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Soil contamination by antibiotics is a global issue of great concern that contributes to the rise of bacterial antibiotic resistance and can have toxic effects on non-target organisms. This study evaluated the variations of molecular, cellular, and histological parameters in Eisenia fetida earthworms exposed to sulfamethazine (SMZ) and tetracycline (TC), two antibiotics commonly found in agricultural soils. The earthworms were exposed for 14 days to a series of concentrations (0, 10, 100, and 1000 mg/kg) of both antibiotics. SMZ and TC did not affect the survival of E. fetida, however, other effects at different levels of biological complexity were detected. The two highest concentrations of SMZ reduced the viability of coelomocytes. At the highest TC concentration, there was a noticeable decline in cell viability, acetylcholinesterase activity (neurotoxicity), and the relative presence of mucopolysaccharides in the epidermis (mucous production). Glutathione S-transferase activity decreased in all TC treatments and at the highest SMZ concentration. However, levels of malondialdehyde and protein carbonyls did not change, suggesting an absence of oxidative stress. Tetracycline was neurotoxic to E. fetida and changed the integrity of the epidermis. Both antibiotics altered the intestinal microbiota of E. fetida, leading to a reduction in the relative abundance of bacteria from the phyla Proteobacteria and Bacteroidetes, while causing an increase in the phylum Actinobacteroidota. All observed changes indicate that both SMZ and TC can disrupt the earthworms' immune system and gut microbiome, while fostering the growth of bacteria that harbour antibiotic resistance genes. Finally, both antibiotics exerted additional metabolic and physiological effects that increased the vulnerability of E. fetida to pathogens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Microplastics and antibiotics coexist in aquatic environments, especially in freshwater aquaculture areas. However, as the second largest production of polyvinyl chloride (PVC) in the world, the effects of co-exposure to microplastics particles and antibiotics on changes in antibiotic resistance gene (ARG) profiles and the microbial community structure of aquatic organism gut microorganisms are poorly understood. Therefore, in this study, carp (Cyprinus carpio) were exposed to single or combined PVC microplastic contamination and oxytetracycline (OTC) or sulfamethazine (SMZ) for 8 weeks. PVC microplastics can enrich potential pathogenic bacteria, such as Enterobacter and Acinetobacter, among intestinal microorganisms. The presence of PVC microplastics enhanced the selective enrichment and dissemination risk of ARGs. PVC microplastics combined with OTC (OPVC) treatment significantly increased the abundance of tetracycline resistance genes (1.40-fold) compared with that in the OTC exposure treatment, revealing an obvious co-selection effect. However, compared with those in the control group, the total abundance of ARGs and MGEs in the OPVC treatment groups were significantly lower, which was correlated with the reduced abundances of the potential host Enterobacter. Overall, our results emphasized the diffusion and spread of ARGs are more influenced by PVC microplastics than by antibiotics, which may lead to antibiotic resistance in aquaculture., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Antibiotics are ubiquitously present in aquatic environments, posing a serious ecological risk to aquatic ecosystems. However, the effects of antibiotics on the photosynthetic light reactions of freshwater algae and the underlying mechanisms are relatively less understood. In this study, the effects of 4 representative antibiotics (clarithromycin, enrofloxacin, tetracycline, and sulfamethazine) on a freshwater alga (Chlorella pyrenoidosa) and the associated mechanisms, primarily focusing on key regulators of the photosynthetic light reactions, were evaluated. Algae were exposed to different concentrations of clarithromycin (0.0-0.3 mg/L), enrofloxacin (0.0-30.0 mg/L), tetracycline (0.0-10.0 mg/L), and sulfamethazine (0.0-50.0 mg/L) for 7 days. The results showed that the 4 antibiotics inhibited the growth, the photosynthetic pigment contents, and the activity of antioxidant enzymes. In addition, exposure to clarithromycin caused a 118.4 % increase in malondialdehyde (MDA) levels at 0.3 mg/L. Furthermore, the transcripts of genes for the adenosine triphosphate (ATP) - dependent chloroplast proteases (ftsH and clpP), genes in photosystem II (psbA, psbB, and psbC), genes related to ATP synthase (atpA, atpB, and atpH), and petA (related to cytochrome b6/f complex) were altered by clarithromycin. This study contributes to a better understanding of the risk of antibiotics on primary producers in aquatic environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nanoplastics can interact with antibiotics, altering their bioavailability and the ensuing toxicity in marine organisms. It is reported that plain polystyrene (PS) nanoplastics decrease the bioavailability and adverse effects of sulfamethazine (SMZ) on the gut microbiota in Oryzias melastigma. However, the influence of surface functional groups on the combined effects with SMZ remains largely unknown. In this study, adult O. melastigma were fed diet amended with 4.62 mg/g SMZ and 3.65 mg/g nanoplastics (i.e., plain PS, PS-COOH and PS-NH 2 ) for 30 days (F0-E), followed by a depuration period of 21 days (F0-D). In addition, the eggs produced on the last day of exposure were cultured under standard protocols without further exposure for 2 months (F1 fish). The results showed that the alpha diversity or the bacterial community of gut microbiota did not differ among the SMZ + PS, SMZ + PS-COOH, and SMZ + PS-NH 2 groups in the F0-E and F1 fish. Interestingly, during the depuration, a clear recovery of gut microbiota (e.g., increases in the alpha diversity, beneficial bacteria abundances and network complexity) was found in the SMZ + PS group, but not for the SMZ + PS-COOH and SMZ + PS-NH 2 groups, indicating that PS-COOH and PS-NH 2 could prolong the toxic effect of SMZ and hinder the recovery of gut microbiota. Compared to plain PS, lower egestion rates of PS-COOH and PS-NH 2 were observed in O. melastigma. In addition, under the simulated fish digest conditions, the SMZ-loaded PS-NH 2 was found to desorb more SMZ than the loaded PS and PS-COOH. These results suggested that the surface -COOH and -NH 2 groups on PS could influence their egestion efficiency and the adsorption/desorption behavior with SMZ, resulting in a long-lasting SMZ stress in the gut during the depuration phase. Our findings highlight the complexity of the carrier effect and ecological risk of surface-charged nanoplastics and the interactions between nanoplastics and antibiotics in natural environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The persistence of antibiotics and nanoplastics in aquatic environment poses a great threat to aquatic organisms. In our previous study, significant decreases of bacterial richness and changes of bacterial communities in the Oryzias melastigma gut after sulfamethazine (SMZ) and polystyrene nanoplastics (PS) exposure were observed. Here, the O. melastigma dietary exposed to SMZ (0.5 mg/g, LSMZ; 5 mg/g, HSMZ), PS (5 mg/g, PS) or PS + HSMZ were depurated for 21 days to assess the extent of which these effects were reversible. Our results revealed that most diversity indexes of bacterial microbiota in the O. melastigma gut from the treatment groups were insignificantly different from the control, suggesting a large recovery of bacterial richness. Although the sequence abundances of a few genera remained significantly changed, the proportion of dominant genus was recovered. Exposure to SMZ affected the complexity of the bacterial networks, and the cooperation and exchange events of positively associated bacteria were enhanced during this period. After depuration, increases in the complexity of networks and intense competitions among bacteria were observed, which was beneficial for the robustness of networks. However, the gut bacterial microbiota was less stable, and several functional pathways were dysregulated, relative to the control. In addition, higher occurrence of pathogenic bacteria was found in the PS + HSMZ group relative to the signal pollutant group after depuration, indicating a greater hazard for the mixture of PS and SMZ. Taken together, this study contributes to a better understanding of the recovery of bacterial microbiota in fish gut after individual and combined exposure to nanoplastics and antibiotics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The combined pollution of antibiotics adsorption by microplastics has become inevitable in soil ecosystems; moreover, the plant biological effects under combined stress remain unclear. This study used soybean variety Jindou 21 as the material and conducted seed germination test and soil-potted seedling experiment to study the effects of different single and combined treatments of polyethylene (PE) and sulfamethazine (SMZ) on seed germination, seedling growth, photosynthetic parameters, chlorophyll fluorescence parameters, and nitrogen metabolism. The results showed that single PE treatment at low levels promoted soybean seed germination and seedling growth physiology; however, inhibited them at a high level. A lower-level PE treatment[10 mg·L -1 (or mg·kg -1 )] could promote soybean seed germination, seedling growth, photosynthesis, and nitrogen metabolism, whereas a higher level PE treatment[100 mg·L -1 and 200 mg·L -1 (or mg·kg -1 )] had significant inhibition. The single SMZ treatment had different degrees of inhibition on soybean seed germination and seedling growth physiology, and the inhibition degree increased with the increase in SMZ treatment level. Under the different levels of combined treatments of PE and SMZ, adding the lower level PE treatment could alleviate the inhibition of the single SMZ treatment on soybean, with 10 mg·L -1 (or mg·kg -1 ) PE+1 mg·L -1 (or mg·kg -1 ) SMZ treatment having the best comprehensive mitigation effect, which could increase soybean seed germination potential, germination rate, germination index, vigor index, plant height, root length, shoot and root fresh weight, P n , G s , T r , chlorophyll contents, F v / F m , Φ PSⅡ , ETR, qP, and key enzyme activities for nitrogen metabolism such as NR and decrease the average germination time, C i , NPQ, and NO 3 - -N and NH 4 + -N contents compared with those in the single SMZ treatment. Adding the higher level PE treatment enhanced the inhibition of SMZ on soybean, and the inhibition degree increased with the increase in SMZ treatment level, in which 200 mg·L -1 (or mg·kg -1 ) PE+50 mg·L -1 (or mg·kg -1 ) SMZ treatment yielded the greatest inhibition. In summary, the lower level PE treatment could alleviate the inhibition of SMZ on soybean seeds and seedlings to a certain extent; however, the higher level PE treatment could produce a synergistic effect with SMZ, thus aggravating the toxic effect of the single stress treatment.

The emerging contaminants removal from the environment has recently been raised concerns due to their presence in higher concentrations. Over usage of emerging contaminant such as sulfamethazine poses serious threat to the aquatic and human health as well. This study deals with rationally structured a novel BiOCl (110)/NrGO/BiVO 4 heterojunction which is used to detoxify sulfamethazine (SMZ) antibiotic efficiently. The synthesised composite was well characterized and the morphological analysis evidenced the formation of heterojunction consisted of nanoplates BiOCl with dominant exposed (110) facets and leaf like BiVO 4 on NrGO layers. Further results revealed that the addition of BiVO 4 and NrGO tremendously increased the photocatalytic degradation efficiency of BiOCl with the rate of 96.9% (k = 0.01783 min -1 ) towards SMZ within 60 min of visible light irradiation. Furthermore, heterojunction energy-band theory was employed to determine the degradation mechanism of SMX in this study. The larger surface area of BiOCl and NrGO layers are believed to be the reason for higher activity which facilitates the excellent charge transfer and improved light absorption. In addition, SMZ degradation products identification was carried out by LC-ESI/MS/MS to determine the pathway of degradation. The toxicity assessment was studied using E. coli as a model microorganism through colony forming unit assay (CFU), and the results indicated a significant reduction in biotoxicity was observed in 60 min of degradation process. Thus, our work gives new methods in developing various materials that effectively treat emerging contaminants from the aqueous environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pesticides and antibiotics are frequently present in aquatic environment which may pose potential risks to aquatic organisms. However, the interaction of pesticides and antibiotics in co-exposure model remains unclear. Here, the effects of the co-exposure of sulfamethazine (SMZ) on the toxicity and bioaccumulation of the organophosphorus insecticide chlorpyrifos (CPF) in zebrafish (Danio rerio) were explored. The 96-h LC 50 of chlorpyrifos to zebrafish was 1.36 mg/L and sulfamethazine at 1 mg/L slightly increased the acute toxicity with the 96-h LC 50 of 1.20 mg/L which was not significant. The 30-day co-exposure of chlorpyrifos with sulfamethazine at 1 mg/L aggravated the oxidative stress, decreased CarE and AChE activity, and increased CYP450 activity significantly. Furthermore, the co-exposure reduced the accumulation of chlorpyrifos and sulfamethazine while prolonged their depuration duration. The results demonstrated the exposure risk of chlorpyrifos to zebrafish may be enhanced in the presence of sulfamethazine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Peracetic acid (PAA) as an emerging oxidative has been concerned increasingly due to its high oxidation capacity and low byproducts formation potential. This study was to investigate the oxidation of sulfamethazine (SMZ) by PAA activated with activated biochar (ABC) after thermal modification. The results demonstrated that PAA could be effectively activated by ABC to degrade SMZ in a wide pH range (3-9), which followed the pseudo-second-order kinetics (R 2  > 0.99). Both non-radicals (singlet oxygen) and free radicals (alkoxy radicals, hydroxyl radicals) existed in the ABC/PAA system, and the degradation of SMZ was dominated by singlet oxygen. Humic acid (HA), SO 4 2- and HCO 3 - slightly inhibited the degradation of SMZ in the ABC/PAA process, while Cl - and Br - promoted the degradation of SMZ. The cleavage of S-N, S-C bond, and SO 2 extraction reaction rearrangement was the main oxidation process of SMZ. Meanwhile, the results of the ECOSAR program showed that the acute toxicity of most by-products was significantly reduced compared to SMZ, which revealed the potential applicability of the ABC/PAA process in the treatment of antibiotics pollution and their detoxification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Antibiotic residue has become an emerging environmental contaminant, while the toxicological effects and underlying mechanisms caused by the co-exposure to multiple veterinary antibiotics were rarely studied. In this study, male Sprague Dawley rats were exposed to monensin (M) (1, 2, 10 mg/(kg·body weight (BW)) combined with sulfamethazine (S) (60, 120, 600 mg/(kg·BW)) or single drugs for 28 consecutive days. The body weight, hematological and blood biochemical parameters, organ coefficients, and histopathology were analyzed to discover their combined toxicity effect. Transcriptomic analysis was used to reveal the possible mechanisms of their joint toxicity. Compared with the control group, the weight gain rate was significantly reduced in the H-M+S and H-S, and alkaline phosphatase in H-M+S was significantly increased. Furthermore, relative liver and kidneys weight was significantly increased, and the liver of H-M+S showed more severe lesions in histopathological analysis. For H-M+S, H-M and H-S, transcriptomic results showed that 344, 246, and 99 genes were differentially expressed, respectively. The Gene Ontology terms mainly differ in sterol biosynthetic process and steroid hydroxylase activity. The Kyoto Encyclopedia of Genes and Genome pathways showed abnormal retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism-cytochrome 450; the common 30 genes were screened from the network of protein-protein interaction. The results showed that mixed contamination of M and S produces hepatotoxicity by interfering with linoleic acid metabolism, retinol metabolism and CYP450 enzyme-dominated drug metabolism. Further analysis showed that Cyp1a2, Cyp2c61, Ugt1a3, and Ugt1a5 might be the key genes. These findings could provide more evidence for investigating the toxic effects and metabolism of mixed antibiotics contamination in mammals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The individual and combined toxicity of antibiotics and nanoplastics in marine organisms has received increasing attention. However, many studies have been mostly focused on the impacts on the directly exposed generation (F0). In this study, intergenerational effects of sulfamethazine (SMZ) and nanoplastic fragments (polystyrene, PS) on the growth and the gut microbiota of marine medaka (Oryzias melastigma) were investigated. The results showed that parental exposure to dietary SMZ (4.62 mg/g) alone and PS (3.45 mg/g) alone for 30 days decreased the body weight (by 13.41% and 34.33%, respectively) and altered the composition of gut microbiota in F1 males (two months after hatching). Interestingly, parental exposure to the mixture of SMZ and PS caused a more modest decrease in the body weight of F1 males than the PS alone (15.60% vs 34.33%). The hepatic igf1 level and the relative abundance of the host energy metabolism related phylum Bacteroidetes for the SMZ + PS group were significantly higher than those for the PS group (igf1, increased by 97.1%; Bacteroidetes, 2.876% vs 0.375%), suggesting that the parentally derived mixture of SMZ and PS might influence the first microbial colonization of gut in a different way to the PS alone. This study contributes to a better understanding of the long-term risk of antibiotics and nanoplastics to marine organisms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The UV/chlorination of three prescription drugs, sulfamethazine (SMZ), gemfibrozil (GEM) and antipyrine (ANT) were studied by the investigation of kinetics, transformation products and combined toxicological assessment. The degradation followed pseudo-first-order kinetics, with half-lives significantly affected by chlorine dosage, without being greatly influenced by pH value and bromide concentration. Based on the Frontier Orbital Theory, the structures of products by hydroxylation or chlorine substitution were proposed and the transformation pathways were introduced, with two, two and one never-before-reported products identified for SMZ, GEM and ANT, respectively. Compared to the results of the experiments with artificial water sample, the degradation kinetics of the three prescription drugs was observed with a prolonged half-lives in both Yangtze River and Taihu Lake water, suggesting that aromatic containing transformation products (TPs) may also exist in UV/chlorine treated natural waters. The results of combined toxicity on E. coli showed that the antagonism effect predominated in most binary and ternary combinations. However, the synergistic toxicity of combinations at low concentrations of prescription drugs subjected to UV/chlorine should be cautioned, which was more close to the natural concentration of prescription drugs in waters.

Antibiotics and nanoplastics are two prevalent pollutants in oceans, posing a great threat to marine ecosystems. As antibiotics and nanoplastics are highly bioconcentrated in lower trophic levels, evaluating their impacts on marine organisms via dietary exposure route is of great importance. In this study, the individual and joint effects of dietborne sulfamethazine (SMZ) and nanoplastic fragments (polystyrene, PS) in marine medaka (Oryzias melastigma) were investigated. After 30 days of dietary exposure, 4.62 mg/g SMZ decreased the Chao1 index (60.86% for females and 26.85% for males) and the Shannon index (68.95% for females and 65.05% for males) and significantly altered the structure of gut microbial communities in both sexes. The female fish exposed to 4.62 mg/g SMZ exhibited higher intestinal sod (43.5%), cat (38.5%) and gpx (39.6%) transcripts, indicating oxidative stress in the gut. PS alone at 3.45 mg/g slightly altered the composition of the gut microbiota. Interestingly, the mixture of SMZ and PS caused more modest effects on the gut microbiota and intestinal antioxidant physiology than the SMZ alone, suggesting that the presence of PS might alleviate the intestinal toxicity of SMZ in a scenario of dietary co-exposure. This study helps better understand the risk of antibiotics and nanoplastics to marine ecosystems., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Microplastics were reported to adsorb antibiotics and may modify their effects on soil systems. But there has been little research investigating how microplastics may affect the toxicities of antibiotics to microbes under future climate conditions. Here, we used a free-air CO 2 enrichment system to investigate the responses of soil microbes to sulfamethazine (SMZ, 1 mg kg -1 ) in the presence of polystyrene microplastics (PS, 5 mg kg -1 ) at different CO 2 concentrations (ambient at 380 ppm and elevated at 580 ppm). SMZ alone decreased bacterial diversity, negatively affected the bacterial structure and inter-relationships, and enriched the sulfonamide-resistance genes (sul1 and sul2) and class 1 integron (intl1). PS, at both CO 2 conditions, showed little effect on soil bacteria but markedly alleviated SMZ's adverse effects on bacterial diversity, composition and structure, and inhibited sul1 transmission by decreasing the intl1 abundance. Elevated CO 2 had limited modification in SMZ's disadvantages to microbial communities but markedly decreased the sul1 and sul2 abundance. Results indicated that increasing CO 2 concentration or the presence of PS affected the responses of soil microbes to SMZ, providing new insights into the risk prediction of antibiotics under future climate conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The present study investigated the biochemical toxicity and potential detoxification mechanisms in earthworms Eisenia fetida exposed to sulfamethazine (SMZ) (7.5, 15 and 30 mg kg -1 ) either alone or in combination with Copper (Cu) (100 mg kg -1 ) in soil. The results showed that increasing concentrations of SMZ in soil activated superoxide dismutase, catalase and glutathione peroxidase isozymes, suggesting reactive oxygen species (ROS) burst in earthworms. Treatment with SMZ and Cu separately or in combination caused protein oxidation and damage, elevating the synthesis of ubiquitin, the 20S proteasome, cytochrome P450 (CYP450), and heat shock protein 70 (HSP70). Such treatments also induced the activities of proteases, endoproteinase (EP) and glutathione S-transferases (GSTs). The results suggested that the ubiquitin-20S proteasome, proteases, EP and HSP70 were involved in degradation or remediation of oxidatively damaged proteins. Elevated levels of CYP450 and GSTs also participated in the detoxification of the earthworms.

A novel superhydrophobic gas diffusion electrode based on carbon black (CB)- polytetrafluoroethylene (PTFE) modified graphite felt cathode was prepared to increase oxygen mass transfer efficiency and produce hydrogen peroxide at the gas-liquid-solid three-phase interface without aeration. The gas diffusion electrode system was further tested for the degradation of sulfamethazine (SMT) by electro-Fenton (EF) and photoelectro-Fenton (PEF). In the EF process, SMT was removed effectively, but the mineralization degree was not high due to the generation of organic acids which were difficult to be further degraded. While in the PEF process, organic contaminant can be destroyed by the combined action of Fe 2+ /H 2 O 2 , UV/H 2 O 2 and UV radiation, and more efficient mineralization (>83.5%) at low current (50 mA) was attained, which might be attributed to the high H 2 O 2 utilization (70-90%), rapid regeneration of Fe 2+ and photolysis of intermediates. In addition, it was verified that the PEF system had a good adaptability to pH and pollutant concentration. Compared with aeration system, the use of this active gas diffusion cathode in electrochemical advanced oxidation processes significantly reduced energy consumption., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The widespread contamination of antibiotics and heavy metals results in imbalance in the ecosystem. However, the effect of the interaction between sulfamethazine (SM2) and copper (Cu) on soil enzymatic activities is unclear. Therefore, this study investigated the effect of single and combined artificial contamination of SM2 and Cu (0, 1.6 mmol kg -1 Cu and 0, 0.05, 0.2, 0.8 mmol kg -1 SM2) on soil enzymatic activities (urease, sucrose, phosphatase, and RubisCO). A single application of Cu at a concentration of 1.6 mmol kg -1 inhibited the urease, phosphatase and sucrase activities, while a stimulating effect on RubisCO activity was observed on day 7, 21, and 28 of incubation. The individual application of SM2 at higher concentration exhibited significant inhibition of sucrase, phosphatase, and urease activities while a stimulatory effect on RubisCO activity was observed on day 14 and 21 of incubation. The combined contamination of SM2 and Cu significantly inhibited the activities of urease, sucrase, and phosphatase. The effect of combined contamination of SM2 and Cu on the activity of RubisCO was different. The analysis results of interaction types show that there are synergistic or antagonistic effects between Cu and SM2, and these effects can amplify or reduce the effect of Cu or SM2 on soil enzyme activities. Integrated biological responses version 2 (IBRv2) analysis showed that the combined contamination of Cu and SM2 had a greater inhibitory or stimulatory effect on soil enzyme activities than the single contamination of Cu and SM2, depending upon dose and time., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sulfamethazine (SMZ), a kind of sulfonamide antibiotics, can exist for a long periods of time and has been widely detected in the environment, which could pose a potential health threat to human beings. In this study, sludge-derived carbon (SC) catalyst was modified and applied to degrade SMZ during catalytic oxidation process. Degradation products and possible transformation pathways were investigated based on data of GC-MS. The toxicity evolution of SMZ degradation after catalytic oxidation process was tested with zebrafish and microbial degradation respirometer. As a consequence, SC modified with nitric acid (SCHNO 3 ) exhibited highly catalytic efficiency reached 92.2% SMZ conversion and 75.2% total organic carbon (TOC) removal rate after 480 min. Ten kinds of possible products were identified by GC-MS during degradation process of SMZ, indicating two possible pathways. No pronounced malformation was observed in the toxicity experiments with zebrafish until 120 h post fertilization (hpf). However, further analysis showed that zebrafish incubated with SMZ solution had higher mortality, lower hatching rate, slower spontaneous movement and shorter body length, compared with the group used normal nutrient solution, while the water after treatment had lower toxicity effects on zebrafish. The toxicity experiments with microbial degradation respirometer showed that SMZ solution had lower value of oxygen uptake, which indicated that SMZ solution had higher values of toxicity and inhibition of pharmaceutical compounds. This study provides a catalyst with low cost and high catalytic efficiency for degradation process of SMZ and gives a deeper insight into the ecotoxicity of treated water., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study investigated the environmental effects of two common emerging contaminants, sulfamethazine (SMZ) and sulfamethoxazole (SMX), and their mixture using a green microalga, Scenedesmus obliquus. The calculated EC 50 values of SMZ, SMX, and their mixture (11:1 wt/wt) after 96 h were 1.23, 0.12, and 0.89 mg L -1 , respectively. The toxicity of the mixture could be better predicted using a concentration addition model than an independent action model. The risk quotients of SMZ, SMX, and their mixture were >1 during the experiment, indicating their high potential risks on aquatic microorganisms. Despite their toxicity, S. obliquus exhibited 17.3% and 29.3% removal of 0.1 mg L -1 and 0.2 mg L -1 after 11 days of cultivation. The changes of SMZ and SMX removal were observed when combined, which showed a significantly improved removal of SMZ (up to 3.4 folds) with addition of SMX (0.2 mg L -1 ). The metabolic pathways of SMZ and SMX were proposed according to mass spectroscopic analysis, which showed six metabolites of SMX and seven intermediates of SMZ, formed as a result of ring cleavage, hydroxylation, methylation, nitrosation, and deamination., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A comprehensive ecotoxicological evaluation of a sulfamethazine (SMZ) and sulfamethoxazole (SMX) mixture was conducted using an indicator microalga, Scenedesmus obliquus. The toxicological effects of this mixture were studied using microalgal growth patterns, biochemical characteristics (total chlorophyll, carotenoid, carbohydrate, fatty acid methyl ester), and elemental and Fourier-transform infrared spectroscopy analyses. The 96-h half maximal effective concentration (EC 50 ) of the SMZ and SMX mixture was calculated to be 0.15 mg L -1 according to the dose-response curves obtained. The chlorophyll content decreased with elevated SMZ and SMX concentrations, while the carotenoid content initially increased and then decreased as concentration raised. The unsaturated fatty acid methyl esters (FAMEs) content was enhanced with higher SMZ and SMX concentrations, while that of saturated FAMEs simultaneously decreased due to SMZ and SMX stress. Elemental analyses showed an improved percentage of nitrogen and sulfur in the microalgal biomass as SMZ and SMX concentrations increased. The microalga S. obliquus was shown to biodegrade the chemicals tested and removed 31.4-62.3% of the 0.025-0.25 mg SMZ L -1 and 27.7-46.8% of the 0.025-0.25 mg SMX L -1 in the mixture after 12 days of cultivation. The greater biodegradation observed at higher SMZ and SMX concentrations indicates that microalgal degradation of SMZ and SMX could act as an efficient adaptive mechanism to antibiotics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The impact of commonly-used livestock antibiotics on soil nitrogen transformations under varying redox conditions is largely unknown. Soil column incubations were conducted using three livestock antibiotics (monensin, lincomycin and sulfamethazine) to better understand the fate of the antibiotics, their effect on nitrogen transformation, and their impact on soil microbial communities under aerobic, anoxic, and denitrifying conditions. While monensin was not recovered in the effluent, lincomycin and sulfamethazine concentrations decreased slightly during transport through the columns. Sorption, and to a limited extent degradation, are likely to be the primary processes leading to antibiotic attenuation during leaching. Antibiotics also affected microbial respiration and clearly impacted nitrogen transformation. The occurrence of the three antibiotics as a mixture, as well as the occurrence of lincomycin alone affected, by inhibiting any nitrite reduction, the denitrification process. Discontinuing antibiotics additions restored microbial denitrification. Metagenomic analysis indicated that Proteobacteria, Bacteroidetes, Actinobacteria, and Chloroflexi were the predominant phyla observed throughout the study. Results suggested that episodic occurrence of antibiotics led to a temporal change in microbial community composition in the upper portion of the columns while only transient changes occurred in the lower portion. Thus, the occurrence of high concentrations of veterinary antibiotic residues could impact nitrogen cycling in soils receiving wastewater runoff or manure applications with potential longer-term microbial community changes possible at higher antibiotic concentrations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Various disinfection byproducts (DBPs) form during the process of chlorination disinfection, posing potential threats to drinking water safety and human health. Sulfamethazine (SMT), the most commonly used and frequently detected veterinary antibiotic, was investigated in detail with regard to its transformation and kinetics in reactions with free available chlorine (FAC). Using liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry, several DBPs were identified based on different confidence levels, and a variety of reaction types, including desulfonation, S-N cleavage, hydroxylation, and chlorine substitution, were proposed. The kinetic experiments indicated that the reaction rate was FAC- and pH-dependent, and SMT exhibits low reactivity toward FAC in alkaline conditions. The DBPs exhibited a much higher acute toxicity than SMT, as estimated by quantitative structure activity relationship models. More importantly, we observed that the FAC-treated SMT reaction solution might increase the genotoxic potential due to the generation of DBPs. This investigation provides substantial new details related to the transformation of SMT in the chlorination disinfection process., (Copyright © 2018. Published by Elsevier B.V.)

Effects of antibiotics on the transformation of nitrate and the associated N 2 O release in paddy fields are obscure. Using soil slurry experiments combined with 15 N tracer techniques, the influence of tetracycline and sulfamethazine (applied alone and in combination) on the denitrification, anaerobic ammonium oxidation (anammox), dissimilatory nitrate reduction to ammonium (DNRA) and N 2 O release rates in the paddy soil were investigated, while genes related to nitrate reduction and antibiotic resistance were quantified to explore the microbial mechanisms behind the antibiotics' effects. The potential rates of denitrification, anammox, and DNRA were significantly (p < 0.05) reduced, which were mainly attributed to the inhibitory effects of the antibiotics on nitrate-reducing microbes. However, the N 2 O release rates were significantly (p < 0.05) stimulated by the antibiotic treatments (0.6-6000 μg kg -1 soil dry weight), which were caused by the different inhibition effects of antibiotics on N 2 O production and N 2 O reduction as suggest by the changes in abundance of nirS (nitrite reduction step) and nosZ (N 2 O reduction to N 2 step) genes. Antibiotic resistance gene (tetA, tetG, sulI, and sulIII) abundances were significantly (p < 0.05) increased under high antibiotic exposure concentrations (>600 μg kg -1 soil dry weight). Our results suggest that the widespread occurrence of antibiotics in paddy soils may pose significant eco-environmental risks (nitrate accumulation and greenhouse effects) by altering nitrate transformation processes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In this study, the impact of sulfamethazine (SMZ), a typical Pharmaceuticals and Personal Care Products (PPCPs) existed in waste activated sludge (WAS), on the production of short-chain fatty acids (SCFA) during sludge anaerobic fermentation was investigated for the first time. Experimental results showed that the production of SCFA was positively affected by SMZ, which increased from 571 mg COD/L in the blank to 989 mg COD/L in the 24 mg/kg VSS SMZ reactor, causing 1.73-fold of increase. Mechanism exploration revealed that SMZ enhanced the disruption of both extracellular polymeric substances (EPS) and cell envelop, thereby benefiting the solubilization of sludge. It was also found that SMZ benefited the acidogenesis and acetogenesis processes but inhibited methonogenesis process, which was another reason for the enhanced SCFA production. Microbial analysis revealed that the abundance of anaerobic functional microorganisms in the SMZ reactor was more advantageous to acetic acid production., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sulfonamides (SNs) are synthetic antimicrobial agents. These substances are continually introduced into the environment, and they may spread and maintain bacterial resistance in the different compartments. The chlorination of 2 SNs, namely, sulfamethazine (SMT) and sulfamethoxypyridazine (SMP), was investigated to study their reactivity with chlorine at typical concentrations for water treatment conditions. Experiments conducted in purified water show an acceleration of SMT and SMP degradation of a factor 1.5 by comparison to drinking water matrix. This difference is due to pH variation and competitive reactions between SNs and mineral and organic compounds, with chlorine in drinking water. In the presence of an excess of chlorine (6.7 μmol·L -1 ) in ultrapure water at pH 7.2, second-order degradation rate constants were equal to 4.5 × 10 2 M -1 ·s -1 and 5.2 × 10 2 M -1 ·s -1 for SMT and SMP, respectively. The structures of transformation products were investigated by liquid chromatography tandem mass spectrometry analyses with equimolar concentrations between chlorine and SNs. SO 2 elimination, cyclization, and electrophilic substitutions were the main pathways of by-products formation. Moreover, the toxicity of the proposed structures was predicted by using toxicity estimation software tool program. The results indicated that most by-products may present developmental toxicity., (Copyright © 2018 John Wiley & Sons, Ltd.)

Toxicological effects of sulfamethazine (SM 2 ) have garnered increasing concern due to its wide applications in aquaculture and persistence in the aquatic environment. Most studies have main focused on freshwater fish (i.e. zebrafish), while information regarding effects of SM 2 on marine species is still scarce. Here, the hepatotoxicities in marine medaka (Oryzias melastigma) with an increasing SM2 concentration exposures (0.01 mg/L, 0.1 mg/L and 1 mg/L) were assessed by comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOF/MS) based metabolomics. Significant metabolites belonging to different metabolites classes were identified by multivariate statistical analysis. The increases levels of amino acids including alanine, asparagine, ornithine, proline, threonine, glutamic acid, lysine, tyrosine and phenylalanine were found in at least two exposure levels. Pathway analysis revealed that amino acids played important biological roles during SM 2 exposure: up-regulation of high energy-related amino acids for energy alteration; immune function disorder, oxidative stress and corresponding toxicities defenses. The down regulations of sugar and fatty acid metabolism were observed with an increasing level of SM2 exposure, suggesting that extra energy for cellular defense and detoxification was demanded in terms of different stress request. This study provided an innovative perspective to explore possible SM2 induced hepatic damages at three exposure levels on a nontarget aquatic specie., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Persistence of antibiotics in aquatic environment may pose a risk to the non-target aquatic organisms. This study provided an integrated evaluation to analyze the toxic stress of sulfamethazine (SMZ) on zebrafish in two lifespan stages (embryo-larval and adult) and three exposure periods (exposure, post-exposure and re-exposure). Zebrafish embryos and adult zebrafish were exposed to SMZ at 0.2, 20 and 2000 μg/L, respectively. The results showed that SMZ at any given concentration inhibited the hatching of embryos at 58-96 hpf (hours post-fertilization). Our result also indicated that two major kinds of the malformation, which was induced by the antibiotic, were edema and spinal curvature. Additionally, the antibiotic stimulated the heartbeat while reduced the body length of the embryo at 72 hpf. Superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents significantly increased at 120 hpf when the embryos were exposed to the lowest concentration (0.2 μg/L) of the antibiotic. On the other hand, the antibiotic induced SOD activities and MDA contents in adult zebrafish in the exposure and re-exposure periods. The MDA contents could recover while SOD activities still increased in 2 d after the exposure. Both SOD activities and MDA contents could recover in 7 d after the exposure. Levels of SOD and MDA in the re-exposure were higher than those in the first exposure. Our results suggested that SMZ had toxic effects on both embryos and adult zebrafish, and provided an integrated evaluation of the toxic effects of SMZ on zebrafish at a new perspective., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Antibiotics in the aquatic environment are dispersed through anthropogenic activities at low concentrations. Despite their sub lethal concentration, these biologically active compounds may still have adverse effects to non-target species. This study examined the response of adult zebrafish to 0.1mg/L concentration of clarithromycin, florfenicol, sulfamethazine, and their mixture using environmental metabolomics. Embryo and larvae of the fish were also used to assess fish embryo acute toxicity and behavior tests respectively. The fish embryo toxicity test did not show any inhibition of growth and development of the embryos after 96h of exposure to the antibiotics. Changes in swimming activity were seen in 5-dpf larvae which is believed to be correlated with the length of exposure to the compounds. Meanwhile, environmental metabolomics revealed diverse metabolites and pathways that were affected after 72h of exposure of the adult fish to sub-lethal concentration of the compounds. We found that even at low concentration of the antibiotics, behavioral and metabolic effects were still observed despite the lack of visible morphological changes. Further studies involving other aquatic organisms and bioactive compounds are encouraged to strengthen the findings presented in this novel research., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The antibiotic sulfamethazine (SM 2 ) is commonly used in agriculture and livestock for its broad-spectrum antibacterial properties. Due to its widespread application, SM 2 is frequently detected in surface water and sediments. The objective of this study was to investigate the bioconcentration, distribution and biomarker responses of SM 2 and its main metabolite, acetylated sulfamethazine (N-SM 2 ) in medaka (Oryzias melastigma). Two treated groups of medaka were exposed to concentrations of 40μg/L and 200μg/L of SM 2 for 24h to simulate the habitual use of those antibiotics in aquiculture activities. SM 2 and its main metabolite, N-SM 2 , were measured in several tissues during the 24h uptake period by UPLC/MS/MS. The bile exhibited the highest SM 2 concentration followed by the liver, gonad, gills, and muscle and the bioconcenration factor (BCF) was 10.69-42.95 in female fish and 2.78-145.36 in male fish. N-SM 2 showed a different distribution pattern from the parent compound, accumulating mainly in the gonad, and its BCF was much higher in the male group. Gender-related differences were also observed in the bioconcentration, transform rate and biomarkers of SM 2 . Biomarkers (SOD, CAT) in the liver changed significantly after 2, 12, and 24h of exposure (P<0.05), and presented a double-peak phenomenon. These results indicated that SM 2 can be absorbed and metabolized through multiple routes by fish in a short time. Interactions between biological systems and SM 2 or its metabolites may induce biochemical disturbances in fish., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Sulfamethazine (SMZ) is one of the most commonly used sulfonamide compounds in fish farming, and its physiological effects on fish are unknown. SMZ was administered to juvenile Nile tilapia (Oreochromis niloticus) at a dose level of 422 mg kg(-1) body weight, for a period of 11 days, via medicated feed. Fish were divided into two groups, the control group (CG) and the group fed with SMZ in feed. The administration of SMZ did not alter the erythrograms and leukograms of the Nile tilapia. The SMZ-fed group showed the same hepatic lipid peroxidation (LPO) concentration as the CG. Nonetheless, the oral administration of SMZ raised the hepatic catalase (CAT) and glutathione S-transferase (GST) activities, the increase probably being sufficient to prevent hepatic LPO production. The oral administration of SMZ affects the hepatic GST and CAT activities of Nile tilapia.

Recently, environmental metabolomics has been introduced as a next generation environmental toxicity method which helps in evaluating toxicity of bioactive compounds to non-target organisms. In general, efficient metabolite extraction from target cells is one of the keys to success to better understand the effects of toxic substances to organisms. In this regard, the aim of this study is (1) to compare two sample extraction methods in terms of abundance and quality of metabolites and (2) investigate how this could lead to difference in data interpretation using pathway analysis. For this purpose, the antibiotic sulfamethazine and zebrafish (Danio rerio) were selected as model toxic substance and target organism, respectively. The zebrafish was exposed to four different sulfamethazine concentrations (0, 10, 30, and 50mg/L) for 72h. Metabolites were extracted using two different methods (Bligh and Dyer and solid-phase extraction). A total of 13,538 and 12,469 features were detected using quadrupole time-of-flight liquid chromatography mass spectrometry (QTOF LC-MS). Of these metabolites, 4278 (Bligh and Dyer) and 332 (solid phase extraction) were found to be significant after false discovery rate adjustment at a significance threshold of 0.01. Metlin and KEGG pathway analysis showed comprehensive information from fish samples extracted using Bligh and Dyer compared to solid phase extraction. This study shows that proper selection of sample extraction method is critically important for interpreting and analyzing the toxicity data of organisms when metabolomics is applied., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Large quantities of veterinary antibiotics (VAs) are being used worldwide in agricultural fields through wastewater irrigation and manure application. They cause damages to the ecosystem when discharged into the environment, but there is a lack of information on their toxicity to plants and animals. This study evaluated the phytotoxic effects of five major VAs, namely tetracycline (TC), sulfamethazine (SMZ), norfloxacin (NOR), erythromycin (ERY) and chloramphenicol (CAP), on seed germination and root elongation in lettuce, tomato, carrot and cucumber, and investigated the relationship between their physicochemical properties and phytotoxicities. Results show that these compounds significantly inhibited root elongation (p<0.05), the most sensitive endpoint for the phytotoxicity test. TC was associated with the highest level of toxicity, followed by NOR, ERY, SMZ and CAP. Regarding crop species, lettuce was found to be sensitive to most of the VAs. The median effect concentration (EC50) of TC, SMZ, NOR, ERY and CAP to lettuce was 14.4, 157, 49.4, 68.8 and 204 mg/L, respectively. A quantitative structure-activity relationship (QSAR) model has been established based on the measured data. It is evident that hydrophobicity was the most important factor governing the phytotoxicity of these compounds to seeds, which could be explained by the polar narcosis mechanism. Lettuce is considered a good biomarker for VAs in the environment. According to the derived equation, phytotoxicities of selected VA compounds on different crops can be calculated, which could be applicable to other VAs. Environmental risks of VAs were summarized based on the phytotoxicity results and other persistent factors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Due to the high use of antibiotics and antiparasitics for the treatment of livestock, there is concern about the potential impacts of the release of these compounds into freshwater ecosystems. In this context, the present study quantified the acute toxicity of two antibiotics (sulfadiazine and sulfadimidine), and three antiparasitic agents (flubendazole, fenbendazole, ivermectin) for nine freshwater invertebrate species. These experiments revealed a low degree of toxicity for the sulfonamide antibiotics, with limited implications in the survival of all test species at the highest test concentrations (50 and 100 mg/L). In contrast, all three antiparasitic agents indicated on the basis of their acute toxicity risks for the aquatic environment. Moreover, chronic toxicity data from the literature for antiparasitics, including effects on reproduction in daphnids, support the concern about the integrity of aquatic ecosystems posed by releases of these compounds. Thus, these pharmaceuticals warrant further careful consideration by environmental risk managers.

Trimethoprim (TMP) and sulfamethazine (SMZ) are two antibiotics that are often administered in combination. We investigated the sorption and desorption behaviors of TMP and SMZ individually as single solute and in combination as co-solute in three representative soils, and evaluated joint antibacterial activity of the soil-adsorbed antibiotics to a reference strain Escherichia coli ATCC 25922. Comparative sorption tests showed that co-solute sorption of TMP and SMZ was not considerably different from their single sorption. Soil-adsorbed TMP was found to effectively inhibit the growth of E. coli at environmentally relevant concentrations in all three soils, and moreover co-presence of SMZ enhanced the antibacterial effects on bacteria both in its dissolved form and soil-adsorbed form. Overall, the results from this study suggest that various soil-adsorbed antibiotic residues could play a joint influencing role in soil bacterial community activity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Dispersed pharmaceuticals such as sulfonamides pose a threat to aquatic ecosystems. We evaluated potential biomarkers of sulfonamide exposure using an extended zebrafish (Danio rerio) toxicity test. The tested sulfonamides induced obvious effects on spontaneous swimming activity and heartbeat rate in zebrafish. Glutathione S-transferase (GST) and malondialdehyde (MDA) were examined to reflect the biomarker response of zebrafish exposed to three sulfonamides (sulfamethoxazole, sulfadiazine (SDZ) and sulfadimidine). Both GST and MDA showed time-dependent responses to sulfonamide exposure. GST activity was significantly increased after exposure to sulfonamides for 3 days, while MDA concentration reached a maximum during the first day and then declined. These results suggest that MDA may be a more sensitive biomarker of sulfonamide toxicity than GST. These investigations demonstrated that SDZ was a typical inducer of metabolic enzymes, suggesting that it poses a potential ecotoxicological risk to aquatic ecosystems., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study we investigated the sorption of sulfamethazine (SMZ) in two soils with different physico-chemical properties and the sulfonamide short-term influence on the microbial community structure and function. The presence of manure increased the SMZ sorption, the uppermost level being measured on soil with the lower pH and the higher manure content allowed by the Italian regulation. The sulfonamide desorption was hysteretic on both soils. SMZ addition to soil at the concentration of 53.6 μg/g had a significant short-term negative impact on readily culturable bacteria, potential metabolic activity (Biolog CLPP) and soil enzyme activity. Moreover, a shift of the culturable microbial populations towards a lower bacteria/fungi ratio was observed after SMZ addition. Despite the observed SMZ effects disappeared almost completely after 7 day, structural changes of microbial communities were still present in SMZ-treated soils. The results presented are remarkable since previous studies addressing the SMZ impact on soil microbial parameters failed to highlight any significant effect of the sulfonamide on microbial abundance and diversity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Antibiotics are widely used in daily life but their abuse has posed a potential threat to human health. The interaction between human serum albumin (HSA) and sulfamethazine (SMZ) was investigated by capillary electrophoresis, fluorescence spectrometry, and circular dichroism. The binding constant and site were determined to be 1.09×10(4) M(-1) and 1.14 at 309.5 K. The thermodynamic determination indicated that the interaction was driven by enthalpy change, where the electrostatic interaction and hydrogen bond were the dominant binding force. The binding distance between SMZ and tryptophan residue of HSA was obtained to be 3.07 nm according to Fǒrster non-radioactive energy transfer theory. The site marker competition revealed that SMZ bound into subdomain IIA of HSA. The binding of SMZ induced the unfolding of the polypeptides of HSA and transferred the secondary conformation of HSA. The equilibrium dialysis showed that only 0.13 mM SMZ decreased vitamin B(2) by 38% transported on the HSA. This work provides a new quantitative evaluation method for antibiotics to cause the protein damage., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Genotoxic potentials and the mechanisms of six pharmaceuticals, which are frequently detected in surface water worldwide, were investigated using isogenic chicken DT40 mutant cell lines. These pharmaceuticals include erythromycin, sulfamethazine, sulfathiazole, chlortetracycline, oxytetracycline, and diclofenac. The genotoxic effects of these pharmaceuticals were determined based on growth kinetics of several mutant cell lines. Genotoxic chemicals were expected to decrease the growth kinetics in at least one of the mutants more significantly than DNA-repair-proficient wild-type cells. The test pharmaceuticals sensitized the cells deficient in homologous recombination (HR) repair (RAD54⁻/⁻), nucleotide excision repair (XPA⁻/), or translesion DNA synthesis (REV3⁻/⁻), suggesting that these pharmaceuticals may induce bulky adducts covalently bound to duplex DNA, like ultraviolet (UV) light. Genotoxicity was confirmed again by analyzing chromosome aberrations (CAs) and γ-H2AX foci in both wild-type and the susceptible mutants (i.e., RAD54⁻/⁻ and XPA⁻/) following the exposure to all the test pharmaceuticals except for erythromycin. The data indicate that these pharmaceuticals induce the DNA damages that stall DNA replication, leading to chromosomal breaks as well as translesion DNA synthesis mediated mutagenesis in DT40 cells., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The present study provides results describing the degradation performance of the Sulfamethazine (SMT) antibiotic via photo-Fenton treatment. Experiments were carried out using 1 L solution samples of SMT (50 mg L(-1)) under different conditions. HPLC results reveal that both Fenton and photo-Fenton reactions were able to completely remove SMT antibiotic from the studied samples in less than 2 min treatment. Half-life times and kinetic parameters (assuming a pseudo-first-order kinetics at reaction initial stage, far from the equilibrium) for SMT degradation were determined and discussed. Hence, appropriate Fenton reagent loads are given to attain different targets proposed. TOC and HPLC data also revealed the presence of reaction intermediates; thus toxicity assays were performed regarding bacterial growth rate. The toxicity of an SMT solution was shown to increase during its degradation by means of photo-Fenton reactions., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Objective: To study the effect of perinatal exposure sulphamethazine on the function of thyroid gland of SD rats., Methods: Dams were given sulphamethazine 0, 50, 100 and 200 mg/(kg x d) respectively from gestational day (GD) 7 to postpartum day (P) 21. The sections of thyroid gland of pups 20 days after birth were stained by hematoxylin-eosin, and the expression of proliferating cell nuclear antigen (PCNA) were observed by immunohistochemistry staining., Results: Compare with control, thyroid gland showed proliferation of follicular epithelium in each experimental group, and the numbers of PCNA positive cells in thyroid gland significantly higher than that of control (P < 0.05)., Conclusion: Perinatal exposure to sulphamethazine may affect the function of thyroid gland of offspring.

Sulfonamides (SAs), the oldest chemotherapeutic agents used for antimicrobial therapy, still play an important role in veterinary mass treatments. Consequently, traces of these compounds, alone or in combinations, have been repeatedly detected in the environment. Sulfamethazine (SMZ) deserves particular attention not only because it is the most used veterinary SA, but also due to its proven effects on fertility in mice and on thyroid hormone homeostasis in rats. In this study, after evaluating the acute toxicity to Daphnia magna of six veterinary SAs and trimethoprim (TMP), the additivity of SMZ to each other compound was tested using the isobologram method. Two reproduction tests on the same biological model were also performed in order to derive LOEC and NOEC of SMZ. The acute EC(50) was in the range 131-270 mgL(-1) for all the compounds tested with the exception of sulfaguanidine (EC(50)=3.86 mgL(-1)). In acute binary tests SMZ showed a complex interaction with sulfaquinoxaline (superadditivity, additivity or subadditivity) at the three different combination ratios tested, simple additivity to TMP and less than additive interaction when paired to the other SAs. LOEC and NOEC of SMZ obtained from reproduction tests were 3.125 and 1.563 mgL(-1), respectively. In conclusion, SMZ should not harm the crustacean population at environmentally realistic concentrations. Its toxicity is comparable to that of other systemic SAs, and their binary interactions are less than additive. The same can not be entirely said for enteric SAs, and considering that these compounds are administered at high doses and mostly excreted in unmetabolised form, further evaluation of their impact to the aquatic environment seems advisable.

The potential impact of six antibiotics (chlortetracycline, tetracycline and tylosin; sulfamethoxazole, sulfamethazine and trimethoprim) on plant growth and soil quality was studied by using seed germination test on filter paper and plant growth test in soil, soil respiration and phosphatase activity tests. The phytotoxic effects varied between the antibiotics and between plant species (sweet oat, rice and cucumber). Rice was most sensitive to sulfamethoxazole with the EC10 value of 0.1 mg/L. The antibiotics tested inhibited soil phosphatase activity during the 22 days' incubation. Significant effects on soil respiration were found for the two sulfonamides (sulfamethoxazole and sulfamethazine) and trimethoprim, whereas little effects were observed for the two tetracyclines and tylosin. The effective concentrations (EC10 values) for soil respiration in the first 2 days were 7 mg/kg for sulfamethoxazole, 13 mg/kg for sulfamethazine and 20 mg/kg for trimethoprim. Antibiotic residues in manure and soils may affect soil microbial and enzyme activities.

We assessed the phototoxicity of several major sulfonamide antibiotics, i.e., sulfathiazole, sulfamethazine, and sulfamethoxazole, using acute 48 and 96 h Daphnia magna immobilization toxicity test under several indoor and outdoor lighting conditions. The lighting conditions were as follows: (1) fluorescent light only, (2) continuous irradiation with 15 microW/cm(2) UVB, (3) pulsed irradiation with 90 microW/cm(2) UVB for 4 h/d, and (4) natural sunlight (outdoors). Laboratory tests showed that phototoxicity resulting from exposure to continuous UVB light generally increased the acute toxicity of the sulfonamides in D. magna by up to 2.3-fold. However, pulsed UVB exposure resulted in a greater increase in phototoxicity. Compared to fluorescent light only (no UVB), pulsed UVB irradiation (96 h) resulted in 12.0-, 5.8-, and 4.4-fold increases in toxicity for sulfamethazine, sulfathiazole, and sulfamethoxazole, respectively. This suggests that the mode of UV irradiation is more important than the dose (UV-intensity x exposure time) for the photo-enhancement of sulfonamide toxicity. Natural sunlight enhanced the toxicity of the sulfonamides to an even greater degree, likely because of the contribution of UVA light. This study suggests that without taking into account the effects of UV irradiation, it is possible to underestimate the actual consequences of phototoxic sulfonamide antibiotics in the aquatic environment.

Objective: To study the effect of Sulphamethazine on the gene expression of FRTL-5 cells, and to explore the mechaniams of environmental thyroid hormone disruptors., Methods: cDNA microarray technique was used to analyze the gene expression of FRTL-5 cells of exponential phase treated by 2.0 microg/ml Sulphamethazine for 24 h. Total RNA from treated and untreated cells were labeled by Cy3 dCTP and Cy5 dCTP respectively. The ratios of Cy3/Cy5 were calculated in order to find the genes which expressed differently., Results: There were 679 genes (approximately 7%, total 9753 genes) exhibiting different expression, in which 395 (4.0%) genes up-regulated and 284 (3.0%) genes down-regulated. These genes related to regulation of gene expression, regulation of cell cycle, metabolism in cells, and so on., Conclusion: The effect of Sulphamethazine on FRTL-5 cells may be related with a series of genes.

The framework developed by the International Programme on Chemical Safety (IPCS) for assessing the mode of action of tumour induction of chemicals in experimental animals has been illustrated with d-limonene, sodium saccharin, di(2-ethylhexyl)phthalate (DEHP) and sulfamethazine as examples. d-Limonene causes renal tumours only in male rats through a response associated with alpha(2u)-globulin. Sodium saccharin induces urinary bladder tumours only in male rats through formation of a urinary precipitate causing erosion of the bladder surface and extensive regenerative hyperplasia. DEHP causes liver tumours in rats and mice through activation of the receptor PPAR alpha leading to peroxisome proliferation and hepatocellular proliferation. Sulfamethazine induces thyroid follicular cell tumours in rats and mice through a mechanism involving altered thyroid hormone homeostasis.

Recently, changes have been proposed in the criteria historically used in the evaluation of the applicability to humans of some of the results obtained from the rodent carcinogenicity bioassay data. These questions center on the suitability of the rodent model for agents that exert their toxic effects via specific enzyme interactions and endocrine mechanisms which appear to be inoperative within humans. Within the U.S. Food and Drug Administration (FDA), this issue has been brought to the forefront of concern with the recent application for a New Animal Drug Application for sulfamethazine (SMZ). A panel of FDA experts from the National Center for Toxicological Research (NCTR), the Center for Veterinary Medicine (CVM), and the Center for Food Safety and Applied Nutrition has reviewed the sum of the scientific evidence available on the toxicology of SMZ. They noted that, in previous feeding studies at NCTR, high doses of SMZ were associated with significant incidences of thyroid tumors in mice and rats. The panel also notes that the tumorigenic activity of SMZ in rodents was due to its goitrogenic activity, resulting in constant stimulation of the thyroid by TSH. Humans, on the other hand, were found to be insensitive to the SMZ-like inhibition of thyroid function. Further, apart from X-irradiation and radioactive iodine, there are no other physical or chemical agents known to cause thyroid tumors in humans. Thus, the expert panel concludes that the best scientific information available indicates that elevated levels of TSH and the consequent thyroid tumors would not be produced under approved use conditions of SMZ. This conclusion is in agreement with recommendations made by three other panels, viz. the World Health Organization, the U.S. Environmental Protection Agency, and CVM, which also evaluated the public health risk of SMZ.

The objective of this review is to correlate endocrinologic data from mechanistic studies with quantitative histopathology in selected examples of toxic endpoints of the endocrine system in laboratory animals. Mechanistic data can aid in the interpretation of animal toxicology findings and help clarify their significance in risk assessment. Endocrine organs of rodents frequently undergo proliferative changes with advancing age and following chronic exposure to large doses of xenobiotic chemicals, and the sensitivity of rodent endocrine tissues appears to be increasing. Many xenobiotic chemicals in large doses disrupt thyroid function in rodents either by a direct effect on the thyroid influencing synthesis of thyroid hormones or by adversely influencing their peripheral metabolism. A number of chemicals disrupt thyroid function by inhibiting the important enzyme, thyroperoxidase (TPO). A contemporary example of a chemical acting as TPO-inhibitor is sulfamethazine. In short-term mechanistic studies in rats there was a log-dose response relationship in circulating levels of thyroid and pituitary hormones plus a similar non-linear dose-response in morphologic changes in thyroid follicular cells. Endocrinologic data from mechanistic studies and histopathologic/ultrastructural findings will also be presented for the effects of the food color, FDC Red No. 3 (Erythrosine), on the thyroid gland in rats and parathyroid hormone-related protein (a major causative factor in cancer-associated hypercalcemia) on parathyroid chief cells in mice.

There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direct carcinogenic effect in the thyroid gland and the other involves chemicals which, through a variety of mechanisms, disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. These secondary mechanisms predominantly involve effects on thyroid hormone synthesis or peripheral hormone disposition. There are important species differences in thyroid gland physiology between rodents and humans that may account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neoplasia, secondary to chemically induced hormone imbalance, is mediated by thyroid-stimulating hormone (TSH) in response to altered thyroid gland function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plasma membrane surface of the follicular cell has receptors for TSH and other growth factors. Small organic molecules are not known to be direct TSH receptor agonists or antagonists; however, various antibodies found in autoimmune disease such as Graves' disease can directly stimulate or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby increase or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chemicals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dysfunction produced by a chemical would present a significant toxicological problem before such exposure would increase the risk for neoplasia in humans.