Effects of sulfamonomethoxine and trimethoprim co-exposures at different environmentally relevant concentrations on microalgal growth and nutrient assimilation.

In aquaculture around the world, sulfamonomethoxine (SMM), a long-acting antibiotic that harms microalgae, is widely employed in combination with trimethoprim (TMP), a synergist. However, their combined toxicity to microalgae under long-term exposures at environmentally relevant concentrations remains poorly understood. Therefore, we studied the effects of SMM single-exposures and co-exposures (SMM:TMP=5:1) at concentrations of 5 µg/L and 500 µg/L on Chlorella pyrenoidosa within one aquacultural drainage cycle (15 days). Photosynthetic activity and N assimilating enzyme activities were employed to evaluate microalgal nutrient assimilation. Oxidative stress and flow cytometry analysis for microalgal proliferation and death jointly revealed mechanisms of inhibition and subsequent self-adaptation. Results showed that exposures at 5 µg/L significantly inhibited microalgal nutrient assimilation and induced oxidative stress on day 7, with a recovery to levels comparable to the control by day 15. This self-adaptation and over 95 % removal of antibiotics jointly contributed to promoting microalgal growth and proliferation while reducing membrane-damaged cells. Under 500 µg/L SMM single-exposure, microalgae self-adapted to interferences on nutrient assimilation, maintaining unaffected growth and proliferation. However, over 60 % of SMM remained, leading to sustained oxidative stress and apoptosis. Remarkably, under 500 µg/L SMM-TMP co-exposure, the synergistic toxicity of SMM and TMP significantly impaired microalgal nutrient assimilation, reducing the degradation efficiency of SMM to about 20 %. Consequently, microalgal growth and proliferation were markedly inhibited, with rates of 9.15 % and 17.7 %, respectively, and a 1.36-fold increase in the proportion of cells with damaged membranes was observed. Sustained and severe oxidative stress was identified as the primary cause of these adverse effects. These findings shed light on the potential impacts of antibiotic mixtures at environmental concentrations on microalgae, facilitating responsible evaluation of the ecological risks of antibiotics in aquaculture ponds.

Persistently Upregulated Hippocampal mTOR Signals Mediated by Fecal SCFAs Impair Memory in Male Pups with SMM Exposure in Utero.

OBJECTIVE: To investigate the molecular mechanisms of the adverse effects of exposure to sulfamonomethoxin (SMM) in pregnancy on the neurobehavioral development of male offspring. METHODS: Pregnant mice were randomly divided into four groups: control- (normal saline), low- [10 mg/(kg•day)], middle- [50 mg/(kg•day)], and high-dose [200 mg/(kg•day)] groups, which received SMM by gavage daily during gestational days 1-18. We measured the levels of short-chain fatty acids (SCFAs) in feces from dams and male pups. Furthermore, we analyzed the mRNA and protein levels of genes involved in the mammalian target of rapamycin (mTOR) pathway in the hippocampus of male pups by RT-PCR or Western blotting. RESULTS: Fecal SCFA concentrations were significantly decreased in dams. Moreover, the production of individual fecal SCFAs was unbalanced, with a tendency for an increased level of total fecal SCFAs in male pups on postnatal day (PND) 22 and 56. Furthermore, the phosphatidylinositol 3-kinase (PI3k)/protein kinase B (AKT)/mTOR or mTOR/ribosomal protein S6 kinase 1 (S6K1)/4EBP1 signaling pathway was continuously upregulated until PND 56 in male offspring. In addition, the expression of Sepiapterin Reductase (SPR), a potential target of mTOR, was inhibited. CONCLUSION: In utero exposure to SMM, persistent upregulation of the hippocampal mTOR pathway related to dysfunction of the gut (SCFA)-brain axis may contribute to cognitive deficits in male offspring.

Perinatal sulfamonomethoxine exposure influences physiological and behavioral responses and the brain mTOR pathway in mouse offspring.

Sulfamonomethoxine (SMM) is widely used in the veterinary field in China. Although some clinical surveys have revealed that sulfonamide antibiotics cause adverse nervous system symptoms, the related mechanisms of maternal SMM exposure on the neurobehavioral development of offspring remain unclear. Here, we investigated the effects of perinatal SMM exposure on the physiological and behavioral responses of pubertal offspring mice and the underlying mechanisms. We randomly allocated pregnant mice into the groups treated with SMM at different doses and the saline-treated groups. Maternal mice were orally administered SMM daily from gestational day 1 to postpartum day 21. On postnatal day (PND) 22, the parameters of growth, endocrine hormones, and brain amino acid composition were assessed, as well as the brain transcript levels of key genes involved in the mammalian target of rapamycin (mTOR) signaling pathway. From PND 50 to 55, a battery of behavioral tests relevant to anxiety and memory were then administered. Analysis of the results indicated that the pups, particularly the pubertal female offspring, showed anxiety-like behavior. Moreover, the pubertal offspring showed cognitive impairments and fat accumulation. Furthermore, the relative mRNA expression of genes involved in the mTOR signaling pathway in females on PND 22 was elevated, whereas the expression of N-methyl-d-aspartate receptor 2B (NR2B) was reduced. Together, the results showed that perinatal SMM exposure perturbs neuroendocrine functions, and further alters gene expression in the mTOR pathway and NR2B gene expression early in life, which may contribute to brain dysfunction in pubertal life.

Physiological and behavioral responses in offspring mice following maternal exposure to sulfamonomethoxine during pregnancy.

Sulfamonomethoxine (SMM), a veterinary antibiotic, is widely used in China. However, the impacts of maternal SMM exposure on neurobehavioral development in early life remain little known. In this study, we investigated the effects of maternal SMM exposure during pregnancy on behavioral and physiological responses in offspring mice. Pregnant mice were randomly divided into three SMM-treated groups, namely low-(10mg/kg/day), medium-(50mg/kg/day), and high-dose (200mg/kg/day), and a control group. The pregnant mice in the SMM-treated groups received SMM by gavage daily from gestational day 1-18, whereas those in the control received normal saline. On postnatal day (PND) 50, spatial memory was assessed using the Morris water maze test, and anxiety was measured using the elevated plus-maze and open field tests. The results showed significantly increased blood glucose in pups whose mothers received a high SMM dose. In addition, maternal SMM exposure increased anxiety-related activities among the offspring; spatial learning and memory were impaired more severely in the male offspring. The contents of tetrahydrobiopterin (BH4) and brain-derived neurotrophic factors (BDNF) on PND 22 were significantly reduced in the male offspring of the high-dose group compared with the controls. These findings indicate that SMM may be identified as a risk factor for cognitive and behavioral development on the basis of gender and that it may be associated with diminished BH4 and BDNF levels early in life.

Toxicity of the veterinary sulfonamide antibiotic sulfamonomethoxine to five aquatic organisms.

The purpose of this study was to investigate the acute and chronic toxicity of sulfamonomethoxine (SMM) to aquatic organisms to evaluate its impact at different trophic levels in the ecosystem. Regarding the growth inhibition of microalgae, SMM exhibited 72-h median effective concentration (EC50) values of 5.9mgL(-1) for freshwater Chlorella vulgaris and 9.7mgL(-1) for marine Isochrysis galbana. In a study on the cladocerans, SMM exhibited acute toxicity and 48-h median lethal concentrations of 48mgL(-1) for Daphnia magna and 283mgL(-1) for D. similis. An examination of chronic toxicity revealed that SMM inhibited the brook production of the cladocerans and exhibited 21-day EC50 values of 14.9mgL(-1) for D. magna and 41.9mgL(-1) for D. similis. This study investigated the potentially adverse effects of SMM on aquatic organisms and revealed that microalgae exhibited higher sensitivity to SMM than cladocerans did. The residue of SMM in water is recommended to be carefully evaluated to reduce ecological impacts after applied to cultured animals.

Eco-toxic effects of sulfadiazine sodium, sulfamonomethoxine sodium and enrofloxacin on wheat, Chinese cabbage and tomato.

Investigation of the toxic effects of three veterinary drugs [sulfadiazine sodium (SDS), sulfamonomethoxine sodium (SMMS), and enrofloxacin (EFLX)] on seed germination, root elongation and shoot elongation of wheat (Triticum aestivum L.), Chinese cabbage (Brassica campestris L.) and tomato (Cyphomandra betacea) was carried out. Significant linear relationships between the root and shoot elongation and the concentration of veterinary drugs addition were observed. The effects of the three veterinary drugs on seed germination of wheat, Chinese cabbages and tomato were not significant (P > 0.05), but on shoot and root elongation they were markedly significant (P < 0.05). The inhibitory rates of veterinary drugs on root and shoot elongation of crops were significantly stronger than that on seed germination. Based on IC(50) (drugs concentration when 50% plants show inhibition) of root elongation, wheat was the most sensitive plant to the toxicity of SDS with a IC(50) value as high as 28.1 mg/kg; Chinese cabbage was the most sensitive plant to the toxicity of SMMS with a IC(50) value as high as 27.1 mg/kg; tomato was the most sensitive plant to the toxicity of EFLX with a IC(50) value as high as 125.7 mg/kg. The toxic effects of sulfadiazine sodium and sulfamonometh-oxine sodium on the three crops were much higher than that of enrofloxacin.