RNA-seq analysis of gestationally Cd-exposed hepatic transcriptome
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150679 | GEO | 2020/12/09
REPOSITORIES: GEO
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Project description:Cadmium is a neurotoxic compound which induces cognitive alterations similar to those produced by Alzheimer's disease (AD). Autophagic flux impairment is a hallmark in Cd-induced AD-like pathology. However, the underlying mechanism remains obscure. In these study, Neuro-2a cells were exposed to different concentrations of Cd (1, 2, and 4 μM) for 72 h, and C57 mice (8 week) were orally administered Cd for 12 weeks. Chronic Cd exposure inhibited autophagosome-lysosome fusion and impaired lysosomal function, thereby contributing to defects in autophagic clearance and subsequently leading to APP accumulation and nerve cell death. Mechanistically, proteomic analysis coupled with Ingenuity Pathway Analysis identified the crucial key target molecule in Cd-impaired autophagic flux. Four-dimensional label-free succinylation quantitative proteomics were performed in Neuro-2a cells with and without 4 μM CdCl2 treatment for 72h. Then, vital molecules and crucial succinylation sites were identified. Moreover, the function and important role of the resulting molecule with crucial succinylation site were determined. These results may thus open an avenue for therapeutic intervention in chronic Cd-induced AD-like pathology.
2024-10-17 | PXD048158 | Pride
Project description:Background and Aims: Cadmium (Cd) exposure in adulthood is associated with non-alcoholic fatty liver disease (NAFLD), characterized by steatosis, inflammation, and fibrosis. NAFLD is the leading type of chronic liver disease, resulting in $103 billion per year in medical costs and affecting 30 % of the adult US population. Diagnosis of NAFLD is occurring at increasingly younger ages, with up to 20 % of adolescents and young adults currently affected, suggesting that susceptibility to NAFLD may be programmed by the environment during early life. However, the role of developmental Cd exposure in programming NAFLD and the underlying mechanisms remain unclear. We have proposed that imprinted genes are strong candidates for connecting the early life environment and later disease. Approach and Results: We established a hybrid mouse model of developmental Cd exposure in which dams were exposed to 0 or 50 ppm CdCl2 five weeks prior to mating until their offspring reached postnatal day (PND) 10. CdCl2 exposure is associated with histological, biochemical, and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA-seq, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up-regulated and over-represented among differentially expressed genes, consistent with a role in developmental Cd-induced NAFLD. In support of this, we show that hepatocyte-specific over-expression of Zac1 is sufficient to drive lipid accumulation in vitro. Conclusions: Our findings demonstrate that developmental CdCl2 exposure is sufficient to program NAFLD in later life, and with our previous work, establish Zac1 and the IGN as key regulators of prosteatotic and profibrotic pathways, two of the major pathological hallmarks of NAFLD
2022-10-21 | GSE201906 | GEO
Project description:PFAS are persistent man-made chemicals considered to be emerging pollutants, with PFOA, PFOS, and PFHxS having associations with liver toxicity and steatosis. PFOA, PFOS, and PFHxS can undergo placental/lactational transfer, however, little is known about the impact of PFAS mixtures during the developmental window, nor maternal diet on PFAS adverse effects. It was hypothesized that gestational/lactational PFAS exposure would alter the pup liver proteome. The work herein evaluated the liver proteome in offspring, identifying potential biochemical/signaling pathways altered via maternal PFAS exposure. Timed-pregnant CD-1 dams were fed a standard chow or 60% kcal high-fat diet. From GD1 until PND20, dams were orally gavaged daily with either 0.5% Tween 20, individual PFOA, PFOS, PFHxS at 1 mg/kg, or a mixture (1 mg/kg each, totaling 3 mg/kg). Livers were collected from PND21 offspring and SWATH-MS pro-teomics was performed. IPA analysis revealed disease and biological function pathways involved in liver damage, xenobiotics, and lipid regulation were modulated by PFAS exposure in the PND21 liver: lipid transport, storage, oxidation, and synthesis, xenobiotic metabolism and transport, liver damage and inflammation, and fatty acid metabolism, oxidation and transport. This indicates the pup liver proteome is altered via maternal exposure and predisposes the pup to metabolic dysfunctions.
2024-05-09 | PXD052106 | Pride
Project description:Maternal low-protein (MLP) diet can lead to hepatic steatosis, which only develops with ageing. It is still unclear whether the young offspring show any signs of past exposure to prenatal adverse conditions. We hypothesized that early nutritional insult would first affect the dynamic responsiveness to nutritional challenges rather than the static state. We analyzed the transcriptome and metabolome profiles of the hepatic response to fasting/refeeding in young male mice offspring to identify changes induced by early gestational MLP diet. Restricted MLP exposure strictly to early gestation was achieved by the embryo transfer method. As a result, significant transcriptional differences between control and MLP pups were found only in the fasted state. The fasting-induced upregulation of genes for long-chain fatty acid metabolism and of stress response genes related to protein folding were significantly diminished in MLP pups. Gene Set Enrichment Analysis showed that peroxisome proliferator activated receptor (PPAR)-mediated induction was impaired in fasted MLP pups. Lipid profiling showed that the hepatic signature of triacylglycerols was shifted to longer acyl-chains and higher saturation by the MLP diet. Taken together, early gestational MLP diet affected the hepatic dynamic response to nutritional stress in seemingly healthy young offspring, accompanied with partial deterioration of PPAR action.
2017-09-14 | GSE100313 | GEO
Project description:Cadmium (Cd) is a toxic heavy metal found throughout the environment and one of the top ten toxicants of major public health concern identified by the World Health Organization.InuteroCd exposure causes fetal growth restriction, malformation, and spontaneous abortion; however, the mechanisms by which Cd impacts these outcomes are poorly understood. Cd accumulates in the placenta, suggesting that these negative outcomes may be a consequence of disrupted placental function and placental insufficiency. To understand the impact of Cd on gene expression within the placenta, we developed a mouse model of Cd-induced fetal growth restriction through maternal consumption of CdCl2 and performed RNA-seq on control and CdCl2 exposed placentae. The top differentially expressed transcript was the Tcl1Upstream Neuron-Associated (Tuna) long non-coding RNA, which was up-regulated over 25-fold in CdCl2 exposed placentae. Tuna has been shown to be critical for neural stem cell differentiation. However, within the placenta, there is no evidence that Tuna is normally expressed or functional at any developmental stage. To determine the spatial expression of Cd-activated Tuna within the placenta, we used in situ hybridization as well as placental layer-specific RNA isolation and analysis. Both methods confirmed the absence of Tuna expression in control samples and determined that Cd-induced Tuna expression is specific to the junctional zone. Since many lncRNAs regulate gene expression, we hypothesized that Tunaforms part of the mechanism of Cd-induced transcriptomic changes. To test this, we over-expressed Tuna in cultured choriocarcinoma cells and compared gene expression profiles to those of control and CdCl2 exposed cells. We demonstrate significant overlap between genes activated byTunaoverexpression and genes activated by CdCl2 exposure, with enrichment in the NRF2-mediated oxidative stress response. Herein we analyze the NRF2 pathway and show that Tuna increases NRF2/NRF2 both at the transcript and protein levels. Tuna drives increased NRF2 target gene expression, a result that is abrogated with the use of an NRF2 inhibitor, confirming that Tuna activates oxidative stress response genes through this pathway. This work identifies the lncRNA Tuna as a potential novel player in Cd-induced placental insufficiency.
2023-05-31 | GSE233252 | GEO
Project description:Cadmium (Cd) is a toxic heavy metal found throughout the environment and one of the top ten toxicants of major public health concern identified by the World Health Organization.InuteroCd exposure causes fetal growth restriction, malformation, and spontaneous abortion; however, the mechanisms by which Cd impacts these outcomes are poorly understood. Cd accumulates in the placenta, suggesting that these negative outcomes may be a consequence of disrupted placental function and placental insufficiency. To understand the impact of Cd on gene expression within the placenta, we developed a mouse model of Cd-induced fetal growth restriction through maternal consumption of CdCl2 and performed RNA-seq on control and CdCl2 exposed placentae. The top differentially expressed transcript was the Tcl1Upstream Neuron-Associated (Tuna) long non-coding RNA, which was up-regulated over 25-fold in CdCl2 exposed placentae. Tuna has been shown to be critical for neural stem cell differentiation. However, within the placenta, there is no evidence that Tuna is normally expressed or functional at any developmental stage. To determine the spatial expression of Cd-activated Tuna within the placenta, we used in situ hybridization as well as placental layer-specific RNA isolation and analysis. Both methods confirmed the absence of Tuna expression in control samples and determined that Cd-induced Tuna expression is specific to the junctional zone. Since many lncRNAs regulate gene expression, we hypothesized that Tunaforms part of the mechanism of Cd-induced transcriptomic changes. To test this, we over-expressed Tuna in cultured choriocarcinoma cells and compared gene expression profiles to those of control and CdCl2 exposed cells. We demonstrate significant overlap between genes activated byTunaoverexpression and genes activated by CdCl2 exposure, with enrichment in the NRF2-mediated oxidative stress response. Herein we analyze the NRF2 pathway and show that Tuna increases NRF2/NRF2 both at the transcript and protein levels. Tuna drives increased NRF2 target gene expression, a result that is abrogated with the use of an NRF2 inhibitor, confirming that Tuna activates oxidative stress response genes through this pathway. This work identifies the lncRNA Tuna as a potential novel player in Cd-induced placental insufficiency.
2023-05-31 | GSE233281 | GEO
Project description:To investigate the mechanism by which paternal exposure to high-fat diet (HFD) exacerbates environmental stress-impaired testicular germ cell development in offspring, testicular RNA sequencing was performed in H+Cd (the offspring were treated with Cd after paternal exposure to one-generational HFD) and H+H+Cd (the offspring were treated with Cd after paternal exposure to bi-generational HFD) groups. Compared with HFD1D group and HFD2D group, 229 mRNAs were upregulated and 268 mRNAs were downregulated, screened for a 1.2-fold change and adjusted with P < 0.05. GO analysis revealed that downregulated mRNAs were related to multiple biological processes, including the "retinol metabolic process," the "reproductive process," and the "spermatogenesis".
2023-12-22 | GSE241413 | GEO
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2019-06-11 | PXD009670 | Pride
Project description:We examined the effect of oral TUDCA treatment on hepatic steatosis and associated changes in hepatic gene expression in ob/ob mice. We administered TUDCA to ob/ob mice at a dose of 500 mg/kg twice a day by gastric gavage for 3 weeks. Body weight, glucose homeostasis, endoplasmic reticulum (ER) stress, and hepatic gene expression were examined in comparison with control ob/ob mice and normal littermate C57BL/6J mice.
2010-12-31 | E-GEOD-22608 | biostudies-arrayexpress
Project description:Many heavy metals, including nickel (Ni), cadmium (Cd), and chromium (Cr) are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the of toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells. H4-II-E-C3 cells were were exposed to nickel (II) chloride (NiCl2), cadmium chloride (CdCl2), or sodium dichromate (Na2Cr2O7) for 24 hours. The cells were treated with a low, mid, and high concentration of each chemical and shared a control for each biological replicated, and we exposed 4 biologcial replicates for a total of 44 samples.
2011-08-18 | E-GEOD-31503 | biostudies-arrayexpress