Valdivieso A, Ribas L, Piferrer F. Ovarian transcriptomic signatures of zebrafish females resistant to different environmental perturbations.
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PROVIDER: PRJNA479895 | ENA |
REPOSITORIES: ENA
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Project description:<h4>Background</h4>Cancer metabolism is emerging as an important focus area in cancer research. However, the in vitro cell culture conditions under which much cellular metabolism research is performed differ drastically from in vivo tumor conditions, which are characterized by variations in the levels of oxygen, nutrients like glucose, and other molecules like chemotherapeutics. Moreover, it is important to know how the diverse cell types in a tumor, including cancer stem cells that are believed to be a major cause of cancer recurrence, respond to these variations. Here, in vitro environmental perturbations designed to mimic different aspects of the in vivo environment were used to characterize how an ovarian cancer cell line and its derived, isogenic cancer stem cells metabolically respond to environmental cues.<h4>Results</h4>Mass spectrometry was used to profile metabolite levels in response to in vitro environmental perturbations. Docetaxel, the chemotherapeutic used for this experiment, caused significant metabolic changes in amino acid and carbohydrate metabolism in ovarian cancer cells, but had virtually no metabolic effect on isogenic ovarian cancer stem cells. Glucose deprivation, hypoxia, and the combination thereof altered ovarian cancer cell and cancer stem cell metabolism to varying extents for the two cell types. Hypoxia had a much larger effect on ovarian cancer cell metabolism, while glucose deprivation had a greater effect on ovarian cancer stem cell metabolism. Core metabolites and pathways affected by these perturbations were identified, along with pathways that were unique to cell types or perturbations.<h4>Conclusions</h4>The metabolic responses of an ovarian cancer cell line and its derived isogenic cancer stem cells differ greatly under most conditions, suggesting that these two cell types may behave quite differently in an in vivo tumor microenvironment. While cancer metabolism and cancer stem cells are each promising potential therapeutic targets, such varied behaviors in vivo would need to be considered in the design and early testing of such treatments.
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Project description:The epigenetic transgenerational actions of environmental toxicants and relevant mixtures on ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1, F2 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling premature ovarian failure (POF). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states were induced by different classes of environmental compounds suggesting a role of environmental epigenetics in ovarian disease etiology. We used transcriptome microarray analysis to determine genes expressed differentially between F3 control and F3 vinclozolin lineage rat ovary granulosa cell and see which genes might be connected to or cause observed ovary diseases RNA samples from granulosa cell of 3 F3-control lineage groups are compared to granulosa cell of 3 F3-vinclozolin lineage groups
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Project description:Understanding the consequences of thermal and chemical variations in aquatic habitats is of importance in a scenario of global change. In ecology, the sex ratio is a major population demographic parameter. Research carried out so far on environmental perturbations on fish sex ratios has usually involved a few model species with a strong genetic basis of sex determination, analyzing juvenile or adult gonads. However, the underlying mechanisms at the time of commitment are poorly understood. The European sea bass has a mixed genetic and environmental sex determination system, which makes it naturally sensitive to environmental cues. Here, we transcriptomically analyzed developing gonads experiencing either testis or ovarian differentiation as a result of thermal and/or estrogen influences. Elevated temperature masculinized genetic females while estrogen exposure resulted in an all-female population. A total of 383 genes were differentially expressed, with an overall downregulation in the expression of genes involved both in testicular and ovarian differentiation in the estrogen-exposed fish achieved by a shutdown of the first steps of steroidogenesis. GO enrichment analysis uncovered affected pathways related to the immune response, xenobiotic metabolism, response to stimulus, signaling and growth. However, once the female phenotype was imposed gonads could continue their normal development, even taking into account that some of the resulting females were fish that otherwise would have developed as males. The data on the underlying mechanisms operating at the molecular level presented here contributes to better understanding the sex ratio response of fish species subjected to a combination of environmental perturbations.
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