Toxic effects of four cardiovascular drugs on the development and epigenetics of zebrafish (Danio rerio).

Due to the prevalence of cardiovascular diseases, therapeutic drugs such as atenolol (ATE), metoprolol (MET), atorvastatin (ATO), and bezafibrate (BZB) have been widely used and thus frequently detected in surface water at ng·L-1-µg·L-1 level. In this study, the developmental toxicity of these drugs (0.5 µg·L-1-500 µg·L-1) to zebrafish, an aquatic model organism, was investigated; and the epigenetic toxicity of BZB was also explored. For all four drugs, the results showed that the drugs exposure could cause sublethal toxic effects on zebrafish larvae, such as decreases in hatching rate, body length, and heart rate. ATO also induced the swelling of the eyes of larvae by 5 %-15 %. Yolk sac edema, pericardial edema, bent spine, and tail malformation were observed in larvae exposed to the drugs, and yolk sac edema was the most common malformation. In addition, the spontaneous movement and free-swimming activity could be inhibited by the drugs. Combined with RNA-seq results, the adverse development of larvae in exposure groups may be caused by the disruption of lipid and carbohydrate metabolism, and the development and function of eye and nervous system. After a 30-day uptake period, the accumulation of BZB and the decrease of global DNA methylation level were observed in the liver, kidneys, gut, gills, and brain of adult zebrafish (4-month-old) exposed to 0.5 µg·L-1 to 500 µg·L-1 BZB. The liver was the main organ for BZB accumulation and the occurrence of DNA hypomethylation. In the liver, overexpression (1.5-7.6 times) of genes related to lipid metabolism (PPARα), DNA methylation (Dnmt1), and apoptosis (p53) was also observed. The results of the current study suggest that long-term exposure to low-concentrations of cardiovascular drugs may pose significant threats to aquatic ecosystems.

Ultraviolet oxidative degradation of typical antidepressants: Pathway, product toxicity, and DFT theoretical calculation.

The ubiquity of antidepressants in the environment has posed a potential threat to eco-systematic safety. In this study, six kinds of antidepressants including fluoxetine (FLU), paroxetine (PAR), sertraline (SER), fluvoxamine (FLX), citalopram (CTP), and venlafaxine (VEN) were selected to explore their degrading kinetics, transformation pathways, and the acute toxicity of the reaction solution during UV oxidation. The results showed that the order of the photodegradation rate was FLU > PAR > SER > CTP > FLX > VEN. The calculation results of density functional theory (DFT) and molecular orbital theory showed that it was positively correlated with the frontier electron density of drugs and negatively correlated with the HOMO-LUMO gap, respectively. Intermediates were identified with UHPLC-Q-TOF/MS/MS to propose the possible degradation pathways of the drugs and the most likely directions of the reactions were determined by the single point energy calculation. The results of toxicity tests indicated that the acute toxicity of the reaction solution of PAR did not change significantly. The photolysates toxicity of FLU, SER, and FLX decreased at the end of the reaction, while that of CTP and VEN was increased by 1.5 and 1.3 times compared with the parent compound, respectively. Toxicity predictions by the quantitative structure activity relationship (QSAR) model showed that except FLU-162, FLX-174, and VEN-230, other degradation products have developmental toxicity. The results revealed the transformation pathways of these drugs under the UV disinfection process in wastewater treatment plants, especially the formation of toxic by-products during the disinfection process.

Analysis of degradation and pathways of three common antihistamine drugs by NaClO, UV, and UV-NaClO methods.

Antihistamines (ANTs) are medicines to treat allergic diseases. They have been frequently detected in the natural water environment, posing potential threats to the ecological environment and human health. In this study, the degradation of three common antihistamines, loratadine, fexofenadine, and cetirizine, was estimated under different oxidation methods (NaClO, UV, and UV-NaClO). The results showed that UV-NaClO had the highest degree of degradation on the drugs under most conditions: 100% degradation for fexofenadine within 20 s at pH 7 and 10. Under UV irradiation, the degradation efficiencies of the three drugs during 150 s were all above 77% at a pH of 7. The drugs' removal by NaClO was much lower than that of the previous two methods. In addition, this study explored the contribution rates of active oxygen species in the photolysis process. Among them, the contribution of 1O2 to the fexofenadine and cetirizine removal rate reached 70%. Different aqueous matrices (HCO3-, NO3-, and humic acid) had varying degrees of influence on the degradation. Acute toxicity tests and ultraviolet scans of the degradation products showed that the drugs were not completely mineralized, and the toxicities of the intermediates were even higher than those of the parent drugs. There were 9, 8, and 10 chloride oxidation products of loratadine, fexofenadine, and cetirizine, respectively, and 8 photolysis products of cetirizine were identified. For cetirizine, it was found that there were three identical intermediates produced by photodegradation and NaClO oxidation.

Toxicological effects of atenolol and venlafaxine on zebrafish tissues: Bioaccumulation, DNA hypomethylation, and molecular mechanism.

The beta-blocker atenolol (ATE), and the selective serotonin and norepinephrine reuptake inhibitor, venlafaxine (VEN) are frequently detected in municipal wastewater effluents, but little is known about their ecotoxicological effect on aquatic animals. Herein, ATE and VEN were selected to explore their accumulation and global DNA methylation (GDM) in zebrafish tissues after a 30-day exposure. Molecular dynamics (MD) stimulation was used to investigate the toxic mechanism of ATE and VEN exposure. The results demonstrated that ATE and VEN could reduce the condition factor of zebrafish. The bioaccumulation capacity for ATE and VEN was in the order of liver > gut > gill > brain and liver > gut > brain > gill, respectively. After a 30-day recovery, ATE and VEN could still be detected in zebrafish tissues when exposure concentrations were ≥10 µg/L. Moreover, ATE and VEN induced global DNA hypomethylation in different tissues with a dose-dependent manner and their main target tissues were liver and brain. When the exposure concentrations of ATE and VEN were increased to 100 µg/L, the global DNA hypomethylation of liver and brain were reduced to 27% and 18%, respectively. In the same tissue exposed to the same concentration, DNA hypomethylation induced by VEN was more serious than that of ATE. After a 30-day recovery, the global DNA hypomethylations caused by the two drugs were still persistent, and the recovery of VEN was slower than that of ATE. The MD simulation results showed that both ATE and VEN could reduce the catalytic activity of DNA Methyltransferase 1 (DNMT1), while the effect of VEN on the 3D conformational changes of the DNMT1 domain was more significant, resulting in a lower DNA methylation rate. The current study shed new light on the toxic mechanism and potential adverse impacts of ATE and VEN on zebrafish, providing essential information to the further ecotoxicological risk assessment of these drugs in the aquatic environment.

Ultraviolet photolysis of four typical cardiovascular drugs: mechanisms, influencing factors, degradation pathways, and toxicity trends.

The cardiovascular drugs (CDDs), such as metoprolol (MET), atenolol (ATE), bezafibrate (BZB), and atorvastatin (ATO), have been frequently detected in the water environment. They can cause potential threats to the ecological environment and human health due to their "pseudo-persistence" effect. In this study, the photolysis kinetics, degradation mechanisms, by-products, influencing factors, and acute toxicity of these four typical CDDs under polychromatic ultraviolet irradiation (200-400 nm) were investigated. The results showed that the photolysis of ATE, BZB, MET, and ATO all followed pseudo-first-order kinetics, and their average photon quantum yields of the wavelength studied were 0.14×10-2, 0.33×10-3, 0.78×10-4, and 0.24×10-4 mol einstein-1, respectively. Singlet oxygen (1O2), hydroxyl radical (·OH), and the triplet-excited state of the cardiovascular drug (3CDD*) were all involved in the photolysis while 1O2 was the dominator. The effects of NO3-, Cl-, HCO3-, and humic acid (HA) on the photolysis were the combination of light-shielding, quenching, and excitation of reactive species. Seven, four, four, and nine photolysis products of ATO, BZB, ATE, and MET were identified, respectively, and their possible degradation pathways were proposed. The acute toxicity of ATE was basically unchanged during photolysis; however, ATO, BZB, and MET toxicity all increased due to the generation of ketonization and hydroxylation products.

Evaluating the stability of prescription drugs in municipal wastewater and sewers based on wastewater-based epidemiology.

Wastewater-based epidemiology (WBE) is considered as an effective tool for monitoring drug consumption, which is often obtained by back-calculation using the influent concentration and other parameters of wastewater treatment plants. Lack of information on the transformation of drugs in municipal wastewater and sewers may lead to inaccurate consumption estimation. Fourteen prescription drugs in four major categories of diseases (cardiovascular, diabetes, depression, and asthma) were selected to study their adsorption and biodegradation in wastewater and biofilm sewers under different temperatures, pH and biofilms conditions. The result demonstrated that the decay percentage of drugs in wastewater is increased with temperature. Within 72 h, eleven of these 14 drugs, such as metformin, metoprolol, bezafibrate, etc., have decay percentages below 20% in wastewater, which are considered as stable drugs; and the decay percentages of the other three, monluster, paroxetine, and sertraline, are greater than 20%, which are the most unstable drugs. In lab-scale aerobic and anaerobic sewers, the decay percentages of metformin, glipizide, metoprolol, gemfibrozil, and atorvastatin are less than 20% within 24 h. The decay percentages of venlafaxine, citalopram, fluoxetine, salmeterol, and salbutamol within 24 h are 20%-60% and paroxetine and sertraline are close to or even exceed 80% within 6 h. Biodegradation of drugs in sewers with aerobic or anaerobic biofilms is higher than that in wastewater systems without biofilms. The results showed that when the per capita consumption of drugs is estimated by using the WBE method, the stability of drugs in wastewater and different types of sewers will significantly affect their residual concentrations.

Metformin-Induced Epigenetic Toxicity in Zebrafish: Experimental and Molecular Dynamics Simulation Studies.

The increased detection of many prescription drugs in aquatic environments has heightened concerns of their potential ecotoxicological effects. In this study, the effects of metformin (MEF) exposure on tissue accumulation, gene expression, and global DNA methylation (GDM) in zebrafish were investigated. The toxic mechanism of MEF exposure was simulated by molecular dynamics (MD) to reveal any conformational changes to DNA methyltransferase 1 (DNMT1). The results showed MEF accumulation in the gills, gut, and liver of zebrafish after 30 days of exposure, and the bioaccumulation capacity was in the order of gut > liver > gills. After a 30 day recovery period, MEF could still be detected in zebrafish tissues in groups exposed to MEF concentrations ≥ 10 µg/L. Moreover, the liver was the main site of GDM, and the restoration of GDM in the liver was slower than that in the gut and gills during the recovery period. Furthermore, MEF could induce the abnormal expression of CYP3A65, GSTM1, p53, and DNMT1 genes in the liver due to the formation of hydrogen bonds between MEF and the protein residues of those genes. The MD simulation allowed for the mechanistic determination of MEF-induced three-dimensional (3D) conformational changes and changes to the catalytic activity of DNMT1.