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Microcystin-LR (MCLR) produced by cyanobacterial blooms have received global attention. MCLR has been recognized as a reproductive toxin to fish and poses a threat to ecosystem stability. It has been proven that probiotic dietary management can improve reproductive performance of fish. It is worth paying attention to exploring whether probiotic management can alleviate the reproductive toxicity caused by MCLR. In this investigation, adult zebrafish were exposed to different doses of MCLR solution (0, 2.2, and 22 μg/L) with or without the Lactobacillus rhamnosus GG supplementation for a duration of 28 days. The results showed that female zebrafish spawning was reduced after exposure to MCLR, but this reduction was reversed when L. rhamnosus GG was added. To elucidate how L. rhamnosus GG mitigates reproductive toxicity caused by MCLR, we examined a series of indicators of MCLR accumulation, ovarian histology, hormones, and transcriptome levels. Our study showed that L. rhamnosus GG could alleviate oogenesis disorders and ultimately attenuate MCLR-induced reproductive toxicity by reducing MCLR accumulation in the gonads, modulating the expression of endocrine system and auto/paracrine factors. The transcriptome results revealed that single or combined exposure of MCLR and L. rhamnosus GG mainly affected the endocrine system, energy metabolism, and RNA degradation and translation. Overall, our results provide new insights for alleviating MCLR-induced reproductive toxicity and help promote healthy 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 Elsevier B.V. All rights reserved.)

Cyanobacterial blooms are common events that releases secondary metabolites into water posing considerable threats to the environment, wildlife, and public health. Some of these metabolites, such as microcystin, have been extensively studied and associated with harmful effects in mammals and aquatic organisms, while the biological effects of others, like geosmin, remain much less investigated. Enhancing our understanding of cyanotoxins effects on organisms is especially relevant facing the complex scenarios projected due to global warming. The aim of this study was to assess the transcriptional modulation in whole zebrafish (Danio rerio) larvae (n = 9) in response to a 7-days immersion exposure to 3 μg L -1 MCLR or 5 μg L -1 geosmin. No mortality or differences in length gain were observed in zebrafish larvae exposed to environmentally realistic doses of both cyanotoxins. The exposure to MCLR and to geosmin caused the differential expression of 164 and 172 genes respectively, being 23 upregulated by MCLR and 98 upregulated by geosmin. Among the upregulated genes, 16 were shared, while 42 were shared among the downregulated genes. Over-representation analysis identified three enriched GO terms only among the genes upregulated by geosmin: organic hydroxy compound metabolic process (1901615), small molecule biosynthetic process (0044283), and lipid metabolic process (0006629). In fact, the expression of 12 of the 13 genes directly involved in the synthesis of cholesterol from acetyl-CoA was upregulated by geosmin. A chronic upregulation of cholesterol biosynthetic pathway is linked to several diseases and metabolic disorders, including alterations in sex-related hormones. Moreover, our results indicate that geosmin and MCLR acts through different mechanisms. Geosmin does not appear to provoke short-term adverse effects as MCLR but could disrupt the endocrine system by altering the lipid and steroid metabolism., 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 Ltd. All rights reserved.)

Cyanobacterial blooms pose a serious threat to the survival of fish because of the hepatotoxicity of microcystins produced by toxic cyanobacteria such as Microcystis. Many studies have investigated the hepatotoxicity of microcystins in common carp, a freshwater fish distributed worldwide, but the hepatotoxicity mechanism has not been fully clarified. The present study aimed to investigate the mechanism underlying the hepatic inflammatory response and hepatocyte apoptosis induced by acute microcystin-LR exposure via intraperitoneal injection (71 μg/kg and 119 μg/kg) or gavage (357.08 μg/kg) and chronic exposure to toxic Microcystis blooms. The results of acute exposure revealed that microcystin-LR caused an increase in serum transaminase activity and increased the levels of inflammatory factors and inflammatory mediators, inducing a significant inflammatory response in the liver of common carp. Moreover, biochemical detection revealed that hepatocyte apoptosis occurred in the fish. Moreover, chronic toxic Microcystis exposure also caused hepatic inflammation and subsequent apoptosis mediated by the tumour necrosis factor-α (TNF-α) pathway and the mitochondrial pathway similar to acute exposure. Therefore, our study suggests that the inflammatory response induced by microcystin-LR exacerbates apoptosis, likely mediated by TNF-α. In summary, both acute microcystin-LR exposure and chronic toxic Microcystis exposure can cause inflammation in the liver of common carp, which subsequently triggers hepatocyte apoptosis mediated by the TNF-α pathway and the mitochondrial pathway. This study helps elucidate the mechanism of liver damage induced by cyanobacterial blooms in natural water., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest in this paper. Haoyang Zhao, Kehui Sun, Xiaodan Nan, Weikai Ding, Junguo Ma, and Xiaoyu Li, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Microcystin-leucine arginine (MC-LR), a representative cyanobacterial toxin, poses an increasing and serious threat to aquatic ecosystems. Despite investigating its toxic effects in various organisms and cells, the toxicity to tissue regeneration and stem cells in vivo still needs to be explored. Planarians are ideal regeneration and toxicology research models and have profound implications in ecotoxicology evaluation. This study conducted a systemic toxicity evaluation of MC-LR, including morphological changes, growth, regeneration, and the underlying cellular and molecular changes after MC-LR exposure, which were investigated in planarians. The results showed that exposure to MC-LR led to time- and dose-dependent lethal morphological changes, tissue damage, degrowth, and delayed regeneration in planarians. Furthermore, MC-LR exposure disturbed the activities of antioxidants, including total superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, and total antioxidant capacity, leading to oxidative stress and DNA damage, and then reduced the number of dividing neoblasts and promoted apoptosis. The results demonstrated that oxidative stress and DNA damage induced by MC-LR exposure caused apoptosis. Excessive apoptosis and suppressed neoblast activity led to severe homeostasis imbalance. This study explores the underlying mechanism of MC-LR toxicity in planarians and provides a basis for the toxicity assessment of MC-LR to aquatic organisms and ecological risk evaluation., (© 2023 International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)

The occurrence of poisoning incidents caused by cyanobacterial blooms has aroused wide public concern. Microcystin-leucine arginine (MC-LR) is a well-established toxin produced by cyanobacterial blooms, which is widely distributed in eutrophic waters. MC-LR is not only hazardous to the water environment but also exerts multiple toxic effects including liver toxicity in both humans and animals. However, the underlying mechanisms of MC-LR-induced liver toxicity are unclear. Herein, we used advanced single-cell RNA sequencing technology to characterize MC-LR-induced liver injury in mice. We established the first single-cell atlas of mouse livers in response to MC-LR. Our results showed that the differentially expressed genes and pathways in diverse cell types of liver tissues of mice treated with MC-LR are highly heterogeneous. Deep analysis showed that MC-LR induced an increase in a subpopulation of hepatocytes that highly express Gstm3, which potentially contributed to hepatocyte apoptosis in response to MC-LR. Moreover, MC-LR increased the proportion and multiple subtypes of Kupffer cells with M1 phenotypes and highly expressed proinflammatory genes. Furthermore, the MC-LR increased several subtypes of CD8 + T cells with highly expressed multiple cytokines and chemokines. Overall, apart from directly inducing hepatocytes apoptosis, MC-LR activated proinflammatory Kupffer cell and CD8 + T cells, and their interaction may constitute a hostile microenvironment that contributes to liver injury. Our findings not only present novel insight into underlying molecular mechanisms but also provide a valuable resource and foundation for additional discovery of MC-LR-induced liver toxicity., 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 article., (Copyright © 2023. Published by Elsevier B.V.)

With global warming and increasing eutrophication of water bodies, a variety of algal toxins, including microcystin (MC), released into water by cyanobacterial blooms pose a serious threat to the survival of aquatic organisms. To investigate the mechanism of the Nrf2/Keap1a pathway on resisting MC-induced oxidative stress and apoptosis in Cristata plicata, we cloned the full-length cDNA of CpBcl-2. The cDNA full-length of CpBcl-2 was 760 bp, encoded a 177 amino acid peptide, and contained a highly conserved Bcl-2-like superfamily domain. MC stimulation increased the expression and activity levels of related antioxidant enzymes. After CpNrf2 knockdown, the transcription levels of NAD(P)H quinone redox Enzyme-1 (NQO1) and related antioxidant enzymes activity in the gills and kidney of C. plicata were significantly down-regulated upon MC stress, but that was significantly upregulated after knockdown of CpKeap1a. Additionally, Upon MC stress, the mRNA levels of CpBcl-2 were increased in the gills and kidney after knockdown of CpNrf2 at 24 h, and that of CpBcl-2 were decreased at 72 and 96 h in the CpKeap1a-siRNA+MC group. Moreover, MC stimulation significantly inhibited CpJNK expression in the gills and kidney, but which regulated the Nrf2/Keap1a pathway in C. plicata. However, the JNK inhibitor SP600125 promoted the expression of CpNrf2 and related enzymes with antioxidant response element (ARE-driven enzyme) in the gills and kidney. Then, we speculated that CpKeap1a was a negative regulator of CpNrf2, and C. plicata resisted MC-induced oxidative damage and apoptosis by inhibiting JNK transcription via the Nrf2/Keap1a pathway., 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 Inc.)

Microcystin-LR (MC-LR) and nitrites from the environment and daily life can be ingested and absorbed by humans via the digestive tract. However, their combined effects on intestinal health remain unclear. Here, the combined impact of MC-LR and sodium nitrite (NaNO 2 ) on the intestines of mice was investigated under actual human exposure conditions. After mice were exposed to MC-LR (10, 100 μg/L) and NaNO 2 (30, 300 mg/L) individual and in combination for 6 months, it was found that MC-LR and NaNO 2 synergistically decreased intestinal permeability and disrupted intestinal physical, chemical, immune, and microbial barriers. In the coexposure groups, the synergistic impairment to the intestinal barrier was noted with increasing concentrations of MC-LR or NaNO 2 , but this adverse effect was alleviated by nicotinamide supplementation. This study underscores the potential risks of simultaneous ingestion of MC-LR and nitrite on intestinal health. The protective role of nicotinamide suggests avenues for therapeutic intervention against environmental toxin-induced intestinal impairment.

Environmental risk assessment (ERA) is critical for protecting life by predicting population responses to contaminants. However, routine toxicity testing often examines only one genotype from surrogate species, potentially leading to inaccurate risk assessments, as natural populations typically consist of genetically diverse individuals. To evaluate the importance of intraspecific variation in translating toxicity testing to natural populations, we quantified the magnitude of phenotypic variation between 20 Daphnia magna clones exposed to two levels of microcystins, a cosmopolitan cyanobacterial toxin. We observed significant genetic variation in survival, growth, and reproduction, which increased under microcystins exposure. Simulations of survival showed that using a single genotype for toxicity tolerance estimates on average failed to produce accurate predictions within the 95% confidence interval over half of the time. Whole genome sequencing of the 20 clones tested for correlations between toxicological responses and genomic divergence, including candidate loci from prior gene expression studies. We found no overall correlations, indicating that clonal variation, rather than variation at candidate genes, predicts population-level responses to toxins. These results highlight the importance of incorporating broad intraspecific genetic variation, without focusing specifically on variation in candidate genes, into ERAs to more reliably predict how local populations will respond to contaminants., (© 2024. The Author(s).)

As a key form of post-transcriptional regulation, microRNAs (miRNAs) regulate gene expression by binding to target mRNAs, leading to mRNA decay or translational repression. Recently, the role of miRNAs in the response of aquatic organisms to environmental stressors has emerged. Daphnia , widely distributed cladocerans, play a crucial role in aquatic ecosystems. Cyanobacterial blooms often cause Daphnia populations to decrease, thereby disrupting ecosystem functionality and water quality. However, the post-transcriptional mechanisms behind Daphnia 's response to toxic cyanobacteria are insufficiently understood. This study investigated the role of miR-210, a multifunctional miRNA involved in stress response and toxicity pathways, and its target genes ( MLH3 , CDHR5 , and HYOU1 ) in two Daphnia magna clones exposed to toxic Microcystis aeruginosa . Results showed that M. aeruginosa inhibited somatic growth rates, led to microcystin accumulation, caused abnormal ultrastructural alterations in the digestive tract, and induced DNA damage in both clones. Notably, exposure significantly increased miR-210 expression and decreased the expression of its target genes compared with the controls. We identified miR-210s regulation on clonal-tolerance variations in D. magna to M. aeruginosa , emphasizing miRNAs' contribution to adaptive responses. Our work uncovered a novel post-transcriptional mechanism of cyanobacterial impact on zooplankton and provided essential insights for assessing cyanobacterial toxicity risks.

Microcystin-leucine arginine (MC-LR) has been reported to exhibit placental toxicity, leading to potential adverse pregnancy outcomes. Placental abnormalities often coincide with congenital heart defects (CHD). However, the extent to which MC-LR-induced placental abnormalities contribute to CHD and the cellular mechanisms underlying this association remain unknown. In this study, we observed abnormal polarization of placental macrophages in pregnant mice exposed to MC-LR during pregnancy, and the embryos developed cardiac developmental defects that persisted into adulthood. Trophoblast-derived extracellular vesicles (T-EVs) increase in number during pregnancy and act as a critical signal in macrophage polarization. However, MC-LR significantly affected the miRNA expression profile of T-EVs. Upon internalization into macrophages, T-EV-derived miR-377-3p specifically targets the 3'UTR region of NR6A1 to inhibit gene expression. Silencing of transcription suppressor NR6A1 leads to abnormal activation of the downstream mTOR/S6K1/SREBP pathway, inducing metabolic reprogramming and ultimately leading to M1 polarization of macrophages. This study elucidated the placental mechanism underlying MC-LR-induced CHD for the first time, providing insights into the environmental risks associated with CHD., Competing Interests: Declaration of competing interest The authors declare they have no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microcystin-LR (MC-LR), a common hepatotoxin produced by bloom-forming cyanobacteria, presents a serious threat to the health of aquatic animals. In this study, we studied the impact of MC-LR on hepatopancreas histopathology, enzyme activity, transcriptome, and apoptosis of Litopenaeus vannamei. Thus, shrimp postlarvae (1.63 ± 0.5 g) exposed to MC-LR at 500 μg/kg caused morphological lesions in the histology of the shrimp hepatopancreas, which exhibited swollen, lighter coloration and unclear edges. Moreover, MC-LR significantly altered the hepatopancreas enzyme activities such as the levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), acid phosphatase (ACP), alkaline phosphatase (AKP) and lysozyme (LZM), including the state of apoptosis in hepatopancreas. From the RNA-seq analysis of the hepatopancreas, a total of 728 differentially expressed genes (DEGs) were identified, and their functions in MC-LR treatment group were involved in cellular processes, metabolic processes, biological regulation, cellular components, catalytic activity and binding. The metabolic pathways primarily associated with the DEGs included reactive oxygen species, glycerophospholipid metabolism and the phospholipase D signaling pathway. Overall, q-PCR results indicated that MC-LR led to significant changes in multiple apoptosis genes of shrimp hepatopancreas. This study expand the understanding of the effect of microcystin-LR on commercially farmed crustaceans., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Microcystis aeruginosa is the main toxic strain in cyanobacterial blooms, and the recruitment stage in its temperature-dependent seasonal succession is considered as the key to its subsequent growth. In this study, a protocol with specific temperature settings was developed as the simulated recruitment stage in order to investigate and confirm the superior inhibitory effects of allelochemicals on M. aeruginosa at that stage of recruitment. One of the most common allelochemicals, gallic acid (GA) (10 mg/L, 20 mg/L) was employed to treat M. aeruginosa under initially low temperature condition (15 °C), then intermediate (20 °C) and last normal (26 °C), which corresponds to the critical temperatures for cyanobacterial recruitment and growth. Growth, metabolism, photosynthetic activity, extracellular polysaccharides (EPS) and microcystins (MCs) release were analyzed and discussed in this study, and a more sustained and better inhibitory effect over a 20-day period was achieved. Notably, GA (10 mg/L) markedly delayed the recruitment of M. aeruginosa from low temperature, with an inhibition efficiency of 85.71 %, and suppressing Fv/Fm and photosynthetic pigments production. It is also observed that M. aeruginosa at recruitment stage exhibited higher sensitivity and poorer resistance to allelochemical treatment, with variable responses suggesting that optimal dosages may alter. The antioxidant enzyme activities remained high under prolonged stress, and the secretion of EPS was stimulated, indicating that cyanobacteria were more inclined to form colonies. While the laboratory-based inhibitory mechanism appeared to increase the release of microcystins in individual cells, the actual concentration of microcystins in natural aquatic environments requires further investigation., 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 B.V. All rights reserved.)

Previous experimental studies have found that exposure to Microcystin-leucine arginine can impact pregnancy outcomes in female mice. The impact of MC-LR on early pregnancy in mammals is not yet well understood. Both mice and humans need to undergo decidualization to maintain pregnancy. In this study, we tried to evaluate whether MC-LR affects decidualization process in mice. Our research showed that MC-LR decreased maternal weight gain, uterine weight, and implantation site weight. These findings suggested that MC-LR exerted adverse effects on decidualization. In mice, we examined decreased number of polyploid decidual cells, but marked proliferation of mouse endometrial stromal cells the expression levels of prolactin (PRL)and insulin-like growth factor binding protein 1 (IGFBP1) were significantly downregulated in the decidual tissue and primary endometrial stromal cells following MC-LR treatment. Furthermore, further in vitro experiments identified that MC-LR promoted endometrial stromal cell division and cycle transition. Lastly, our study demonstrated that MC-LR impaired decidualization through the PI3K/AKT/FOXO1 pathway. Collectively, these data suggested that exposure to MC-LR impaired decidualization during early pregnancy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jiang Wu reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they 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 Ltd. All rights reserved.)

Harmful algal blooms (HABs) - proliferated algae densities, often producing toxins - have increasingly been found in ocean and coastal areas. Recent studies show that rising temperatures contribute to HAB occurrence, but the broader influence of climate change on these outbreaks is less quantified. Of particular concern is the limited research on HAB toxin effects under varying temperatures, especially regarding primary consumers such as copepods, a crucial component of aquatic ecosystems. Therefore, we examined the impact of marine toxins on the harpacticoid copepod Nitokra spinipes, a model organism for marine ecotoxicology, in the context of climate change. We evaluated the toxicity of four purified, commonly occurring algal toxins, at three different temperatures in the laboratory. First, adult females were exposed to a concentration series of toxins at 15, 20, and 25 °C for 48 h. EC50 values of domoic acid ranged from 8.79 ± 1.93 μg L -1 to 25.97 ± 11.96 μg L -1 . Nauplii, aged 48-72 h, were exposed at 18, 20 and 22 °C for the same duration. Less sensitive compared to adults, the EC50 of domoic acid in this case varied from 57.26 ± 6.82 μg L -1 to 97.24 ± 6.45 μg L -1 . Both results indicated a temperature-dependent EC50. For the chronic toxicity tests, larval development ratio (LDR), brood size and inter-brood time of domoic acid (DA), yessotoxin (YTX), saxitoxin (STX), and microcystin-LR (MC-LR) were examined at 18, 20 and 22 °C. We observed that with increasing temperatures, LDR increased, whereas brood size significantly decreased as DA, YTX or STX concentrations rose. No interaction between temperature and algal toxins was found but a temperature dependent sensitivity of copepods towards DA, YTX and STX was revealed. Our research provides insights into the effects of long-term exposure to algal toxins on marine copepods and the potential impacts of climate warming., 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 Ltd. All rights reserved.)

Plastic contamination in aquatic ecosystems all around the world is on the rise. Microplastics (MPs) interfere with the ecological functions of different aquatic animals, including zooplankton. Other contaminants can also be transported by microplastics, resulting in higher toxicity. Here, we evaluated the effect of microplastics alone and in combination with cyanotoxins (CT) on the demographic and feeding responses of the freshwater rotifer Brachionus calyciflorus. The microplastics used were polystyrene spheres of 30 μm diameter. The cyanobacteria were obtained from a sample collected from the Valle de Bravo reservoir in Central Mexico, and the secondary metabolites were obtained after 5 cycles of freezing, thawing and sonication. We conducted acute (LC 50 , 24h bioassay) and chronic toxicity tests involving population growth, life table experiments, and feeding experiments. The LC 50 value using microplastics was 21.91 mg/L, and for the cyanobacterial crude extract it was 2.56 μg/L, but the combination of both resulted in a higher adverse effect (16.64 mg/L) due to the microplastics. Rotifer survival, reproduction, and feeding decreased in the presence of either MPs or CT but the adverse effect was more in the presence of both contaminants. We found that the adverse effects of MPs and CT on the test rotifer species were enhanced when exposed to both contaminants simultaneously., Competing Interests: Declaration of competing interest We have no conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cyanobacterial harmful algal blooms can pose risks to ecosystems and human health worldwide due to their capacity to produce natural toxins. The potential dangers associated with numerous metabolites produced by cyanobacteria remain unknown. Only select classes of cyanopeptides have been extensively studied with the aim of yielding substantial evidence regarding their toxicity, resulting in their inclusion in risk management and water quality regulations. Information about exposure concentrations, co-occurrence, and toxic impacts of several cyanopeptides remains largely unexplored. We used liquid chromatography-mass spectrometry (LC-MS)-based metabolomic methods associated with chemometric tools (NP Analyst and Data Fusion-based Discovery), as well as an acute toxicity essay, in an innovative approach to evaluate the association of spectral signatures and biological activity from natural cyanobacterial biomass collected in a eutrophic reservoir in southeastern Brazil. Four classes of cyanopeptides were revealed through metabolomics: microcystins, microginins, aeruginosins, and cyanopeptolins. The bioinformatics tools showed high bioactivity correlation scores for compounds of the cyanopeptolin class (0.54), in addition to microcystins (0.54-0.58). These results emphasize the pressing need for a comprehensive evaluation of the (eco)toxicological risks associated with different cyanopeptides, considering their potential for exposure. Our study also demonstrated that the combined use of LC-MS/MS-based metabolomics and chemometric techniques for ecotoxicological research can offer a time-efficient strategy for mapping compounds with potential toxicological risk. Environ Toxicol Chem 2024;43:2222-2231. © 2024 SETAC., (© 2024 SETAC.)

Suspended particulate matter (SPM) and biofilm are critical in removing contaminants in aquatic environments, but the environmental behavior and ecological toxicity of SPM-biofilm aggregates modulated by turbulence intensities are largely unknown. This study determined the removal pathways of microcystin-LR (MC-LR) by SPM and its biofilm under different turbulence intensities (2.25 × 10 -3 , 1.01 × 10 -2 , and 1.80 × 10 -2 m 2 /s 3 ). Then, we evaluated the toxicity of SPM-biofilm aggregates to Daphnia magna. The results revealed that SPM contributed to the adsorption of MC-LR, and the removal of MC-LR can be accelerated with biofilm formation on SPM, with 95.66 % to 97.45 % reduction in MC-LR concentration under the studied turbulence intensities. Higher turbulence intensity triggered more frequent contact of SPM and MC-LR, formed compact but smaller clusters of SPM-biofilm aggregates, and enhanced the abundance of mlrA and mlrB; thus benefiting the adsorption, biosorption, and biodegradation of MC-LR. Furthermore, the SPM-biofilm aggregates formed in turbulent water triggered oxidative stress to Daphnia magna, while a weak lethal toxic effect was identified under moderate turbulence intensity. The results indicate that the toxicity of SPM-biofilm aggregates fail to display a linear relationship with turbulence intensity. These findings offer new perspectives on understanding the environmental behavior and ecological outcomes of SPM and its biofilms in turbulent aquatic 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 © 2024 Elsevier Ltd. All rights reserved.)

Microcystin-LR (MCLR) exposure has been associated with development of hepatocellular carcinoma (HCC). Many of the carcinogenic mechanisms for MCLR have been attributed to the induction of cell survival and proliferation through altered protein phosphorylation pathways by inhibition of protein phosphatases 1 (PP1) and PP2A. The current study determined MCLR effects on the phosphoproteome in human HepaRG cells. Differentiated HepaRG cells were treated with either vehicle or MCLR followed by phosphoproteomic analysis and Western blotting of MAPK-activated proteins. MCLR decreased cell viability at 24 h at doses as low as 0.03 μM. MCLR also caused a dose-dependent increase in phosphorylation of signaling and stress kinases. The number of decreased phosphosites by 0.1 μM MCLR was similar between the 2 h (212) and 24 h (154) timepoints. In contrast, a greater number of phosphosites were increased at 24 h (567) versus the 2 h timepoint (136), indicating the hyperphosphorylation state caused by MCLR-mediated inhibition of PPs is time-dependent. A kinase perturbation analysis predicted that MCLR exposure at both 2 h and 24 h increased the function of aurora kinase B (AURKB), checkpoint kinase 1 (CHEK1), and serum and glucocorticoid-regulated kinase 1 (SGK1). STRING database analysis of the phosphosites altered by MCLR exposure revealed pathways associated with cell proliferation and survival, including ribosomal protein S6 kinase (RSK), and vascular endothelial growth factor receptor (VEGFR2)-mediated vascular permeability. In addition, several cancer-related KEGG pathways were enriched at both 2 h and 24 h timepoints, and multiple cancer-related disease-gene associations were identified at the 24 h timepoint. Many of the kinases and pathways described above play crucial roles in the development of HCC by affecting processes such as invasion and metastasis. Overall, our data indicate that MCLR-mediated changes in protein phosphorylation involve biological pathways related to carcinogenesis that may contribute to the development of HCC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: John Clarke reports financial support was provided by National Institutes of Health. If there are other authors, they 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 Ltd. All rights reserved.)

Cyanobacterial blooms have emerged as a significant environmental issue worldwide in recent decades. However, the toxic effects of microcystin-LR (MC-LR) on aquatic organisms, such as frogs, have remained poorly understood. In this study, frogs (Pelophylax nigromaculatus) were exposed to environmentally relevant concentrations of MC-LR (0, 1, and 10 μg/L) for 21 days. Subsequently, we assessed the impact of MC-LR on the histomorphology of the frogs' livers and conducted a global MS-based nontarget metabolomics analysis, followed by the determination of substances involved in lipid metabolism. Results showed that MC-LR significantly induced histological alterations in the frogs' hepatopancreas. Over 200 differentially expressed metabolites were identified, primarily enriched in lipid metabolism. Biochemical analysis further confirmed that MC-LR exposure led to a disorder in lipid metabolism in the frogs. This study laid the groundwork for a mechanistic understanding of MC-LR toxicity in frogs and potentially other aquatic organisms., 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 Ltd. All rights reserved.)

Several toxic metabolites, such as aflatoxin M1 (AFM1), are known to contaminate dairy milk. However, as mentioned in an external EFSA report, there is a knowledge gap regarding the carry-over of certain emerging toxins such as microcystin-LR (MC-LR). Therefore, this work aimed to develop an LC-MS/MS method for MC-LR quantification in dairy milk. Also, the method included AFM1 as a common fungal metabolite and applied to analyze 113 dairy milk samples collected directly after the end of the summer peak. Both toxins were below their LODs, keeping the question on MC-LR carry-over still unanswered. Moreover, an in silico analysis, using a 3D molecular modeling was performed, pointing to a possible interaction between MC-LR and milk proteins, especially β-lactoglobulin. Since AFM1 and MC-LR are hepatotoxic, their interaction in inducing mitochondrial dysfunction in HepG2 cells was investigated at low (subcytotoxic) concentrations. Live cell imaging-based assays showed an inhibition in cell viability, without involvement of caspase-3/7, and a hyperpolarization in the mitochondrial membrane potential after the exposure to a mixture of 100 ng mL -1 AFM1 and 1000 ng mL -1 MC-LR for 48h. Extracellular flux analysis revealed inhibitions of several key parameters of mitochondrial function (basal respiration, ATP-linked respiration, and spare respiratory capacity)., 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 study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cyanobacteria blooms (CBs) caused by eutrophication pose a global concern, especially Microcystis aeruginosa (M. aeruginosa), which could release harmful microcystins (MCs). The impact of microplastics (MPs) on allelopathy in freshwater environments is not well understood. This study examined the joint effect of adding polystyrene (PS-MPs) as representative MPs and two concentrations (2 and 8 mg/L) of pyrogallol (PYR) on the allelopathy of M. aeruginosa. The results showed that the addition of PS-MPs intensified the inhibitory effect of 8 mg/L PYR on the growth and photosynthesis of M. aeruginosa. After a 7-day incubation period, the cell density decreased to 69.7 %, and the chl-a content decreased to 48 % compared to the condition without PS-MPs (p < 0.05). Although the growth and photosynthesis of toxic Microcystis decreased with the addition of PS-MPs, the addition of PS-MPs significantly resulted in a 3.49-fold increase in intracellular MCs and a 1.10-fold increase in extracellular MCs (p < 0.05). Additionally, the emission rates of greenhouse gases (GHGs) (carbon dioxide, nitrous oxide and methane) increased by 2.66, 2.23 and 2.17-fold, respectively (p < 0.05). In addition, transcriptomic analysis showed that the addition of PS-MPs led to the dysregulation of gene expression related to DNA synthesis, membrane function, enzyme activity, stimulus detection, MCs release and GHGs emissions in M. aeruginosa. PYR and PS-MPs triggered ROS-induced membrane damage and disrupted photosynthesis in algae, leading to increased MCs and GHG emissions. PS-MPs accumulation exacerbated this issue by impeding light absorption and membrane function, further heightening the release of MCs and GHGs emissions. Therefore, PS-MPs exhibited a synergistic effect with PYR in inhibiting the growth and photosynthesis of M. aeruginosa, resulting in additional risks such as MCs release and GHGs emissions. These results provide valuable insights for the ecological risk assessment and control of algae bloom in freshwater ecosystems., 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 B.V. All rights reserved.)

Cyanobacterial toxins are the most common algal toxins, which are highly toxic and can persist in the aquatic environment without easy degradation, posing risks to the ecosystem and human health that cannot be ignored. Although microbiological methods for the removal of cyanobacterial toxins from aqueous environments are highly efficient, their degradation efficiency is susceptible to many abiotic environmental factors. In this paper, Microcystin-LR (MC-LR) and its microbial degrading enzymes were selected to study the effects of common environmental factors (temperature (T), NO 3 - , NH 4 + , Cu 2+ , Zn 2+ ) and their levels during microbial degradation of cyanobacterial toxins in aqueous environments by using molecular docking, molecular dynamics simulation, analytical factor design, and the combined toxicokinetics of TOPKAT (toxicity prediction). It was found that the addition of T, NO 3 - and Cu 2+ to the aqueous environment promoted the microbial degradation of MC-LR, while the addition of NH 4 + and Zn 2+ inhibited the degradation; The level effect study showed that the microbial degradation of MC-LR was promoted by increasing levels of added T and NO 3 - in the aqueous environment, whereas it was inhibited and then promoted by increasing levels of NH 4 + , Cu 2+ and Zn 2+ . In addition, the predicted toxicity of common Microcystins (MCs) showed that MC-LR, Microcystin-RR (MC-RR) and Microcystin-YR (MC-YR) were not carcinogenic, developmentally toxic, mutagenic or ocular irritants in humans. MC-LR and MC-RR are mild skin irritants and MC-YR is not a skin irritant. MC-YR has a higher chronic and acute toxicity in humans than MC-LR and MC-RR. Acute/chronic toxicity intensity for aquatic animals: MC-YR > MC-LR > MC-RR and for aquatic plants: MC-LR > MC-YR > MC-RR. This suggests that MC-YR also has a high environmental health risk. This paper provides theoretical support for optimizing the environmental conditions for microbial degradation of cyanobacterial toxins by studying the effects of common environmental factors and their level effects in the aquatic environment., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Microcystin-LR (MC-LR), frequently generated by cyanobacteria, has been demonstrated to raise the likelihood of liver disease. Few previous studies have explored the potential antagonist against MC-LR. Astaxanthin (ASX) has been shown to possess various beneficial effects in regulating lipid metabolism in the liver. However, whether ASX could alleviate MC-LR-induced hepatic lipid metabolic dysregulation is as yet unclear. In this work, the important roles and mechanisms of ASX in countering MC-LR-induced liver damage and lipid metabolic dysregulation were explored for the first time. The findings revealed that ASX not only prevented weight loss but also enhanced liver health after MC-LR exposure. Moreover, ASX effectively decreased triglyceride, total cholesterol, aspartate transaminase, and alanine aminotransferase contents in mice that were elevated by MC-LR. Histological observation showed that ASX significantly alleviated lipid accumulation and inflammation induced by MC-LR. Mechanically, ASX could significantly diminish the expression of genes responsible for lipid generation ( Srebp-1c , Fasn , Cd36 , Scd1 , Dgat1 , and Pparg ), which probably reduced lipid accumulation induced by MC-LR. Analogously, MC-LR increased intracellular lipid deposition in THLE-3 cells, while ASX decreased these symptoms by down-regulating the expression of key genes in the lipid synthesis pathway. Our results implied that ASX played a crucial part in lipid synthesis and effectively alleviated MC-LR-induced lipid metabolism dysregulation. ASX might be developed as a novel protectant against hepatic impairment and lipid metabolic dysregulation associated with MC-LR. This study offers new insights for further management of MC-LR-related metabolic diseases.

Irrigation of crops with cyanotoxin-contaminated water poses a significant risk to human health. The direct phytotoxic effects of microcystin-LR (MC-LR), one of the most toxic and prevalent microcystin variants in water bodies, can induce physiological stress and hinder crop development and production. This study investigated the impact of environmentally relevant concentrations of MC-LR (1 to 10 µg L -1 ) on photosynthetic parameters and antioxidant response of lettuce (Lactuca sativa L.) and arugula (Eruca sativa L.) following irrigation with contaminated water. During the 15-day experiment, lettuce and arugula were exposed to various concentrations of MC-LR, and their photosynthetic rates, stomatal conductance, leaf tissue transpiration, and intercellular CO 2 concentrations were measured using an infrared gas analyzer. These results suggest that the influence of MC-LR on gas exchange in crops is concentration-dependent, with notable disruptions during exposure and recovery tendency during detoxification. Antioxidant response analysis revealed that glutathione S-transferase (GST) and superoxide dismutase (SOD) activities were upregulated during the exposure phase in the presence of MC-LR. However, GST activity decreased during the detoxification phase in both crops, although the effects of the toxin at 10 µg L -1 were still evident in arugula. The internal H 2 O 2 concentration in the crops increased after exposure to MC-LR, showing a time- and concentration-dependent pattern, with an increase during the exposure phase (days 1-7) and a decrease during the detoxification phase (days 8-15). Irrigation of lettuce and arugula with MC-LR-contaminated water affected various aspects of the photosynthetic apparatus and antioxidant responses, which could influence the general health and productivity of exposed crops at environmentally relevant microcystin concentrations. Furthermore, investigation of additional vegetable species and long-term MC-LR exposure can be crucial for understanding the extent of contamination risk, detoxification mechanisms, and other parameters affecting these crops., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The toxicity of triclosan (TCS) to various aquatic organisms has been demonstrated at environmental concentrations. However, the effects and mechanisms of TCS on toxic cyanobacteria remains largely unexplored. This study investigated the physiological and molecular variations in two representative toxic Microcystis species (M. aeruginosa and M. viridis) under exposure to TCS for 12 d. Our findings demonstrated that the median effective concentration (EC 50 ) of TCS for both Microcystis species were close to the levels detected in the environment (M. aeruginosa: 9.62 μg L -1 ; M. viridis: 27.56 μg L -1 ). An increased level of reactive oxygen species (ROS) was observed in Microcystis, resulting in oxidative damage when exposed to TCS at concentrations ranging from 10 μg L -1 to 50 μg L -1 . The photosynthetic activity of Microcystis had a certain degree of recovery capability at low concentrations of TCS. Compared to M. aeruginosa, the higher recovery capability of the photosynthetic system in M. viridis would be mainly attributed to the increased ability for PSII repair and phycobilisome synthesis. Additionally, the synthesis of microcystins in the two species and the release rate in M. viridis significantly increased under 10-50 μg L -1 TCS. At the molecular level, exposure to TCS at EC 50 for 12 d induced the dysregulation of genes associated with photosynthesis and antioxidant system. The upregulation of genes associated with microcystin synthesis and nitrogen metabolism further increased the potential risk of microcystin release. Our results revealed the aquatic toxicity and secondary ecological risks of TCS at environmental concentrations, and provided theoretical data with practical reference value for TCS monitoring., 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 Ltd. All rights reserved.)

Harmful algal blooms (HABs) are a persistent and increasing problem globally, yet we still have limited knowledge about how they affect wildlife. Although semi-aquatic and aquatic amphibians and reptiles have experienced large declines and occupy environments where HABs are increasingly problematic, their vulnerability to HABs remains unclear. To inform monitoring, management, and future research, we conducted a literature review, synthesized the studies, and report on the mortality events describing effects of cyanotoxins from HABs on freshwater herpetofauna. Our review identified 37 unique studies and 71 endpoints (no-observed-effect and lowest-observed-effect concentrations) involving 11 amphibian and 3 reptile species worldwide. Responses varied widely among studies, species, and exposure concentrations used in experiments. Concentrations causing lethal and sublethal effects in laboratory experiments were generally 1 to 100 µg/L, which contains the mean value of reported HAB events but is 70 times less than the maximum cyanotoxin concentrations reported in the environment. However, one species of amphibian was tolerant to concentrations of 10,000 µg/L, demonstrating potentially immense differences in sensitivities. Most studies focused on microcystin-LR (MC-LR), which can increase systemic inflammation and harm the digestive system, reproductive organs, liver, kidneys, and development. The few studies on other cyanotoxins illustrated that effects resembled those of MC-LR at similar concentrations, but more research is needed to describe effects of other cyanotoxins and mixtures of cyanotoxins that commonly occur in the environment. All experimental studies were on larval and adult amphibians; there were no such studies on reptiles. Experimental work with reptiles and adult amphibians is needed to clarify thresholds of tolerance. Only nine mortality events were reported, mostly for reptiles. Given that amphibians likely decay faster than reptiles, which have tissues that resist decomposition, mass amphibian mortality events from HABs have likely been under-reported. We propose that future efforts should be focused on seven major areas, to enhance our understanding of effects and monitoring of HABs on herpetofauna that fill important roles in freshwater and terrestrial environments. Environ Toxicol Chem 2024;43:1936-1949. Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Microcystins (MCs) are secondary metabolites generated by cyanobacterial blooms, among which microcystin-LR (MC-LR) stands out as the most widely distributed variant in aquatic environments. However, the effects of MC-LR on the colorectum and its role in promoting colorectal tumor progression remain unclear. Therefore, this study aims to scrutinize the impact of MC-LR on a mice model of colitis-associated colorectal cancer and elucidate the potential underlying molecular mechanisms. In this study, we used AOM/DSS mice and orally administered MC-LR at doses of 40 µg/kg or 200 µg/kg. Exposure to MC-LR increased tumor burden, promoted tumor growth, shortened colon size, and decreased goblet cell numbers and tight junction protein levels in intestinal tissues. Additionally, exposure to MC-LR induced alterations in the structure of gut microbiota in the mouse colon, characterized by an increase in the relative abundance of Escherichia&#95;coli and Shigella&#95;sonnei, and a decline in the relative abundance of Akkermansia&#95;muciniphila. Transcriptomic analysis revealed that MC-LR exposure activated the IL-17 signaling pathway in mouse colorectal tissues and participated in inflammation regulation and immune response. Immunofluorescence results demonstrated an increase in T-helper 17 (Th17) cell levels in mouse colorectal tumors following MC-LR exposure. The results from RT-qPCR revealed that MC-LR induced the upregulation of IL-6, IL-1β, IL-10, IL-17A, TNF-α, CXCL1, CXCL2, CXCL5 and CCL20. The novelty of this study lies in its comprehensive approach to understanding the mechanisms by which MC-LR may contribute to CRC progression, offering new perspectives and valuable reference points for establishing guidance standards regarding MC-LR in drinking water. Our findings suggest that even at guideline value, MC-LR can have profound effects on susceptible mice, emphasizing the need for a reevaluation of guideline value and a deeper understanding of the role of environmental toxins in cancer progression., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ting Wang reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they 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 Inc. All rights reserved.)

Microcystin (MC) is the byproduct of cyanobacteria metabolism that is associated with oxidative stress and heart damage. This study aimed to investigate the effect of ginsenoside Rg3 on MC-induced cardiotoxicity. A mouse model of myocardial infarction was constructed by oral MC administration. H9C2 cells were used for in vitro analysis. Cellular oxidative stress, apoptosis, and the relationship between miR-128-3p and double minute 4 protein (MDM4) were analyzed. MiR-128-3p expression was upregulated in vitro and in vivo after MC treatment, which was downregulated after Rg3 treatment. Left ventricular ejection fraction (LVEF) and left ventricular systolic pressure (LVSP) were increased and left ventricular end-diastolic pressure (LVEDP) was decreased after Rg3 treatment. Moreover, Rg3 alleviated MC-induced pathological changes and apoptosis in myocardial tissues. Meanwhile, Rg3 treatment decreased the lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels and inhabited cell apoptosis and oxidative stress in MC-treated myocardial cells. MiR-128-3p overexpression attenuated the protective effect of Rg3 on MC-induced cardiotoxicity. MiR-128-3p negatively regulated MDM4 expression. This study revealed that Rg3 alleviated MC-induced cardiotoxicity through the miR-128-3p/MDM4 axis, which emphasized the potential of Rg3 as a therapeutic agent for MC-induced cardiotoxicity, and miR-128-3p as a target for the Rg3 therapy.

Cyanobacterial blooms are worldwide distributed and threaten aquatic ecosystems and public health. The current studies mainly focus on the adverse impacts of planktonic cyanobacteria or pure cyanotoxins, while the benthic cyanobacteria-induced ecotoxic effects are relatively lacking. The cyanobacterial cell-induced toxic effects on aquatic organisms might be more serious and complex than the pure cyanotoxins and crude extracts of cyanobacteria. This study explored the chronic effects of toxin-producing planktonic Microcystis aeruginosa (producing microcystin) and benthic Oscillatoria sp. (producing cylindrospermopsin) on the behaviors, tissue structures, oxidative stress, apoptosis, and inflammation of the Asian clams (Corbicula fluminea) under 28-d exposure. The data showed that both M. aeruginosa and Oscillatoria sp. can decrease the behaviors associated with the feeding activity and induce tissue damage (i.e. gill and digestive gland) in clams. Furthermore, two kinds of cyanobacteria can alter the antioxidant enzyme activities and increase antioxidant, lipid oxidation product, and neurotransmitter degrading enzyme levels in clams. Moreover, two kinds of cyanobacteria can activate apoptosis-related enzyme activities and enhance the proinflammatory cytokine levels of clams. In addition, two kinds of cyanobacteria can disturb the transcript levels of genes linked with oxidative stress, apoptosis, and inflammation. These results suggested harmful cyanobacteria can threaten the survival and health of clams, while the benthic cyanobacteria-induced adverse effects deserve more attention. Our finding also indicated that it is necessary to focus on the entire algal cell-induced ecotoxicity when concerning the ecological impacts of cyanobacterial blooms., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Contributing to the assessment of potential physiological changes in microalgae subjected to different concentrations and types of cyanotoxins, this study investigated the inhibitory effects of cyanotoxins on the growth, density, biomass, and ecotoxicity of Chlorella vulgaris. Chlorella vulgaris was exposed to crude extracts of cyanobacteria producing microcystin-LR (MC-LR), saxitoxin (SXT), anatoxin-a (ATX-A), and cylindrospermopsin (CYN) with initial concentrations of 5.0, 2.05, 0.61, and 1.42 μg.L -1 , respectively. The experiments were conducted under controlled conditions, and monitoring of growth and cell inhibition occurred at 24h, 48h, 72h, and 96h. Chlorophyll-a content and ecotoxicity assessment were conducted with samples collected after 96h of exposure to cyanotoxins. The growth assays of Chlorella vulgaris, with results expressed in terms of average growth rates (doublings/day), indicated the following order for cyanotoxins: SXT (2.03) > CYN (1.66) > MC-LR (1.56) > ATX-A (0.18). This assay revealed the prominent inhibitory potential of ATX-A on Chlorella vulgaris growth compared to the other toxins evaluated. Regarding the inhibition of the photosynthetic process, expressed in terms of the percentage inhibition of Chlorophyll-a, the following order for cyanotoxins was obtained: ATX-A (82%) > MC-LR (76%) > STX (46%) > CYN (16%). These results also indicated that among the cyanotoxins, ATX-A was the most detrimental to the photosynthetic process. However, contrary to the observations in the growth study, SXT proved to be more harmful than CYN in terms of Chlorophyll-a inhibition. Finally, the results of the toxicity assay revealed that only ATX-A and MC-LR exerted a chronic influence on Chlorella vulgaris under the investigated conditions., 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 Ltd. All rights reserved.)

To date there are only pirfenidone (PFD) and nintedanib to be given conditional recommendation in idiopathic pulmonary fibrosis (IPF) therapies with slowing disease progression, but neither has prospectively shown a reduced mortality. It is one of the urgent topics to find effective drugs for pulmonary fibrosis in medicine. Previous studies have demonstrated that microcystin-RR (MC-RR) effectively alleviates bleomycin-induced pulmonary fibrosis, but the mechanism has not been fully elucidated yet. We further conducted a comparison of therapeutic effect on the model animals of pulmonary fibrosis between MC-RR and PFD with histopathology and the expression of the molecular markers involved in differentiation, proliferation and metabolism of myofibroblasts, a major effector cell of tissue fibrosis. The levels of the enzyme molecules for maintaining the stability of interstitial structure were also evaluated. Our results showed that MC-RR and PFD effectively alleviated pulmonary fibrosis in model mice with a decreased signaling and marker molecules associated with myofibroblast differentiation and lung fibrotic lesion. In the meantime, both MC-RR and PFD treatment are beneficial to restore molecular dynamics of interstitial tissue and maintain the stability of interstitial architecture. Unexpectedly, MC-RR, rather than PFD, showed a significant effect on inhibiting PKM2-HIF-1α signaling and reducing the level of p-STAT3. Additionally, MC-RR showed a better inhibition effect on FGFR1 expression. Given that PKM2-HIF-1α and activated STAT3 molecular present a critical role in promoting the proliferation of myofibroblasts, MC-RR as a new strategy for IPF treatment has potential advantage over PFD., 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 Ltd. All rights reserved.)

The systemic toxicity of cyclic peptides produced by cyanobacteria (CCPs) is not yet completely understood. Apart from the most known damages to the liver and kidneys, symptoms of their neurotoxicity have also been reported. Hepatotoxic CCPs, like microcystins, as well as non-hepatotoxic anabaenopeptins and planktopeptins, all exhibit cytotoxic and cytostatic effects on mammalian cells. However, responses of different cell types to CCPs depend on their specific modes of interaction with cell membranes. This study demonstrates that non-hepatotoxic planktopeptin BL1125 and anabaenopeptins B and F, at concentrations up to 10 µM, affect normal and tumor human astrocytes (NHA and U87-GM) in vitro by their almost immediate insertion into the lipid monolayer. Like microcystin-LR (up to 1 µM), they inhibit Ser/Thr phosphatases and reorganize cytoskeletal elements, with modest effects on their gene expression. Based on the observed effects on intermediate filaments and intermediate filament linkage elements, their direct or indirect influence on tubulin cytoskeletons via post-translational modifications, we conclude that the basic mechanism of CCP toxicities is the induction of inter- and intracellular communication failure. The assessed inhibitory activity on Ser/Thr phosphatases is also crucial since the signal transduction cascades are modulated by phosphorylation/dephosphorylation processes.

Objective: Microcystin-leucine-arginine (MC-LR) exposure induces lipid metabolism disorders in the liver. Secreted frizzled-related protein 5 (SFRP5) is a natural antagonist of winglesstype MMTV integration site family, member 5A (Wnt5a) and an anti-inflammatory adipocytokine. In this study, we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5, which has anti-inflammatory effects, can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase (JNK) pathway., Methods: We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders. Subsequently, mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR, and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed., Results: MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner. SFRP5 overexpression in AML12 cells suppressed MC-LR-induced inflammation. Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK., Conclusion: MC-LR can induce lipid metabolism disorders in mice, and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Anthropic eutrophication leads to water quality degradation because it may cause the development of harmful cyanobacterial blooms, affecting aquatic biota and threatening human health. Because in the natural environment zooplankters are exposed continuously or intermittently to cyanotoxins in the water or through cyanobacterial consumption, this study aimed to assess the effects of the toxigenic Microcystis aeruginosa VU-5 by different ways of exposure in Daphnia curvirostris . The acute toxicity produced by the cells, the aqueous crude extract of cells (ACE), and the cell-free culture medium (CFM) were determined. The effect on the survival and reproduction of D. curvirostris under continuous and intermittent exposure was determined during 26 d. The LC 50 was 407,000 cells mL -1 ; exposure to the ACE and CFM produced mortality lower than 20%. Daphnia survivorship and reproduction were significantly reduced. Continuous exposure to Microcystis cells caused 100% mortality on the fourth day. Exposure during 4 and 24 h in 48 h cycles produced adult mortality, and reproduction decreased as the exposure time and the Microcystis concentrations increased. The higher toxicity of cells than the ACE could mean that the toxin's absorption is higher in the digestive tract. The temporary exposure to Microcystis cells produced irreversible damage despite the recovery periods with microalgae as food. The form and the continuity in exposure to Microcystis produced adverse effects, warning about threats to the zooplankton during HCBs.

Cyanobacterial blooms are increasingly common during winters, especially when they are mild. The goal of this study was to determine the summer and winter phytoplankton community structure, cyanotoxin presence, and toxigenicity in a eutrophic lake susceptible to cyanobacterial blooms throughout the year, using classical microscopy, an analysis of toxic cyanometabolites, and an analysis of genes involved in biosynthesis of cyanotoxins. We also assessed whether cyanobacterial diversity in the studied lake has changed compared to what was reported in previous reports conducted several years ago. Moreover, the bloom-forming cyanobacterial strains were isolated from the lake and screened for cyanotoxin presence and toxigenicity. Cyanobacteria were the main component of the phytoplankton community in both sampling times, and, in particular, Oscillatoriales were predominant in both summer ( Planktothrix / Limnothrix ) and winter ( Limnothrix ) sampling. Compared to the winter community, the summer community was denser; richer in species; and contained alien and invasive Nostocales, including Sphaerospermopsis aphanizomenoides , Raphidiopsis raciborskii , and Raphidiopsis mediterranea . In both sampling times, the blooms contained toxigenic species with genetic determinants for the production of cylindrospermopsin and microcystins. Toxicological screening revealed the presence of microcystins in the lake in summer but no cyanotoxins in the winter period of sampling. However, several cyanobacterial strains isolated from the lake during winter and summer produced anabaenopeptins and microcystins. This study indicates that summer and winter blooms of cyanobacteria in the temperate zone can differ in biomass, structure, and toxicity, and that the toxic hazards associated with cyanobacterial blooms may potentially exist during winter.

Ecological risk of micro/nano-plastics (MPs/NPs) has become an important environmental issue. Microcystin-leucine-arginine (MC-LR) produced by Microcystis aeruginosa (M. aeruginosa) is the most common and toxic secondary metabolites (SM). However, the influencing mechanism of MPs and NPs exposure on MC-LR synthesis and release have still not been clearly evaluated. In this work, under both acute (4d) and long-term exposure (10d), only high-concentration (10 mg/L) exposure of amino-modified polystyrene NPs (PS-NH 2 -NPs) promoted MC-LR synthesis (32.94 % and 42.42 %) and release (27.35 % and 31.52 %), respectively. Mechanistically, PS-NH 2 -NPs inhibited algae cell density, interrupted pigment synthesis, weakened photosynthesis efficiency, and induced oxidative stress, with subsequent enhancing the MC-LR synthesis. Additionally, PS-NH 2 -NPs exposure up-regulated MC-LR synthesis pathway genes (mcyA, mcyB, mcyD, and mcyG) combined with significantly increased metabolomics (Leucine and Arginine), thereby enhancing MC-LR synthesis. PS-NH 2 -NPs exposure enhanced the MC-LR release from M. aeruginosa via up-regulated MC-LR transport pathway genes (mcyH) and the shrinkage of plasma membrane. Our results provide new insights into the long-time coexistence of NPs with algae in freshwater systems might pose a potential threat to aquatic environments and human health., 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 B.V. All rights reserved.)

The degradation of cyanobacterial blooms releases hazardous contaminants such as microcystin-LR (MC-LR) and nitrite, which may collectively exert toxicity on various bodily systems. To evaluate their individual and combined toxicity in the kidney, mice were subjected to different concentrations of MC-LR and/or nitrite over a 6-month period in this study. The results revealed that combined exposure to MC-LR and nitrite exacerbated renal pathological alterations and dysfunction compared to exposure to either compound alone. Specifically, the protein and mRNA expression of kidney injury biomarkers, such as kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), were notably increased in combined exposure group. Concurrently, co-exposure to MC-LR and nitrite remarkedly upregulated levels of proinflammatory cytokines TNF-α, IL-6 and IL-1β, while decreasing the anti-inflammatory cytokine IL-10. Notably, MC-LR and nitrite exhibited synergistic effects on the upregulation of renal IL-1β levels. Moreover, MC-LR combined with nitrite not only elevated mRNA levels of proinflammatory cytokines but also increased protein levels of pyroptosis biomarkers such as IL-1β, Gasdermin D (GSDMD), and Cleaved-GSDMD. Mechanistic investigations revealed that co-exposure to MC-LR and nitrite promoted pyroptosis both in vivo and in vitro, possibly through the activation of the TLR4/NLRP3/GSDMD pathway. Pretreatment with TLR4 inhibitor and NLRP3 inhibitor effectively suppressed pyroptosis induced by the co-exposure of these two toxins in HEK293T cells. These findings provide compelling evidence that MC-LR combined with nitrite synergistically induces pyroptosis in the kidney by activating the TLR4/NLRP3/GSDMD pathway. Overall, this study significantly enhances our comprehension of how environmental toxins interact and induce harm to the kidneys, offering promising avenues for identifying therapeutic targets to alleviate their toxic effects on renal health., 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 Inc. All rights reserved.)

The mass proliferation of cyanobacteria, episodes known as blooms, is a concern worldwide. One of the most critical aspects during these blooms is the production of toxic secondary metabolites that are not limited to the four cyanotoxins recognized by the World Health Organization. These metabolites comprise a wide range of structurally diverse compounds that possess bioactive functions. Potential human and ecosystem health risks posed by these metabolites and co-produced mixtures remain largely unknown. We studied acute lethal and sublethal effects measured as impaired mobility on the freshwater microcrustaceans Thamnocephalus platyurus for metabolite mixtures from two cyanobacterial strains, a microcystin (MC) producer and a non-MC producer. Both cyanobacterial extracts, from the MC-producer and non-MC-producer, caused acute toxicity with LC 50 (24 h) values of 0.50 and 2.55 mg dw&#95;biomass /mL, respectively, and decreased locomotor activity. Evaluating the contribution of different cyanopeptides revealed that the Micropeptin-K139-dominated fraction from the MC-producer extract contributed significantly to mortality and locomotor impairment of the microcrustaceans, with potential mixture effect with other cyanopeptolins present in this fraction. In the non-MC-producer extract, compounds present in the apolar fraction contributed mainly to mortality, locomotor impairment, and morphological changes in the antennae of the microcrustacean. No lethal or sublethal effects were observed in the fractions dominated by other cyanopetides (Cyanopeptolin 959, Nostoginin BN741). Our findings contribute to the growing body of research indicating that cyanobacterial metabolites beyond traditional cyanotoxins cause detrimental effects. This underscores the importance of toxicological assessments of such compounds, also at sublethal levels., Competing Interests: Declaration of competing interest There are no competing interests regarding the publication, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nanoplastics (NPs) and microcystin-LR (MC-LR) are two common and harmful pollutants in water environments, especially at aquafarm where are full of plastic products and algae. It is of great significance to study the toxic effects and mechanisms of the NPs and/or MC-LR on fish at the early stage. In this study, the embryo and larvae of a filtering-feeding fish, Aristichthys nobilis, were used as the research objects. The results showed that the survival and hatching rates of the embryo were not significantly affected by the environmental concentration exposure of these two pollutants. Scanning electron microscopy (SEM) observation displayed that NPs adhered to the surface of the embryo membrane. Transcriptomic and bioinformatic analyses revealed that the NPs exposure activated neuromuscular junction development and skeletal muscle fiber in larvae, and affected C5-Branched dibasic acid metabolism. The metabolic and biosynthetic processes of zeaxanthin, xanthophyll, tetraterpenoid, and carotenoid were suppressed after the MC-LR exposure, which was harmful to the retinol metabolism of fish. Excessive production of superoxide dismutase (SOD) was detected under the MC-LR exposure. The MC-LR and NPs coexposure triggered primary immunodeficiency and adaptive immune response, leading to the possibility of reduced fitness of A.nobilis during the development. Collectively, our results indicate that environmental concentration NPs and MC-LR coexposure could cause toxic damage and enhance sick risk in A.nobilis, providing new insights into the risk of NPs and MC-LR on filtering-feeding fish., 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 B.V. All rights reserved.)

This study explored the regulatory role of bta-miR-149-3p in the inflammatory response induced by microcystin-leucine arginine (MC-LR) exposure in bovine Sertoli cells. The research endeavored to enhance the comprehension of the epigenetic mechanisms underlying MC-LR-induced cytotoxicity in Sertoli cells and establish a foundation for mitigating these effects in vitro. In this study, we elucidated the regulatory mechanism of bta-miR-149-3p in the MC-LR-induced inflammatory response by verifying the target gene of bta-miR-149-3p through luciferase assays and treating the cells with a bta-miR-149-3p inhibitor for 24 h. The results demonstrate that nuclear factor κB (NF-κB) acts as a downstream target gene of bta-miR-149-3p, which inhibits the MC-LR-induced inflammatory response in bovine Sertoli cells. This inhibition occurs by regulating the downregulation of tight junction constitutive proteins of the blood-testis barrier (BTB) through the suppression of the TLR-4/NF-κB signaling pathway (p < 0.05) and the up-regulation of the adhesion junction protein β-catenin (p < 0.05). Notably, MC-LR exposure resulted in the up-regulation (p < 0.05) of inflammatory cytokines (IL-6, IL-1β, and NLRP3) and the down-regulation (p < 0.05) of BTB tight junction constitutive proteins (ZO-1, Occludin) in Sertoli cells. Furthermore, the BTB constitutive protein ZO-1 exhibited significant down-regulation in Sertoli cells pretreated with the bta-miR-149-3p inhibitor compared to controls (p < 0.05), while Occludin showed no significant difference from CTNNB1 (p > 0.05). In summary, our findings suggest that bta-miR-149-3p suppresses the MC-LR-induced inflammatory response and alterations in the expression of BTB proteins in bovine Sertoli cells by inhibiting the TLR-4/NF-κB signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Peracetic acid (PAA) shows potential for use in drinking water treatment as an alternative to prechlorination, such as for mussel control and disinfection by-product precursor destruction, though its impact as a preoxidant during cyanobacterial blooms remains underexplored. Here, Microcystis aeruginosa inactivation and microcystin-LR and -RR release and degradation using PAA were explored. The toxin degradation rates were found to be higher in alkaline conditions than in neutral and acidic conditions. However, all rates were significantly smaller than comparable rates when using free chlorine. The inactivation of M. aeruginosa cells using PAA was faster at acidic pH, showing immediate cell damage and subsequent cell death after 15-60 min of exposure to 10 mg/L PAA. In neutral and alkaline conditions, cell death occurred after a longer lag phase (3-6 h). During cell inactivation, microcystin-LR was released slowly, with <35% of the initial intracellular toxins measured in solution after 12 h of exposure to 10 mg/L PAA. Overall, PAA appears impractically slow for M. aeruginosa cell inactivation or microcystin-LR and -RR destruction in drinking water treatment, but this slow reactivity may also allow it to continue to be applied as a preoxidant for other purposes during cyanobacterial blooms without the risk of toxin release.

Potentially toxic cyanobacterial blooms (cyanoHABs) have become a problem in public water supply reservoirs. Temperature rise caused by climate change can increase the frequency and intensity of blooms, which may influence the cyanotoxins concentration in the environment. This study aimed to evaluate the effect of the temperature on the responses of a Neotropical catfish exposed to a neurotoxin-rich cyanobacterial crude extract (Raphidiopsis raciborskii T3). Juveniles of Rhamdia quelen were exposed to four treatments, based on study data: control at 25 °C (C25), control at 30 °C (C30), crude extract equivalent to 10 5  cells.mL -l of R. raciborskii at 25 °C (CE25) and 30 °C (CE30). After 96 h of exposure, the fish were anesthetized and blood was taken. After euthanasia, the gill, posterior kidney, brain, muscle, liver and gonad were sampled for hematological, biochemical, genotoxic and histopathological biomarker analysis. Liver was sampled for proteomic analysis for identification of proteins related to energy production. Water samples were collected at the beginning and the end of the experiment for neurotoxins quantification. Different parameters in both males and females were altered at CE25, evidencing the effects of neurotoxins in freshwater fish. At CE30, a water warming scenario, more effects were observed in females than at 25 °C, such as activation of saxitoxin metabolism pathway and genotoxicity. More damage to macromolecules was observed in females at the higher temperature, demonstrating that the increase in temperature can aggravate the toxicity of neurotoxins produced by R. raciborskii T3., 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 Ltd. All rights reserved.)

Microcystins (MCs) are toxic to the central nervous system of mammals. However, the direct toxicity of MCs on mammalian brain cells and the involved molecular mechanisms are not fully elucidated. Here, we incubated primary astrocytes, the major glial cell-type in the brain, with 0-12.5 μM concentrations of MC-LR for 48 h, and the impairment was evaluated. We found that MC-LR caused significant increases in the cell viability at the range of 0.05-1 μM concentrations with the highest density at 0.1 μM concentration. Treatment with 0.1 μM MC-LR induced YAP nuclear translocation and decreased the ratio of p-YAP to YAP. It also decreased mRNA levels of the upstream regulator (AMOT), and enhanced expressions of YAP interacted genes (Egfr, Tead1, and Ctgf) in primary astrocytes. Overexpression of AMOT significantly attenuated the increase of MC-LR-induced astrocyte proliferation and the expression of YAP downstream genes. These results indicate that Hippo signaling contributed to MC-LR-caused astrocyte proliferation. Further, reactive astrogliosis was observed in the mice brain after MC-LR exposure to environmentally relevant concentrations (20 or 100 μg/L) through drinking water for 16 weeks. Pathological observations revealed that 100 μg/L MC-LR exposure caused neuronal damages with characteristics of shrunken or vacuolation in the region of the cerebral cortex, striatum and cerebellum. These results were accompanied with increased oxidative stress and inflammatory response. Our data reveal the potential astrocytic mechanisms in MC-induced neurotoxicity and raise an alarm for neurodegenerative disease risk following daily exposure to MC-LR., 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 Inc. All rights reserved.)

Global climate change as well as human activities have been reported to increase the frequency and severity of both salinization and harmful algal blooms (HABs) in many freshwater systems, but their co-effect on benthic invertebrates has rarely been studied. This study simultaneously examined the joint toxicity of salinity and different cyanobacterial diets on the behavior, development, select biomarkers, and partial life cycle of Chironomus pallidivittatus (Diptera). High concentrations of salts (e.g., 1 g/L Ca 2+ and Mg 2+ ) and toxic Microcystis had synergistic toxicity, inhibiting development, burrowing ability and causing high mortality of C. pallidivittatus, especially for the Mg 2+ treatment, which caused around 90% death. Low Ca 2+ concentration (e.g., 0.01 g/L) promoted larval burrowing ability and inhibited toxin accumulation, which increased the tolerance of Chironomus to toxic Microcystis. However, low Mg 2+ concentration (e.g., 0.01 g/L) was shown to inhibit the behavior, development and increase algal toxicity to Chironomus. Toxic Microcystis resulted in microcystin (MC) accumulation, inhibited the burrowing ability of larvae, and increased the proportion of male adults (>50%). The combined toxicity level from low to high was verified by the weight of evidence and the grey TOPSIS model, which integrated five lines of evidence to increase the risk assessment accuracy and efficiency. This is the first study that provided insights into ecological risk arising from the joint effect of salinity and harmful algae on benthic organisms. We suggest that freshwater salinization and HABs should be considered together when assessing ecological threats that arise from external stress., 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 Ltd. All rights reserved.)

Microcystin-LR (MC-LR) and sodium nitrite (NaNO 2 ) co-exist in the environment and are hepatotoxic. The liver has the function of lipid metabolism, but the impacts and mechanisms of MC-LR and NaNO 2 on liver lipid metabolism are unclear. Therefore, we established a chronic exposure model of Balb/c mice and used LO2 cells for in vitro verification to investigate the effects and mechanisms of liver lipid metabolism caused by MC-LR and NaNO 2 . The results showed that after 6 months of exposure to MC-LR and NaNO 2 , the lipid droplets content was increased, and the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were raised in the liver (P < 0.05). Moreover, MC-LR and NaNO 2 synergistically induced hepatic oxidative stress by decreasing total superoxide dismutase (T-SOD) activity and glutathione (GSH) levels and increasing malondialdehyde (MDA) content levels. In addition, the levels of Nrf2, HO-1, NQO1 and P-AMPK was decreased and Keap1 was increased in the Nrf2/HO-1 pathway. The key factors of lipid metabolism, SREBP-1c, FASN and ACC, were up-regulated in the liver. More importantly, there was a combined effect on lipid deposition of MC-LR and NaNO 2 co-exposure. In vitro experiments, MC-LR and NaNO 2 -induced lipid deposition and changes in lipid metabolism-related changes were mitigated after activation of the Nrf2/HO-1 signaling pathway by the Nrf2 activator tertiary butylhydroquinone (TBHQ). Additionally, TBHQ alleviated the rise of reactive oxygen species (ROS) in LO2 cells induced by MC-LR and NaNO 2 . Overall, our findings indicated that MC-LR and NaNO 2 can cause abnormal liver lipid metabolism, and the combined effects were observed after MC-LR and NaNO 2 co-exposure. The Nrf2/HO-1 signal pathway may be a potential target for prevention and control of liver toxicity caused by MC-LR and NaNO 2 ., 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 Inc.)

The health risks associated with combined exposure to microplastics (MPs) and cyanobacteria toxins have gained increasing attention due to the large-scale prevalence of cyanobacterial blooms and accumulation of MPs in aquatic environments. Therefore, we explored the cardiovascular toxic effects of microcystin-LR (MC-LR, 1, 10, 100 μg/L) in the presence of 5 μm polystyrene microplastics (PS-MPs, 100 μg/L) and 80 nm polystyrene nanoplastics (PS-NPs, 100 μg/L) in zebrafish models. Embryos were exposed to certain PS-MPs and PS-NPs conditions in water between 3 h post-fertilization (hpf) and 168 hpf. Compared to MC-LR alone, a significant decrease in heart rate was observed as well as notable pericardial edema in the MC-LR + PS-MPs/NPs groups. At the same time, sinus venosus and bulbus arteriosus (SV-BA) distances were significantly increased. Furthermore, the addition of PS-MPs/NPs caused thrombosis in the caudal vein and more severe vascular damage in zebrafish larvae compared to MC-LR alone. Our findings revealed that combined exposure to PS-NPs and MC-LR could significantly decreased the expression of genes associated with cardiovascular development (myh6, nkx2.5, tnnt2a, and vegfaa), ATPase (atp1a3b, atp1b2b, atp2a1l, atp2b1a, and atp2b4), and the calcium channel (cacna1ab and ryr2a) compared to exposure to MC-LR alone. In addition, co-exposure with PS-MPs/NPs exacerbated the MC-LR-induced reactive oxygen species (ROS) production, as well as the ROS-stimulated apoptosis and heightened inflammation. We also discovered that astaxanthin (ASTA) treatment partially attenuated these cardiovascular toxic effects. Our findings confirm that exposure to MC-LR and PS-MPs/NPs affects cardiovascular development through calcium signaling interference and ROS-induced cardiovascular cell apoptosis. This study highlights the potential environmental risks of the co-existence of MC-LR and PS-MPs/NPs for fetal health, particularly cardiovascular development., 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 Ltd. All rights reserved.)

Microcystin-leucine arginine (MC-LR) is a common cyantotoxin produced by hazardous cyanobacterial blooms, and eutrophication is increasing the contamination level of MC-LR in drinking water supplies and aquatic foods. MC-LR has been linked to colorectal cancer (CRC) progression associated with tumor microenvironment, however, the underlying mechanism is not clearly understood. In present study, by using GEO, KEGG, GESA and ImmPort database, MC-LR related differentially expressed genes (DEGs) and pathway- and gene set-enrichment analysis were performed. Of the three identified DEGs (CXCL1, GUCA2A and GDF15), CXCL1 was shown a positive association with tumor infiltration, and was validated to have a dominantly higher upregulation in MC-LR-treated tumor-associated macrophages (TAMs) rather than in MC-LR-treated CRC cells. Both CRC cell/macrophage co-culture and xenograft mouse models indicated that MC-LR stimulated TAMs to secrete CXCL1 resulting in promoted proliferation, migration, and invasion capability of CRC cells. Furtherly, IP-MS assay found that interaction between TAMs-derived CXCL1 and CRC cell-derived IGHG1 may enhance CRC cell proliferation and migration after MC-LR treatment, and this effect can be attenuated by silencing IGHG1 in CRC cell. In addition, molecular docking analysis, co-immunoprecipitation and immunofluorescence further proved the interactions between CXCL1 and IGHG1. In conclusion, CXCL1 secreted by TAMs can trigger IGHG1 expression in CRC cells, which provides a new clue in elucidating the mechanism of MC-LR-mediated CRC progression., 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 Ltd. All rights reserved.)

The rise in cyanobacterial blooms due to eutrophication and climate change has increased cyanotoxin presence in water. Most current water treatment plants do not effectively remove these toxins, posing a potential risk to public health. This study introduces a water treatment approach using nanostructured beads containing magnetic nanoparticles (MNPs) for easy removal from liquid suspension, coated with different adsorbent materials to eliminate cyanotoxins. Thirteen particle types were produced using activated carbon, CMK-3 mesoporous carbon, graphene, chitosan, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidised cellulose nanofibers (TOCNF), esterified pectin, and calcined lignin as an adsorbent component. The particles' effectiveness for detoxification of microcystin-LR (MC-LR), cylindrospermopsin (CYN), and anatoxin-A (ATX-A) was assessed in an aqueous solution. Two particle compositions presented the best adsorption characteristics for the most common cyanotoxins. In the conditions tested, mesoporous carbon nanostructured particles, P1-CMK3, provide good removal of MC-LR and Merck-activated carbon nanostructured particles, P9-MAC, can remove ATX-A and CYN with high and fair efficacy, respectively. Additionally, in vitro toxicity of water treated with each particle type was evaluated in cultured cell lines, revealing no alteration of viability in human renal, neuronal, hepatic, and intestinal cells. Although further research is needed to fully characterise this new water treatment approach, it appears to be a safe, practical, and effective method for eliminating cyanotoxins from water.

The physical and chemical properties of silver nanoparticles (AgNPs) have led to their increasing use in various fields such as medicine, food, and industry. Evidence has proven that AgNPs cause adverse effects in aquatic ecosystems, especially when the release of Ag is prolonged in time. Several studies have shown short-term adverse effects of AgNPs on freshwater phytoplankton, but few studies have analysed the impact of long-term exposures on these populations. Our studies were carried out to assess the effects of AgNPs on growth rate, photosynthesis activity, and reactive oxygen species (ROS) generation on the freshwater green algae Scenedesmus armatus and the cyanobacteria Microcystis aeruginosa, and additionally on microcystin (MC-LR) generation from these cyanobacteria. The tests were conducted both in single-species cultures and in phytoplanktonic communities exposed to 1 ngL -1 AgNPs for 28 days. The results showed that cell growth rate of both single-species cultures decreased significantly at the beginning and progressively reached control-like values at 28 days post-exposure. This effect was similar for the community-cultured cyanobacteria, but not for the green algae, which maintained a sustained decrease in growth rate. While gross photosynthesis (Pg) increased in both strains exposed in single cultures, dark respiration (R) and net photosynthesis (Pn) decreased in S. armatus and M. aeruginosa, respectively. These effects were mitigated when both strains were exposed under community culture conditions. Similarly, the ROS generation shown by both strains exposed in single-species cultures was mitigated when exposure occurred in community cultures. MC-LR production and release were significantly decreased in both single-species and community exposures. These results can supply helpful information to further investigate the potential risks of AgNPs and ultimately help policymakers make better-informed decisions about their utilization for environmental restoration., 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 B.V. All rights reserved.)

Microcystins (MCs) have a significant influence on aquatic ecosystems, but little is known about their terrestrial fate and impact. Here, we investigated the fate of two MCs (MC-LR and MC-RR) in the soil-earthworm system, with consideration of their congener-specific impact on earthworm health, soil bacteria, and soil metabolome. Although MCs had little acute lethal effect on earthworms, they caused obvious growth inhibition and setae rupture. Relative to MC-RR, MC-LR exhibited higher bioaccumulation and the resulting dermal lesions and deformation of longitudinal muscles. While the incorporation of both MCs into soils stimulated pathogenic bacteria and depressed oxidative stress tolerant bacteria, the response among soil nitrification and glutathione metabolism differed between the two congeners. The dissipation kinetics of MCs obeyed the first-order model. Earthworms stimulated soil N-cycling enzyme activities, increased the abundance of MC-degrading bacteria, and promoted bacterial metabolic functions related to glutathione metabolism, xenobiotics biodegradation, and metabolism of amino acids that comprise MCs, which accelerated the dissipation of MC-LR and MC-RR by 227% and 82%, respectively. These results provide evidence of significant congener differences in the terrestrial fate and impact of MCs, which will enable a better understanding of their role in mediating soil functions and ecosystem services., 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 B.V. All rights reserved.)