Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Analysis of MicroRNA Expression in Embryonic Developmental Toxicity Induced by microcystin arginine arginine (MC-RR).

ABSTRACT: In this study, we used zebrafish embryos as a model system to investigate the toxic effects of MC-RR on early development and try to elucidate the underlying developmental toxicological mechanisms in a global view at posttranscriptional level. Altered expression pattern of miRNAs in embryos treated with MC-RR was detected by miRNA microarray. We examined microRNA expression profiling in paired MC-RR treated and control embroys of zebrafish. There are 4 biological replicates in MC-RR treated group and control group, respectively.

ORGANISM(S): Danio rerio

SUBMITTER: Yanyan Zhao

PROVIDER: E-GEOD-29329 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Analysis of microRNA expression in embryonic developmental toxicity induced by MC-RR.

Zhao Yanyan Y Xiong Qian Q Xie Ping P

PloS one 20110729 7

As cynobacterial blooms frequently occur in fresh waters throughout the world, microcystins (MCs) have caused serious damage to both wildlife and human health. MCs are known to have developmental toxicity, however, the possible molecular mechanism is largely unknown. This is the first toxicological study to integrate post-transcriptomic, proteomic and bioinformatics analysis to explore molecular mechanisms for developmental toxicity of MCs in zebrafish. After being microinjected directly into em ...[more]

PMID: 21829477

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Project description:Microcystins (MCs) are cyclic hepatotoxins produced worldwide by various species of cyanobacteria. Their structure includes two variable amino acids (AAs) and most of the studies focused on the most toxic variant: the microcystin LR (MC-LR). However, more than 80 MC variants have been described to date. Despite ingestion being the major pathway of human exposure, few in vivo studies have demonstrated macroscopic effects on the gastro-intestinal tract, but no data are available on the affected pathways by several variants on intestinal cells. Here, using a non-selective method, we investigated for the first time the effect of MC-RR and MC-LR on the human intestinal cell line Caco-2 and compared their response at the pangenomic scale. The cells were incubated for 4 hrs or 24 hrs with the same range of sub-lethal concentrations of MC-RR or MC-LR. Low effects were observed for both variants after a short-term exposure. On the contrary, dose-dependent modulations of the genes transcription levels were noticed with MC-RR and MC-LR after 24 hrs. Furthermore, the genomic profiles induced by both variants were similar suggesting a common toxicity mechanism but with higher modulation following MC-LR than MC-RR exposure. However, the functional annotation revealed major differences between the variants effects. Indeed, the well-known MC-LR affected mainly two pathways, the oxidative stress response and the cell cycle regulation, which did not elicit significant alteration following MC-RR exposure. This work is the first comparative description of the MC-LR and MC-RR effects on a human intestinal cell model. It allowed us to suggest differences in the mechanism of toxicity for MC-RR and MC-LR. These results illustrate that the toxicity of MC variants remains a key point for risk assessment. Differentiated Caco-2 cells were exposed to microcystins in free FCS culture medium for either 4 or 24 hours. Sub-lethal concentrations of 10, 50 and 100 M-BM-5M of MC-LR or MC-RR were chosen for 4 hours, while 1, 5 and 10 M-BM-5M were selected for 24 hours. For each condition (including the controls), the solvent concentration was fixed to 2% EtOH for MC-LR and 1.5% of 80% MeOH for MC-RR. Four to five culture replicates per condition were done.

Project description:Zebrafish (Danio rerio) were obtained from the Zebrafish Research Facility maintained in the Center for Environmental Biotechnology at the University of Tennessee. Fish husbandry, spawning, and experimental procedures were conducted with approval from the University of Tennessee Institutional Animal Care and Use Committee (Protocol #1690-1007). Water for holding fish and conducting experiments (hereafter referred to as fish water) consisted of MilliQ water (Millipore, Bedford, MA) with ions added: 19 mg/L NaHCO3, 1 mg/L sea salt (Instant Ocean Synthetic Sea Salt, Mentor, OH), 10 mg/L CaSO4, 10 mg/L MgSO4, 2 mg/L KCl. Embryos were obtained by spawning adult fish with no history of contaminant exposure. Fertilization of embryos took place at the same time (Â± 15 min.), such that larvae used in experiments were of similar age at the time of exposure. All activities (maintenance of adult fish, spawning, and experiments) were conducted in an environmental chamber with a temperature of 27Â± 1 ÂºC and 14:10h light:dark photoperiod. Experiment Overall Design: At 72 h post-fertilization, zebrafish larvae were exposed to lyophilized Microcystis and purified MC-LR at concentrations of 100 and 1,000 Âµg/L. Controls consisted of zebrafish system water (negative control) and zebrafish system water containing 0.05% ethanol (vehicle control). Larvae from both control groups as well as 100 Âµg/L MC-LR, 1,000 Âµg/L MC-LR, and lyophilized Microcystis were exposed in groups of 50 with three replicates and were sacrificed after 96 hours for total RNA extraction and subsequent microarray analysis. All larvae were exposed in beakers containing 100 ml of solution. Experiment Overall Design: Water samples for microcystin analysis and water quality measurements were taken during the experiment, and mortality and behavioral observations were recorded at 24-hour intervals. Microcystin analysis was conducted by protein phosphatase inhibition assay. Measured concentrations of microcystin-LR were 140 Â± 12 SD (low concentration) and 1,703 Â± 71 SD (high concentration). The concentration of microcystin-LR in the lyophilized Microcystis treatment was 4.5 Âµg/L. Water quality parameters measured included dissolved oxygen (6.7 mg/L), pH (6.9), total alkalinity (36 mg/L as CaCO3), total hardness (18 mg/L as CaCO3), and ammonia (<0.2 mg/L). No significant mortality or behavioral changes in larvae were observed during the exposure.

Project description:Endometrial cancer is the most commonly diagnosed gynecologic malignancy in women after breast, lung and colorectal cancer. Despite numerous scientific advances, the incidence and mortality rate of endometrial cancer is on the rise. Considerable research effort has therefore been placed on understanding the pathogenesis of this disease to combat this growing issue. There is now emerging evidence to suggest a putative role for dysregulation of the renin angiotensin system (RAS) and in particular the (pro)renin receptor ((P)RR), in the ontogenesis of endometrial cancer. Support for this notion arises from previous literature implicating (P)RR in cancer pathophysiology (e.g., breast cancer and pancreatic carcinoma) by virtue of its role in proliferation, angiogenesis, fibrosis, migration and invasion. In view of these data, we aimed to investigate the functional role of (P)RR in human endometrial cancer progression and development. To this end, we employed an siRNA-mediated knock down approach to abrogate (P)RR expression in the immortalized endometrial epithelial cell lines; Ishikawa, AN3CA and HEC-1A to explore the role of (P)RR in cellular proliferation and cellular viability. To further extend these analyses we also carried out a sophisticated proteomic screen, that investigated the potential pathways via which (P)RR is acting in endometrial cancer physiology. These data confirmed that (P)RR is critical for endometrial cell cancer development, contributing to both its proliferative capacity and in the maintenance cell viability. This is likely mediated through proteins such as MGA, SLC4A7, SLC7A11 or DHRS2, which were reduced following (P)RR knockdown. These putative protein interactions/pathways, which rely on the presence of (P)RR, are likely to contribute to endometrial cancer progression and could therefore, represent several novel therapeutic targets in the treatment of this cancer. Finally we contend that (P)RR, in its soluble form (s(P)RR) in blood, may have substantial potential as a novel biomarker for cancer diagnosis and prognosis prediction going forward.

Dataset Information

Analysis of MicroRNA Expression in Embryonic Developmental Toxicity Induced by microcystin arginine arginine (MC-RR).

Publications

Analysis of microRNA expression in embryonic developmental toxicity induced by MC-RR.

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