Harmful algal bloom toxin microcystin-LR interferes with PP1-mediated PI3K/AKT/FOXO1 signaling in granulosa cells to disrupt ovarian follicle maturation and ovulation
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ABSTRACT:
PROVIDER: PRJNA833085 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18964469_1.fastq.gz | Fastqsanger.gz | |||
| SRR18964469_2.fastq.gz | Fastqsanger.gz | |||
| SRR18964470_1.fastq.gz | Fastqsanger.gz | |||
| SRR18964470_2.fastq.gz | Fastqsanger.gz | |||
| SRR18964471_1.fastq.gz | Fastqsanger.gz |
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Project description:Harmful algal blooms (HABs) arise from the rapid growth of algae in both marine and freshwater ecosystems due to the continuous global temperature rise and anthropogenic eutrophication. Humans are at a great risk of exposure to toxins released from HABs through drinking water, food, and recreational activities, making HAB toxins contaminants of emerging concern (CECs). The impact of HAB toxins on women’s reproductive health, however, remains poorly understood. Here, we investigated the effects of microcystin-LR (MC-LR), the most common HAB toxin, on the ovary, the female gonad, and associated ovarian functions. The results of a chronic daily oral mouse exposure model and an acute exposure using the mouse superovulation model revealed that MC-LR accumulated in the ovary and environmentally-relevant exposure to MC-LR perturbed follicle-stimulating hormone (FSH)-dependent follicle maturation to disrupt ovulation and luteinization. Using an ex vivo mouse follicle maturation and ovulation assay and in vitro culture of human primary granulosa cells, mechanistic studies such as the single-follicle RNA sequencing analysis and others elucidated that MC-LR inhibited protein phosphatase 1 (PP1) and interfered with PP1-mediated PI3K/AKT/FOXO1 signaling in granulosa cells, which suppressed follicle maturation, ovulation, luteinization, and progesterone secretion. Together, our study demonstrates that environmentally-relevant exposure to MC-LR acts a PP1 inhibitor to interfere with the PI3K/AKT/FOXO1 signaling in granulosa cells, which disrupts follicle maturation and results in adverse female reproductive outcomes. As a newly identified ovarian endocrine disrupting chemical (EDC), exposure to MC-LR poses a serious threat to women’s reproductive health and fertility.
2024-06-15 | GSE201806 | GEO
Project description:BackgroundCyanobacterial harmful algal blooms (CyanoHABs) originate from the excessive growth or bloom of cyanobacteria often referred to as blue-green algae. They have been on the rise globally in both marine and freshwaters in recently years with increasing frequency and severity owing to the rising temperature associated with climate change and increasing anthropogenic eutrophication from agricultural runoff and urbanization. Humans are at a great risk of exposure to toxins released from CyanoHABs through drinking water, food, and recreational activities, making CyanoHAB toxins a new class of contaminants of emerging concern.ObjectivesWe investigated the toxic effects and mechanisms of microcystin-LR (MC-LR), the most prevalent CyanoHAB toxin, on the ovary and associated reproductive functions.MethodsMouse models with either chronic daily oral or acute intraperitoneal exposure, an engineered three-dimensional ovarian follicle culture system, and human primary ovarian granulosa cells were tested with MC-LR of various dose levels. Single-follicle RNA sequencing, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, immunohistochemistry (IHC), and benchmark dose modeling were used to examine the effects of MC-LR on follicle maturation, hormone secretion, ovulation, and luteinization.ResultsMice exposed long term to low-dose MC-LR did not exhibit any differences in the kinetics of folliculogenesis, but they had significantly fewer corpora lutea compared with control mice. Superovulation models further showed that mice exposed to MC-LR during the follicle maturation window had significantly fewer ovulated oocytes. IHC results revealed ovarian distribution of MC-LR, and mice exposed to MC-LR had significantly lower expression of key follicle maturation mediators. Mechanistically, in both murine and human granulosa cells exposed to MC-LR, there was reduced protein phosphatase 1 (PP1) activity, disrupted PP1-mediated PI3K/AKT/FOXO1 signaling, and less expression of follicle maturation-related genes.DiscussionUsing both in vivo and in vitro murine and human model systems, we provide data suggesting that environmentally relevant exposure to the CyanoHAB toxin MC-LR interfered with gonadotropin-dependent follicle maturation and ovulation. We conclude that MC-LR may pose a nonnegligible risk to women's reproductive health by heightening the probability of irregular menstrual cycles and infertility related to ovulatory disorders. https://doi.org/10.1289/EHP12034.
| S-EPMC10284350 | biostudies-literature
Project description:Microcystin-LR (MC-LR), the most toxic member of microcystin family, inhibits protein phosphatase PP2A, triggers oxidative stress and induces hepatotoxicity. Gene expression profiling of MC-LR treated larvae using DNA microarray analysis revealed effects in the retinal visual cycle and pigmentation synthesis pathways that have not been previously associated with MC-LR. Liver-related genes were also differentially expressed. The microarray data were confirmed by quantitative real-time PCR. Our findings provide new evidence that microcystin-LR exposure of zebrafish larvae modulates the retinal visual cycle and pigmentation synthesis pathways and ultimately alter larval zebrafish behavior
2017-02-16 | GSE73739 | GEO
Project description:Microcystins are produced by the cyanobacteria, most commonly Microcystis aerµginosa. Upon ingestion, toxic microcystins are actively absorbed by fish, birds and mammals where they are primarily liver toxins. Groups of 4-6 rats were exposed to 0, 1, 10, 50 or 100 µg/kg microcystin-LR for 0.5, 1, 3 or 6 hours and gene expression analysis performed on liver with samples hybridized to whole rat genome RG230_2.0 GeneChip arrays (Affymetrix, CA).
2014-07-25 | E-GEOD-59495 | biostudies-arrayexpress
Project description:The bacterium Novosphingobium sp. THN1 (THN1) is capable of degrading microcystin-LR (MCLR). To get an insight into genes expression during MCLR degradation and the regulation of different carbon concentrations on MCLR degradation, we performed RNA-seq of THN1 during MCLR degradation under different carbon concentrations.
2019-01-30 | GSE125827 | GEO
Project description:We report microcystin-LR, a cyclic heptapeptide that acts as a potent hepatotoxin and carcinogen, was used to induce the malignant transformation of the WRL-68 cell line and alterations in microRNA (miRNA) expression in the transformed cells.
2012-07-31 | GSE30560 | GEO
Project description: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.
2025-02-05 | PXD054405 | Pride
Project description:Human hepatocytes, HepaRG cells and HCC HepG2 cells were treated with 50nM of Microcystin-LR and cylindrospermopsin (CYN) to observe changes in gene expression.
2023-05-12 | E-MTAB-12881 | biostudies-arrayexpress
Project description:Cyanobacterial harmful algal blooms (cHABs) have the potential to adversely affect public health through the production of toxins such as microcystins, which consist of numerous molecularly distinct congeners. Microcystins have been observed in the atmosphere after emission from freshwater lakes, but little is known about the health effects of inhaling microcystins and the factors contributing to microcystin aerosolization. This study quantified total microcystin concentrations in water and aerosol samples collected around Grand Lake St. Marys (GLSM), Ohio. Microcystin concentrations in water samples collected on the same day ranged from 13 to 23 μg/L, dominated by the d-Asp3-MC-RR congener. In particulate matter <2.5 μm (PM2.5), microcystin concentrations up to 156 pg/m3 were detected; the microcystins were composed primarily of d-Asp3-MC-RR, with additional congeners (d-Asp3-MC-HtyR and d-Asp3-MC-LR) observed in a sample collected prior to a storm event. The PM size fraction containing the highest aerosolized MC concentration ranged from 0.44 to 2.5 μm. Analysis of total bacteria by qPCR targeting 16S rDNA revealed concentrations up to 9.4 × 104 gc/m3 in aerosol samples (≤3 μm), while a marker specific to cyanobacteria was not detected in any aerosol samples. Concentrations of aerosolized microcystins varied even when concentrations in water were relatively constant, demonstrating the importance of meteorological conditions (wind speed and direction) and aerosol generation mechanism(s) (wave breaking, spillway, and aeration systems) when evaluating inhalation exposure to microcystins and subsequent impacts on human health.
| S-EPMC11406202 | biostudies-literature
Project description:We report microcystin-LR, a cyclic heptapeptide that acts as a potent hepatotoxin and carcinogen, was used to induce the malignant transformation of the WRL-68 cell line and alterations in microRNA (miRNA) expression in the transformed cells. In this work, MC-LR was used to induce the malignant transformation of the WRL-68 cell line and alterations in microRNA (miRNA) expression in the transformed cells.
2012-07-30 | E-GEOD-30560 | biostudies-arrayexpress