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Microcystins (MCs) and nitrites are coexisted in the environment and have reproductive toxicity. The combined toxic effect and mechanism of MCs and nitrite on spermatogenesis remain largely unclear. In the present study, co-exposure to microcystin-leucine arginine (MC-LR) and sodium nitrite (NaNO 2 ) aggravated testicular damage of Balb/c mice and mitochondrial impairment of spermatogonia, Sertoli cells, and sperm. Furthermore, MC-LR and NaNO 2 reduced sperm density with a synergistic effect. In addition, MC-LR and NaNO 2 synergistically induced oxidative stress in the reproductive system by decreasing superoxide dismutase (SOD) activity and glutathione (GSH) levels and increasing levels of mitochondrial reactive oxygen species (mtROS) and reactive oxygen species (ROS). More importantly, mitoquidone mesylate (MitoQ), an inhibitor of mtROS, blocked MC-LR and NaNO 2 -induced spermatogonia and Sertoli cell apoptosis by inhibiting high expression of Bax, Fadd, Caspase-8, and cleaved-Caspase-3. On the other hand, MitoQ suppressed pyroptosis of Sertoli cells by inhibiting the expression of NLRP3, N-GSDMD, and cleaved-Caspase-1. Additionally, MitoQ alleviated co-exposure-induced sperm density reduction and organ index disorders in F1 generation mice. Together, co-exposure of MC-LR and NaNO 2 can enhance spermatogenic disorders by mitochondrial oxidative impairment-mediated germ cell death. This study emphasizes the potential risks of MC-LR and NaNO 2 on reproduction in realistic environments and highlights new insights into the cause and treatment of spermatogenic disorders., 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 Ltd.. All rights reserved.)

Microcystin-LR (MC-LR) is a toxin produced by cyanobacteria, which is widely distributed in eutrophic water bodies and has multi-organ toxicity. Previous cytotoxicity studies have mostly elucidated the effects of MC-LR on intracellular-related factors, proteins, and DNA at the molecular level. However, there have been few studies on the adverse effects of MC-LR on cell ultrastructure and function. Therefore, research on the cytotoxicity of MC-LR in recent years was collected and summarized. It was found that MC-LR can induce a series of cytotoxic effects, including decreased cell viability, induced autophagy, apoptosis and necrosis, altered cell cycle, altered cell morphology, abnormal cell migration and invasion as well as leading to genetic damage. The above cytotoxic effects were related to the damage of various ultrastructure and functions such as cell membranes and mitochondria. Furthermore, MC-LR can disrupt cell ultrastructure and function by inducing oxidative stress and inhibiting protein phosphatase activity. In addition, the combined toxic effects of MC-LR and other environmental pollutants were investigated. This review explored the toxic targets of MC-LR at the subcellular level, which will provide new ideas for the prevention and treatment of multi-organ toxicity caused by MC-LR., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Eutrophication of water bodies can lead to cyanobacterial blooms, with the resultant release of microcystins (MCs), posing a threat to the ecosystem and human health. MCs are environmental toxins with male reproductive toxicity. However, there is a dearth of reviews focusing on sperm or spermatogenesis. In this paper, studies on sperm toxicity caused by MCs in recent 20 years were collected and summarized, aiming at revealing the toxic effects and potential mechanisms of MCs on sperm. Based on the previous findings, MCs can decline sperm quality and count, and cause malformation in vertebrates and invertebrates. The reason might be that MCs cause indirect damage to sperm through impairing the structure and function of the testis. The mechanisms of MCs-induced sperm toxicity mainly result from alterations in genetic material, abnormalities in the structure and function of sperm. The epigenetic modifications such as miRNA and piRNA were also involved in MC-LR-induced sperm damage. In conclusion, MCs exposure is harmful to sperm, but its direct effects and mechanisms on sperm are still not known, which remains a significant research direction. Our review will provide a basis for the protection of male reproductive health damage caused by microcystins., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Microcystin-leucine arginine (MC-LR), an important hepatoxin, has the effect of promoting hepatocarcinogenesis. MicroRNA-122 (miR-122), an important tumor suppressor in liver, plays an important role in promoting cell apoptosis. Previous studies found that the expression of miR-122 was reduced after MC-LR exposure in liver. In this study, C57BL/6 mice were exposed to saline, negative control agomir, and MC-LR with or without miR-122 agomir transfection. The results indicated that MC-LR promoted the expressions of tumor suppressor genes and decreased the expressions of anti-apoptotic proteins B cell lymphoma-2 (Bcl-2) and Bcl-2-like 2 (Bcl-w), causing hepatocyte apoptosis. Under MC-LR exposure, miR-122 agomir transfection could further increase the expressions of tumor suppressor genes and the release of cytochrome-c (Cyt-c) and decrease the expressions of Bcl-2 and Bcl-w. In conclusion, miR-122 reduction can mitigate MC-LR-induced apoptosis to a certain extent, which in turn, it is likely to have contributed to MC-LR-induced hepatocarcinogenesis.

Microcystin-leucine arginine (MC-LR), ubiquitous in water and food, is a threat to public health. In the present study, after C57BL/6J mice were fed with environmental concentrations of MC-LR (0, 1, 30, 60, 90, and 120 μg/L) for 6, 9, and 12 months, it was found that MC-LR could enter into mouse lung tissues and cause microstructural damage, as shown by western blotting and HE staining. Electron microscopy examination showed that MC-LR could damage the lung barrier by disruption of the tight junctions, which was confirmed by the decreased expression of tight junction markers, including Occludin, Claudin1, and ZO-1. In addition, MC-LR also increased the ubiquitination of Claudin1, indicating that MC-LR could disrupt tight junctions by promoting the degradation of Claudin1. Furthermore, MC-LR increased the levels of TNF-α and IL-6 in mouse lung tissues, leading to pneumonia. Importantly, pretreatment with PP2A activator D-erythro-sphingosine (DES) was found to significantly alleviate MC-LR-induced decrease of Occludin and Claudin1 by inhibiting the P-AKT/Snail pathway in vitro . Together, this study revealed that chronic exposure to MC-LR causes lung barrier damage, which involves PP2A activity inhibition and enhancement of Claudin1 ubiquitination. This study broadens the awareness of the toxic effects of MC-LR on the respiratory system, which has deep implications for public health.

Microcystins (MCs) are the most widely distributed cyanotoxins, which can be ingested by animals and human body in multiple ways, resulting in a threat to human health and the biodiversity of wildlife. Therefore, the study on toxic effects and mechanisms of MCs is one of the focuses of attention. Recently, the Omics techniques, i.e. genomics, transcriptomics, proteomics and metabolomics, have significantly contributed to the comprehensive understanding and revealing of the molecular mechanisms about the toxicity of MCs. This paper mainly reviews current literature using the Omics approaches to explore the toxicity mechanism of MCs in liver, gonad, spleen, brain, intestine and lung of multiple species. It was found that MCs can exert strong toxic effects on various metabolic activities and cell signal transduction in cell cycle, apoptosis, destruction of cell cytoskeleton and redox disorder, at protein, transcription and metabolism level. Meanwhile, it was also revealed that the alteration of non-coding RNAs (miRNA, circRNA and lncRNA, etc.) and gut microbiota plays an essential regulatory role in the toxic effects of MCs, especially in hepatotoxicity and reproductive toxicity. In addition, we summarized current research gaps and pointed out the future directions for research. The detailed information in this paper shows that the application and development of Omics techniques have significantly promoted the research on MCs toxicity, and it is also a valuable resource for exploring the toxic mechanism of MCs., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As an emerging pollutant in the aquatic environment, microcystin-LR (MC-LR) can enter the body through multiple pathways, and then induce apoptosis and gonadal damage, affecting reproductive function. Previous studies focused on male reproductive toxicity induced by MC-LR neglecting its effects on females. The apoptotic signal-regulated kinase 1 (ASK1) is an upstream protein of P38/JNK pathway, closely associated with apoptosis and organ damage. However, the role of ASK1 in MC-LR-induced reproductive toxicity is unclear. Therefore, this study investigated the role of ASK1 in mouse ovarian injury and apoptosis induced by MC-LR. After MC-LR exposure, ASK1 expression in mouse ovarian granulosa cells was increased at the protein and mRNA levels, and decreased following pretreatment by antioxidant N-acetylcysteine, suggesting that MC-LR-induced oxidative stress has a regulatory role in ASK1 expression. Inhibition of ASK1 expression with siASK1 and NQDI-1 could effectively alleviate MC-LR-induced mitochondrial membrane potential damage and apoptosis in ovarian granulosa cells, as well as pathological damage, apoptosis and the decreased gonadal index in ovaries of C57BL/6 mice. Moreover, the P38/JNK pathway and downstream apoptosis-related proteins (P-P38, P-JNK, P-P53, Fas) and genes (MKK4, MKK3, Ddit3, Mef2c) were activated in vivo and vitro, but their activation was restrained after ASK1 inhibition. Data presented herein suggest that the ASK1-mediated P38/JNK pathway is involved in ovarian injury and apoptosis induced by MC-LR in mice. It is confirmed that ASK1 has an important role in MC-LR-induced ovarian injury, which provides new insights for preventing MCs-induced reproductive toxicity in females., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Microcystins (MCs) are the most common cyanobacteria toxins in eutrophic water, which have strong hepatotoxicity. In the past decade, epidemiological and toxicological studies on liver damage caused by MCs have proliferated, and new mechanisms of hepatotoxicity induced by MCs have also been discovered and confirmed. However, there has not been a comprehensive and systematic review of these new findings. Therefore, this paper summarizes the latest advances in studies on the hepatotoxicity of MCs to reveal the effects and mechanisms of hepatotoxicity induced by MCs. Current epidemiological studies have confirmed that symptoms or signs of liver damage appear after human exposure to MCs, and a long time of exposure can even lead to liver cancer. Toxicological studies have shown that MCs can affect the expression of oncogenes by activating cell proliferation pathways such as MAPK and Akt, thereby promoting the occurrence and development of cancer. The latest evidence shows that epigenetic modifications may play an important role in MCs-induced liver cancer. MCs can cause damage to the liver by inducing hepatocyte death, mainly manifested as apoptosis and necrosis. The imbalance of liver metabolic homeostasis may be involved in hepatotoxicity induced by MCs. In addition, the combined toxicity of MCs and other toxins are also discussed in this article. This detailed information will be a valuable reference for further exploring of MCs-induced hepatotoxicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Microcystin-leucine arginine (MC-LR), an intracellular toxin to cause reproduction toxicity, is produced by blooming cyanobacteria and widely distributed in eutrophic waters. It is revealed that MC-LR-induced female reproductive toxicity is more severe than male reproductive toxicity. Previous studies mainly focused on male reproductive toxicity, and the molecular mechanisms of MC-LR-induced apoptosis, follicular atresia and infertility in female remain largely unclear. Here, it was found that MC-LR treatment could induce apoptosis, inflammation, follicular atresia, and decrease of gonadal index in mice ovaries. RNA-Seq data showed that the up-regulation of DNA-damage inducible transcript 3 (Ddit3) under endoplasmic reticulum (ER) stress had predominantly regulatory role in MC-LR-induced apoptotic pathway. Furthermore, MC-LR exposure promoted cleavage of activating transcription factor 6 (ATF6, 50kd), inositol-requiring enzyme 1 (Ire1) expression, phosphorylation of IRE1, mitogen-activated protein kinase 5 (Map3k5) and Ddit3 expression, which was accompanied by the upregulation of death receptor 5 (Dr5) and active-caspase-3, and a decrease in Bcl-2 expression. ER stress inhibitor 4-Phenyl butyric acid (4-PBA) ameliorated these MC-LR-induced changes in protein or mRNA level. More importantly, knockdown of Ddit3 suppressed MC-LR-induced cell apoptosis and follicular atresia by directly regulating Dr5 and Bcl-2. Additionally, it was also found that MC-LR increased Map3k5 phosphorylation by inhibiting protein phosphatase 2A (PP2A) activity, and then promoted Ddit3 expression. In short, our data suggests that Ddit3 promotes MC-LR-induced mice ovarian cells apoptosis and follicular atresia via ER stress activation, which provides a new insight into the relation between infertility in females and the emerging water pollutant MC-LR., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Microcystin-LR (MC-LR) is an emerging environmental pollutant produced by cyanobacteria that poses a threat to wild life and human health. In recent years, the reproductive toxicity of MC-LR has gained widespread attention, a large number of toxicological studies have filled the gaps in past research and more molecular mechanisms have been elucidated. Hence, this paper reviews the latest research advances on MC-LR-induced reproductive toxicity. MC-LR can damage the structure and function of the testis, ovary, prostate, placenta and other organs of animals and then reduce their fertility. Meanwhile, MC-LR can also be transmitted through the placenta to the offspring causing trans-generational and developmental toxicity including death, malformation, growth retardation, and organ dysfunction in embryos and juveniles. The mechanisms of MC-LR-induced reproductive toxicity mainly include the inhibition of protein phosphatase 1/2 A (PP1/2 A) activity and the induction of oxidative stress. On the one hand, MC-LR triggers the hyperphosphorylation of certain proteins by inhibiting intracellular PP1/2 A activity, thereby activating multiple signaling pathways that cause inflammation and blood-testis barrier destruction, etc. On the other hand, MC-LR-induced oxidative stress can result in cell programmed death via the mitochondrial and endoplasmic reticulum pathways. It is worth noting that epigenetic modifications are also involved in reproductive cell apoptosis, which may be an important direction for future research. Furthermore, this paper proposes for the first time that MC-LR can produce estrogenic effects in animals as an environmental estrogen. New findings and suggestions in this review could be areas of interest for future research., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Microcystin-LR (MC-LR) is an emerging water pollutant produced by blooming cyanobacteria. It could be absorbed into human body via contaminated food and drinking water causing severe reproductive toxicity. Previous studies showed that MC-LR could regulate autophagy by inducing endoplasmic reticulum (ER) stress thereby causing female reproductive toxicity. However, the molecular mechanisms of MC-LR-induced autophagy remain to be elucidated. It is known that IRE1 and CaMKKβ pathways are two important pathways involved in autophagy induced by ER stress. Hence, this study investigated the roles of both pathways in MC-LR-induced autophagy in mouse ovarian cells. The results showed that MC-LR significantly up-regulated the expression of autophagy marker proteins LC3Ⅱ and BECLIN1 and down-regulated the expression of P62 in vivo and in vitro. MC-LR-caused increase of autophagosomes could be observed in KK-1 cells by MDC staining. MC-LR induced the formation of autolysosomes as indicated by the overlap of LAMP1 and LC3. Meanwhile, MC-LR significantly activated the proteins in IRE1 pathway (IRE1, XBP1 and JNK) and in CaMKKβ pathway (CaMKKβ, AMPK, mTOR). Furthermore, MC-LR caused weight loss and ovarian histopathological damage in mice. In contrast, after the expression and function of IRE1 and CaMKKβ were inhibited with siRNA in vitro and by inhibitors (4μ8C and STO-609, respectively) in vivo, the up-regulation of LC3Ⅱ and BECLIN1 and the degradation of P62 induced by MC-LR were significantly suppressed. MC-LR-induced autophagosomes in KK-1 cells and autolysosomes in mouse ovarian cells were also decreased. Moreover, the knockdown of IRE1 and CaMKKβ relieved MC-LR-induced histopathological injury to mouse ovaries. These results indicated that MC-LR induced ovarian cell autophagy and ovarian injury via IRE1 and CaMKKβ pathways. This study is the first study revealing the molecular mechanisms of MC-LR-induced autophagy of ovarian cells and providing new insights into the female reproductive toxicity of MC-LR., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA-122 (miR-122) is specifically expressed in the liver. This study focuses on the role of miR-122 in MC-LR-induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 μg/kg·BW MC-LR, 25 μg/kg·BW MC-LR, Negative control agomir and 25 μg/kg·BW MC-LR + miR-122 agomir). The results show that MC-LR decreases the expressions of miR-122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR-122 agomir pretreatment improves MC-LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR-122 agomir can prevent the accumulation of hepatic iron induced by MC-LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL-6/STAT signaling pathways., (© 2020 Wiley Periodicals, Inc.)

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide, produced by aquatic cyanobacteria such as microcystis, with strong reproductive toxicity which poses greater threat to the reproductive abilities of humans and animals. By exploring the role of trimethylation of histone H3 at lysine 4 (H3K4me3) and the role of oxidative stress in MC-LR-induced apoptosis in testicular Sertoli cells in Sprague-Dawley (SD) rats, this study indicated that MC-LR increased the expression levels of apoptosis-related genes by raising the levels of H3K4me3. 5'-Deoxy-5'-methylthioadenosine (MTA), the inhibitor of H3K4me3, reduced apoptosis, indicating for the first time that epigenetic modification is closely related to the testicular reproductive toxicity induced by MC-LR. MC-LR also induced oxidative stress by stimulating the generation of reactive oxygen species (ROS), and subsequently triggering mitochondria-mediated apoptotic pathway by decreasing mitochondrial membrane potential and increasing the levels of Bax, Bcl-2, Caspase-3, and so on. MC-LR-induced apoptosis of testicular cells could be decreased after pretreatment with oxidative stress inhibitor N-acetyl-cysteine (NAC). Furthermore, the pathological damage to mitochondria and testes were observed in SD rats. These results show that MC-LR can induce apoptosis by raising the levels of H3K4me3, and pretreatment with MTA can ameliorate the MC-LR-induced apoptosis of cocultured cells by lowering the levels of H3K4me3. Furthermore, NAC has a protective effect on MC-LR-induced apoptosis of testicular cells in SD rats by inhibiting the oxidative stress., (© 2019 Wiley Periodicals, Inc.)

Microcystin-leucine arginine (MC-LR) is a variant of microcystins (MCs), which poses a serious threat to the reproductive system. Histone acetylation modification can regulate the expressions of apoptosis-related genes. However the mechanisms of histone acetylation involving MC-LR-induced apoptosis were not understood. This study investigated the change of histone acetylation and its role in apoptosis and cell cycle arrest induced by MC-LR. MC-LR enhanced the activity of histone deacetylase (HDAC), decreased the activity of histone acetylase (HAT), up-regulated the expression of HDAC1, and down-regulated the expressions of Ac-H3 and Ac-H4 in vitro and vivo. Meanwhile, MC-LR induced testicular tissue injury and increased the expressions of apoptosis-related genes, such as Bax, Caspase3 and Caspase8, ultimately causing cells apoptosis in testicular tissues. Furthermore, MC-LR also induced cell cycle arrest in S phase, increased the expression of P21 Wif1/Cip1 , and inhibited the expressions of cyclinD1, cyclinE1, CDK2 and E2F1. Importantly, HDAC inhibitor Trichostatin A (TSA) could ameliorate MC-LR-induced apoptosis and cell cycle arrest by reverse-regulating the expressions of these proteins. These results indicated that MC-LR could activate the mitochondrial apoptotic pathway and disorder the cell cycle pathway to induce the cell apoptosis by enhancing HDAC activity and reducing histone acetylation of normal testicular cells in SD rats. Hence, histone acetylation has a vital function in MC-LR-induced apoptosis in SD rat testicular cells, which provides a new insight on the reproductive toxicity of male induced by MC-LR., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Microcystin-LR (MC-LR), a potent endotoxin, can induce reproductive toxicity. In order to investigate the role and mechanisms of apoptosis (p53-dependent and mitochondrial pathways) of germ cells induced by MC-LR, the co-cultured primary Sertoli-germ cells from Sprague-Dawley rats were used for the experiments. Expression levels of proteins, genes, and mitochondrial membrane potential (MMP) were obtained after exposing co-cultured Sertoli-germ cells to MC-LR with or without the addition of the p53 inhibitor, pifithrin-α (PFT-α), and MMP inhibitor, cyclosporin A (CsA). Results indicated that MC-LR could activate p53-dependent pathway-associated proteins in Sertoli-germ cells, leading to a decrease in MMP (indicating the opening of mitochondrial permeability transition pore [mPTP] and the release of Cytochrome-c [Cyt-c]) from the mitochondria into the cytoplasm and eventually the induction of apoptosis. PFT-α inhibited the expression ofp53, ameliorated the MMP of the co-cultured Sertoli-germ cells, and prevented the release of Cyt-c from the mitochondria into the cytoplasm, which reduces the occurrence of apoptosis. Similarly, the decreased release of Cyt-c from the mitochondria into the cytoplasm and the declined level of apoptosis in Sertoli-germ cells induced by MC-LR were observed after the addition of CsA. These results indicated that the apoptosis of the co-cultured Sertoli-germ cells induced by MC-LR was mediated by the p53-dependent pathway, with the involvement of the opening of mPTP., (© 2019 Wiley Periodicals, Inc.)

The widespread distribution of cyanobacteria in the aquatic environment is increasing the risk of water pollution caused by cyanotoxins, which poses a serious threat to human health. However, the structural characterization, distribution and identification techniques of cyanotoxins have not been comprehensively reviewed in previous studies. This paper aims to elaborate the existing information systematically on the diversity of cyanotoxins to identify valuable research avenues. According to the chemical structure, cyanotoxins are mainly classified into cyclic peptides, alkaloids, lipopeptides, nonprotein amino acids and lipoglycans. In terms of global distribution, the amount of cyanotoxins are unbalanced in different areas. The diversity of cyanotoxins is more obviously found in many developed countries than that in undeveloped countries. Moreover, the threat of cyanotoxins has promoted the development of identification and detection technology. Many emerging methods have been developed to detect cyanotoxins in the environment. This communication provides a comprehensive review of the diversity of cyanotoxins, and the detection and identification technology was discussed. This detailed information will be a valuable resource for identifying the various types of cyanotoxins which threaten the environment of different areas. The ability to accurately identify specific cyanotoxins is an obvious and essential aspect of cyanobacterial research.

The liver is an important iron storage site and a primary MC-LR target. C57BL/6 and Hfe -/- mice were used to investigate effects and mechanisms of MC-LR on systematic iron homeostasis. Body weight, tissue iron content, hematological and serological indexes, and histopathological were evaluated. Ultrastructure and iron metabolism-related genes and proteins were analyzed. MC-LR induced dose-dependent increases in red blood cells, hemoglobin, and hematocrit. In contrast MC-LR-induced dose-dependent decreases in mean corpuscular volume, hemoglobin, and hemoglobin concentration were observed both C57BL/6 and Hfe -/- mice. In both mouse species, serological indexes increased. Aggravated liver and spleen iron were observed in C57BL/6 mice, consistent with Perls' Prussian blue staining. However, an opposite trend was observed in Hfe -/- mice. C57BL/6 mice had lower Hamp1 (Hepcidn), Bmp6, Il-6, and Tmprss6. Significant increased Hjv, Hif-1α and Hif-2α were observed in both C57BL/6 and Hfe -/- mice. MC-LR-induced pathological lesions were dose-dependent increase in C57BL/6 mice. More severe pathological injuries in MC-LR groups (25 μg/kg) were observed in Hfe -/- mice than in C57BL/6 mice. In Hfe -/- mice, upon exposure to 25 μg/kg MC-LR, mitochondrial membranes were damaged and mitochondrial counts increased with significant swelling. These results indicated that MC-LR can induce the accumulation of iron in C57BL/6 mice with the occurrence of anemia, similar to thalassemia. Moreover, dysregulation of iron homeostasis may be due to MC-LR-induced Hamp1 downregulation, possibly mediated by hypoxia or the IL6-STAT3 and BMP-SMAD signaling pathways., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Microcystin-leucine arginine (MC-LR), a cyclic heptapeptide produced by cyanobacteria, is a strong reproductive toxin. Studies performed in rat Sertoli cells and Chinese hamster ovary cells have demonstrated typical apoptosis after MC-LR exposure. However, little is known on how to protect against the reproductive toxicity induced by MC-LR. The present study aimed to explore the possible molecular mechanism underlying the anti-apoptosis and protective effects of resveratrol (RES) on the co-culture of Sertoli⁻germ cells and rat testes. The results demonstrated that MC-LR treatment inhibited the proliferation of Sertoli⁻germ cells and induced apoptosis. Furthermore, sirtuin 1 (SIRT1) and Bcl-2 were inhibited, while p53 and Ku70 acetylation, Bax expression, and cleaved caspase-3 were upregulated by MC-LR. However, RES pretreatment ameliorated MC-LR-induced apoptosis and SIRT1 inhibition, and downregulated the MC-LR-induced increase in p53 and Ku70 acetylation, Bax expression, and caspase-3 activation. In addition, RES reversed the MC-LR-mediated reduction in Ku70 binding to Bax. The present study indicated that the administration of RES could ameliorate MC-LR-induced Sertoli⁻germ cell apoptosis and protect against reproductive toxicity in rats by stimulating the SIRT1/p53 pathway, suppressing p53 and Ku70 acetylation and enhancing the binding of Ku70 to Bax.

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide intracellular toxin released by cyanobacteria that exhibits strong reproductive toxicity. However, little is known about its biotoxicity to the female reproductive system. The present study investigates unexplored molecular pathways by which oxidative stress acts on MC-LR-induced endoplasmic reticulum stress (ERs) and autophagy. In the present study, immortalized murine ovarian granular cells (KK-1 cells) were exposed to 8.5, 17, and 34 μg/mL (IC50) of MC-LR with or without N -acetyl-l-cysteine (NAC, 10 mM) for 24 h, and C57BL/6 mice were treated with 12.5, 25.0, and 40.0 μg/kg⋅bw of MC-LR with or without NAC (200 mg/kg⋅bw) for 14 days. The results revealed that MC-LR could induce cells apoptosis and morphologic changes in ovarian tissues, induce oxidative stress by stimulating the generation of reactive oxygen species (ROS), destroying antioxidant capacity, and subsequently trigger ERs and autophagy by inducing the hyper-expression of ATG12, ATG5, ATG16, EIF2α (phosphorylated at S51), CHOP, XBP1, GRP78, Beclin1, and PERK (Thr980). Furthermore, NAC pretreatment partly inhibited MC-LR-induced ERs and autophagy via the PERK/ATG12 and XBP1/Beclin1 pathways. These results suggest that oxidative stress mediated MC-LR-induced ERs and autophagy in KK-1 cells and C57BL/6 mice ovaries. Therefore, oxidative stress plays an important role in female toxicity induced by MC-LR. [ABSTRACT FROM AUTHOR]