Effects of preconception exposure to rotenone on progeny depend on the degree of maternal toxicity
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ABSTRACT:
PROVIDER: PRJNA1237332 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32736200_1.fastq.gz | Fastqsanger.gz | |||
| SRR32736200_2.fastq.gz | Fastqsanger.gz | |||
| SRR32736201_1.fastq.gz | Fastqsanger.gz | |||
| SRR32736201_2.fastq.gz | Fastqsanger.gz | |||
| SRR32736202_1.fastq.gz | Fastqsanger.gz |
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Project description:Parental exposure to toxicants can affect progeny health, including when those exposures occur prior to conception. However, most published preconception studies have involved exposures that result in loading of pollutants to gametes, or toxic effects to parents which could indirectly affect germ cell or gamete health. Here, we took advantage of the biology of Caenorhabditis elegans to carry out a preconception study in which we minimized the potential for maternal loading of toxicants, and used an exposure paradigm that either did (high concentration) or did not (low concentration) significantly impact the health of the P0 generation. We hypothesized that preconception exposure to mitochondrial toxicants (rotenone, and in some cases antimycin A or pyraclostrobin) during germ cell and gamete development, at levels not causing P0 toxicity, would impact mitochondrial processes in germ cells or gametes prior to conception, and that changes would be observed in offspring. The high rotenone concentration altered P0 growth, mitochondrial respiration, gene expression, induction of the mitochondrial unfolded protein response, and susceptibility to secondary challenge-induced dopaminergic neurodegeneration. However, we observed minor or no P0 effects at the low concentration. The F1 progeny of both low and high concentrations showed few effects, with most occurring in the high-exposure offspring. The only effects observed in the F1 offspring of the low exposure were a 1.7% decrease in egg size (but size later in development was not different from offspring of controls), and a slightly increased sensitivity to dopaminergic neurodegeneration caused by a secondary rotenone exposure. This study is a follow-up of Mello et. al. 2022 (PMID: 35273616; GEO: GSE195584)
2025-03-20 | GSE292176 | GEO
Project description:The standardized extract of Centella asiatica (ECa233) contains >80% triterpenoids with a ratio of madecassoside to asiaticoside of 1.5(±0.5):1. Hepatoprotective effect of ECa233 has not yet been reported. The aim of this study was to examine the effect of ECa233 on liver metabolome of rotenone-treated rats to better understand the underlying mechanisms of this bioactive substance in liver tissue. Rats were randomly divided into three groups (with six rats/group): sham negative control, rotenone positive control, and the ECa233 test group. Rats in the ECa233 group received 10 mg/kg ECa233 orally for 20 days, followed by 2.5 mg/kg intraperitoneal rotenone injection to induce toxicity before being sacrificed. The liver samples were collected for antioxidant assays and untargeted metabolomic analysis using a GC-MS. Antioxidant tests revealed that ECa233 inhibited lipid peroxidation and increased catalase activities in liver tissue. Orthogonal partial least squares-discriminant analysis clearly showed complete separation between control and rotenone groups, whereas the ECa233 group was located between these two groups and tended to reverse the effects of rotenone treatment. Two candidate markers were identified, pipecolinic acid and Unknown #21. Findings from this study suggested that supplementation of ECa233 protected rat liver against rotenone toxicity. However, further investigations are needed to elucidate the mechanisms involved.
2018-10-11 | MTBLS522 | MetaboLights
Project description:To date, most in vitro toxicity testing has focused on acute effects of compounds at high concentrations. This testing strategy does not reflect real-life exposures, which might contribute to long-term disease outcome. We used a 3D-human dopaminergic in vitro LUHMES cell line model to determine whether effects of short-term rotenone exposure (100 nM, 24 h), are permanent or reversible. A decrease in complex I activity, ATP, mitochondrial diameter and neurite outgrowth were observed acutely. After compound removal, complex I activity was still inhibited, however, ATP levels were increased, cells were electrically active and aggregates restored neurite outgrowth integrity and mitochondrial morphology. We identified significant transcriptomic changes after 24 h which were not present 7 days after wash-out. Our results suggest that testing short-term exposures in vitro may capture many acute effects which cells can overcome, missing adaptive processes and long-term mechanisms. Additionally, to study cellular resilience, cells were re-exposed to rotenone after wash-out. Pre-exposed cells maintained higher metabolic activity than controls and presented a different expression pattern in genes previously shown to be altered by rotenone. NEF2L2, ATF4 and EAAC1 were downregulated upon single hit on day 15, but unchanged in pre-exposed aggregates. DAT and CASP3 were only altered after re-exposure to rotenone while TYMS and MLF1IP were downregulated in both single-exposed and pre-exposed aggregates. In summary, our study shows that a human cell-based 3D model can be used to assess cellular adaptation, resilience and long-term mechanisms relevant to neurodegenerative research. In this study acute and delayed effects of rotenone on transcriptome in 3D LUHMES were assessed by microarray. The goal was to characterize perturbations in gene expression immediately after exposure to rotenone and identify whether these perturbations persist after compound wash-out and recovery period
2018-06-27 | GSE116280 | GEO
Project description:Rotenone is a naturally occurring toxic substance from the Leguminosa plant and belongs to the group of compounds known as rotenoids (Bové et al., 2005). It is commercially used as a pesticide and is epidemiologically linked to PD. Being lipophilic, rotenone can diffuse across biological membranes in the body and gain entry to all the organs and cells (Bové et al., 2005). Rotenone can bind to complex I of the electron transport chain (ETC) and inhibit the enzymatic activity of the NADH-ubiquinone reductase (Schuler and Casida, 2001). This interferes with the oxidation phosphorylation process, and eventually causes cell damage via oxidative stress. Rotenone may also cause the depolymerisation of microtubules into tubulin monomers (Marshall and Himes, 1978). Accumulation of tubulin monomers is potentially cytotoxic, and it is believed that parkin reverses cytotoxicity by ubiquitinating these monomers and targeting them for proteasome degradation (Ren et al., 2003.). Unfortunately, in PD patients with parkin mutations, this is not possible and tubulin accumulates to harmful levels in the cells. A total of 13 RNA samples were analyzed. Cultured murine primary cortical neurons were treated with 10nM rotenone over a time-course of 8h, 15h and 24h (n=3) in addition to the vehicle control (n=4).
2013-12-31 | E-GEOD-22997 | biostudies-arrayexpress
Project description:Polyunsaturated fatty acids in particular omega-3 fatty acids, such as docosahexaenoic acid (DHA) are essential nutrients and components of the plasma membrane. They are involved in various processes, among them synaptic development, functionality, integrity and plasticity and are therefore thought to have general neuroprotective properties. Considerable research evidence further supports beneficial effects of omega-3 fatty acids specifically on mitochondrial structure and function through their antioxidant and anti-apoptotic properties, which makes it an attractive addition in treatment options for neurodegenerative disorders, in which mitochondrial alterations are commonly observed. However, so far precise information on the underlying protective mechanisms are still lacking. Thus in this study, we utilized the most common neuronal cell line (SH-SY5Y) and induced mitochondrial oxidative stress through the addition of rotenone. To study the potential protective effect of DHA, cells were additionally pre-treated with DHA prior rotenone administration. By combining SILAC labelling, mitochondria enrichment, and subsequent proteomic analyses, we aimed to determine the capacity of DHA to alleviate mitochondrial oxidative stress in vitro and further shed light on molecular mechanisms contributing to the proposed neuroprotective effect. Indeed we confirmed a general increase in intensity of mitochondrial proteins in DHA pre-treated cells. Furthermore, we were able to define a compensatory mechanism by which the inhibition of complex I is overcome by an increased activity of the fatty acid beta oxidation in response to DHA pre-treatment.
2025-02-24 | PXD049302 | Pride
Project description:We investigated an subacute study in male Wistar rats, treated daily with 400 ppm rotenone for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. Rotenone is a strong mitochondrial respiratory chain complex I inhibitor. Inhibitors of complex I are suggested to exert anti-tumor activity of those tumors relying on oxidative metabolism and are therefore of interest in oncology research. Nevertheless, the safety profile of these inhibitors needs to be rigorously assessed. Rotenone has shown anti-carcinogenic activity in several studies. In this context we used rotenone in our study as tool compound with the aim to identify suitable biomarker candidates and enhance mechanistic insights into the biologic and cellular effects of complex I inhibitors at the organ level after in vivo treatment. Various parameters, including hematology, clinical chemistry and histopathology, major blood cell population phenotyping using FACS and enzymatic activity assays were measured and/or evaluated. Moreover gene expression profiles were determined to investigate pathways and functions affected by rotenone at the molecular level. As organs, liver, heart and brain stem were chosen due to the high metabolic activity, the high energy demand and due to the known neurotoxic effect of rotenone, respectively. The strongest rotenone-induced effects on gene expression were observed in the liver (1444 deregulated genes) compared to heart (650 deregulated genes) and brain stem (52 deregulated genes). These findings, together with the histopathological results, show that liver is a target organ of rotenone.
2017-01-02 | GSE86352 | GEO
Project description:Rotenone is a naturally occurring toxic substance from the Leguminosa plant and belongs to the group of compounds known as rotenoids (Bové et al., 2005). It is commercially used as a pesticide and is epidemiologically linked to PD. Being lipophilic, rotenone can diffuse across biological membranes in the body and gain entry to all the organs and cells (Bové et al., 2005). Rotenone can bind to complex I of the electron transport chain (ETC) and inhibit the enzymatic activity of the NADH-ubiquinone reductase (Schuler and Casida, 2001). This interferes with the oxidation phosphorylation process, and eventually causes cell damage via oxidative stress. Rotenone may also cause the depolymerisation of microtubules into tubulin monomers (Marshall and Himes, 1978). Accumulation of tubulin monomers is potentially cytotoxic, and it is believed that parkin reverses cytotoxicity by ubiquitinating these monomers and targeting them for proteasome degradation (Ren et al., 2003.). Unfortunately, in PD patients with parkin mutations, this is not possible and tubulin accumulates to harmful levels in the cells.
2013-12-31 | GSE22997 | GEO
Project description:Human fibroblasts at different population doublings were treated with low amounts of rotenone (mild stress) and compared to untreated fibroblasts. Two different cell lines were used (MRC-5, HFF). Illumina sequencing (HiSeq2000) was applied to generate 50bp single-end reads. 60 samples: 3 biological replicates for each group: MRC-5 cells at 4 different population doublings (PD) with and without rotenone; HFF cells at 6 different population doublings with and without rotenone
2015-08-26 | E-GEOD-64553 | biostudies-arrayexpress
Project description:We investigated an subacute study in male Wistar rats, treated daily with 400 ppm rotenone for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. Rotenone is a strong mitochondrial respiratory chain complex I inhibitor. Inhibitors of complex I are suggested to exert anti-tumor activity of those tumors relying on oxidative metabolism and are therefore of interest in oncology research. Nevertheless, the safety profile of these inhibitors needs to be rigorously assessed. Rotenone has shown anti-carcinogenic activity in several studies. In this context we used rotenone in our study as tool compound with the aim to identify suitable biomarker candidates and enhance mechanistic insights into the biologic and cellular effects of complex I inhibitors at the organ level after in vivo treatment. Various parameters, including hematology, clinical chemistry and histopathology, major blood cell population phenotyping using FACS and enzymatic activity assays were measured and/or evaluated. Moreover gene expression profiles were determined to investigate pathways and functions affected by rotenone at the molecular level. As organs, liver, heart and brain stem were chosen due to the high metabolic activity, the high energy demand and due to the known neurotoxic effect of rotenone, respectively. The strongest rotenone-induced effects on gene expression were observed in the liver (1444 deregulated genes) compared to heart (650 deregulated genes) and brain stem (52 deregulated genes). These findings, together with the histopathological results, show that liver is a target organ of rotenone.
2017-01-02 | GSE86350 | GEO