Stage-specific metabolic features of differentiating neurons: implications for toxicant sensitivity
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PROVIDER: PRJNA422137 | ENA |
REPOSITORIES: ENA
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Project description:Developmental neurotoxicity (DNT) may be induced when chemicals disturb a key neurodevelopmental process, and many tests focus on this type of toxicity. Alternatively, DNT may occur when chemicals are cytotoxic only during a specific neurodevelopmental stage. The toxicant sensitivity is affected by the expression of toxicant targets and by resilience factors. Although cellular metabolism plays an important role, little is known how it changes during human neurogenesis, and how potential alterations affect toxicant sensitivity of mature vs. immature neurons. We used immature (d0) and mature (d6) LUHMES cells (dopaminergic human neurons) to provide initial answers to these questions. Transcriptome profiling and characterization of energy metabolism suggested a switch from predominantly glycolytic energy generation to a more pronounced contribution of the tricarboxylic acid cycle (TCA) during neuronal maturation. Therefore, we used pulsed stable isotope-resolved metabolomics (pSIRM) to determine intracellular metabolite pool sizes (concentrations), and isotopically non-stationary 13C-metabolic flux analysis (INST 13C MFA) to calculate metabolic fluxes. We found that d0 cells mainly use glutamine to fuel the TCA. Furthermore, they rely on extracellular pyruvate to allow continuous growth. This metabolic situation does not allow for mitochondrial or glycolytic spare capacity, i.e. the ability to adapt energy generation to altered needs. Accordingly, neuronal precursor cells displayed a higher sensitivity to several mitochondrial toxicants than mature neurons differentiated from them. In summary, this study shows that precursor cells lose their glutamine dependency during differentiation while they gain flexibility of energy generation and thereby increase their resistance to low concentrations of mitochondrial toxicants.
2017-12-13 | GSE107999 | GEO
Project description:Paternal exposure to a range of environmental and lifestyle factors elicits distinct changes to the sperm sncRNA profile; modifications that have significant post-fertilization consequences. Despite this knowledge, there remains limited mechanistic understanding of how paternal exposures effect the sperm sncRNA landscape. Here, we report the acute sensitivity of the sperm sncRNA profile to the potent reproductive toxicant, acrylamide. Further, we traced the differential accumulation of acrylamide responsive sncRNAs to coincide with sperm transit of the proximal (caput) segment of the epididymis, wherein acrylamide exposure altered the expression of several transcription factors implicated in the expression of acrylamide-sensitive sncRNAs. We also identified extracellular vesicles secreted from the caput epithelium in relaying altered sncRNA profiles to maturing spermatozoa, the implications of which manifest in the form of dysregulated gene expression during early embryonic development. These data provide a causative mechanistic link to account for how environmental insults can alter the sperm epigenome and compromise the transcriptomic profile of early embryos
2021-10-07 | PXD022865 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE38926: Patterns of aberrant DNA methylation after toxicant-induced malignant transformation (MeDIP-chip dataset 1) GSE38928: Patterns of aberrant DNA methylation after toxicant-induced malignant transformation (MeDIP-chip dataset 2) GSE38929: Patterns of aberrant DNA methylation after toxicant-induced malignant transformation (miRNA dataset) Refer to individual Series
2012-06-25 | E-GEOD-38930 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE21008: Linking toxicant physiological mode of action with induced gene expression changes in Caenorhabditis elegans: atrazine GSE21010: Linking toxicant physiological mode of action with induced gene expression changes in Caenorhabditis elegans: cadmium GSE21011: Linking toxicant physiological mode of action with induced gene expression changes in Caenorhabditis elegans: fluoranthene Refer to individual Series
2010-03-23 | E-GEOD-21012 | biostudies-arrayexpress
Project description:Aberrant DNA methylation is frequently observed in cancer. The aim of this study was to determine how DNA methylation is changed after toxicant-induced malignant transformation. This study also puts the DNA methylation changes into context with respect to the aberrant DNA methylation events that occur in bladder and prostate carcinogenesis not associated with toxicant exposure.
2012-06-26 | GSE38928 | GEO
Project description:Aberrant DNA methylation is frequently observed in cancer. The aim of this study was to determine how DNA methylation is changed after toxicant-induced malignant transformation. This study also puts the DNA methylation changes into context with respect to the aberrant DNA methylation events that occur in bladder and prostate carcinogenesis not associated with toxicant exposure.
2012-06-26 | GSE38926 | GEO
Project description:Hypoxia in coastal waters is an increasing concern, with the frequency of hypoxic events rising because of climate change and human-driven impacts such as eutrophication. The Atlantic killifish (Fundulus heteroclitus), an estuarine species known for its resilience to environmental stressors, provides a valuable model to investigate the physiological, transcriptional, and epigenetic mechanisms underlying adaptation. Some killifish populations, like those in New Bedford Harbor (NBH), Massachusetts, have evolved resistance to dioxin-like polychlorinated biphenyls (PCBs) due to chronic exposure. These populations offer a unique opportunity to investigate how toxicant resistance might influence responses to secondary stressors like hypoxia. The objective of this study is to characterize the impacts of evolved resistance to toxicants on the ability to cope with acute hypoxia. We compared hepatic gene expression and DNA methylation patterns in response to two levels of hypoxia in killifish from NBH and Scorton Creek (SC), a reference population from a relatively pristine environment. We hypothesized that NBH fish would exhibit altered molecular responses to hypoxia due to trade-offs associated with toxicant resistance. Our results revealed significant differences between the two populations. SC fish demonstrated a dose-dependent increase in gene expression in response to hypoxia, while NBH fish exhibited a muted transcriptional response to severe hypoxia, indicating potential impairment in their ability to cope with hypoxic stress. Interestingly, NBH fish showed significant DNA methylation changes in response to hypoxia, while SC fish did not exhibit notable epigenetic alterations. These findings suggest that toxicant-adapted killifish may face trade-offs in their response to additional environmental stressors, with potential consequences for their ability to survive in increasingly hypoxic coastal habitats. Further research is needed to elucidate the functional implications of these epigenetic modifications and their role in adaptive stress responses.
2024-10-02 | GSE278569 | GEO
Project description:In this paper, a nonlinear mathematical model is proposed and analyzed to study the
effect of environmental toxicant on the immune response of the body. Criteria for local
stability, instability and global stability are obtained. It is shown that the immune
response of the body decreases as the concentration of environmental toxicant increases,
and certain criteria are obtained under which it settles down at its equilibrium level.
In the absence of toxicant, an oscillatory behavior of immune system and pathogenic
growth is observed. However, in the presence of toxicant, oscillatory behavior is not
observed. These studies show that the toxicant may have a grave effect on our body’s
defense mechanism.
Keywords: Pathogen; Immune Response; Toxicant; Stability.
2024-09-02 | BIOMD0000000905 | BioModels
Project description:In this paper, a nonlinear mathematical model is proposed and analyzed to study the
effect of environmental toxicant on the immune response of the body. Criteria for local
stability, instability and global stability are obtained. It is shown that the immune
response of the body decreases as the concentration of environmental toxicant increases,
and certain criteria are obtained under which it settles down at its equilibrium level.
In the absence of toxicant, an oscillatory behavior of immune system and pathogenic
growth is observed. However, in the presence of toxicant, oscillatory behavior is not
observed. These studies show that the toxicant may have a grave effect on our body’s
defense mechanism.
Keywords: Pathogen; Immune Response; Toxicant; Stability.
2024-09-02 | BIOMD0000000906 | BioModels
Project description:Homo sapiens have been exposed to various toxins and harmful compounds that change according to various phases of human evolution. Population genetics studies showed that such exposures lead to adaptive genetic changes; while observing present exposures to different toxicants, the first molecular mechanism that confers plasticity is epigenetic remodeling and, in particular, DNA methylation variation, a molecular mechanism proposed for medium-term adaptation. A large amount of scientific literature from clinical and medical studies revealed the high impact of such exposure on human biology; thus, in this review, we examine and infer the impact that different environmental toxicants may have in shaping human evolution. We first describe how environmental toxicants shape natural human variation in terms of genetic and epigenetic diversity, and then we describe how DNA methylation may influence mutation rate and, thus, genetic variability. We describe the impact of these substances on biological fitness in terms of reproduction and survival, and in conclusion, we focus on their effect on brain evolution and physiology.
| S-EPMC9775150 | biostudies-literature