oxidative stress, peroxidative damage and neurotoxicity at 20 mg/L, inducing 18% and 7.5% of larvae mortality and morphological abnormalities, respectively (Mhadhbi et al, 2020).…”

“…Pharmaceutical compounds such as hydroxychloroquine have become emerging environmental pollutants due to Frontiers in Environmental Science frontiersin.org humans' massive administration and more remarkable persistence in the environment. Following the massive and widespread use of hydroxychloroquine to treat COVID-19 worldwide (Lagier et al, 2020;Mendonça-Gomes et al, 2021), an appreciable high amount is expected to end up in sewage systems in coastal marine areas (Table 3). It may significantly affect the meiobenthic nematode community, both quantitatively and qualitatively (Ben Ali et al, 2021), thus affecting the diversity of these species and the community structure itself, which affects the functioning of the ecosystem.…”

How toxic is the COVID-19 drug azithromycin in the presence of Posidonia oceanica? Toxicokinetics and experimental approach of meiobenthic nematodes from a metallically pristine area

“…This antibiotic was previously proved to induce both chronic and acute toxic effects on wildlife, including the marine biota ( Shiogiri et al, 2017 ). Indeed, the toxicity of azythromycin was investigated by experiments carried mainly on fish species such as the Chinook salmon Oncorhynchus tshawytscha ( Fairgrieve et al, 2005 ), the tilapia Oreochromis niloticus ( Shiogiri et al, 2017 ), and the zebrafish Danio rerio ( Mendonça-Gomes et al, 2021 ). The results found supported diverse physiological effects and a reduction in total protein levels.…”