Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptomic single-cell analysis of murine neonatal growth plate with conditional G6PDH deletion

ABSTRACT: The growth plate controls bone lengthening and provides a template for bone formation. However, chondrocytes function in an avascular milieu and the supply of glucose is important to support the metabolic needs of this highly anabolic structure. Besides being an energetic source, we questioned whether glucose is also important for biosynthesis and redox homeostasis. We focused on the Pentose Phosphate Pathway, which provides intermediates for nucleotide synthesis and generates reducing power, necessary for biosynthesis and scavenging of reactive oxygen species. We therefore performed scRNA-seq analysis of chondrocytes isolated from wild-type and G6PDH-null neonatal murine growth plates (postnatal day 3). Chondrocyte-specific G6PDH-null mice were obtained by crossing G6pdh-floxed mice (provided by P. Carmeliet) with transgenic mice expressing Cre recombinase under the control of the collagen type II promotor (Ovchinnikov, DA. et al., 2000). Wild-type littermates were used as control.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Bram Boeckx

PROVIDER: E-MTAB-14554 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid (PFAA) and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as perfluorooctanoic acid (PFOA), PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPARα) and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, it’s mode of action is independent of PPARα. Wild-type (WT) and PPARα-null (Null) mice were dosed with 0, 3, or 10 mg/kg/day PFOS for 7 days. Animals were euthanized, livers weighed, and liver samples collected for histology and preparation of total RNA. Gene profiling was conducted using Affymetrix 430_2 microarrays. In WT mice, PFOS induced changes that were characteristic of PPARα transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPARα-independent changes were indicated in both WT and Null mice by altered expression of genes related to lipid metabolism, inflammation, and xenobiotic metabolism. Such results are similar to prior studies done with PFOA and are consistent with modest activation of the constitutive androstane receptor (CAR) and possibly PPARγ and/or PPARβ/δ. Unique treatment-related effects were also found in Null mice including altered expression of genes associated with ribosome biogenesis, oxidative phosphorylation and cholesterol biosynthesis. Of interest was up-regulation of Cyp7a1, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPARα, PFOS induces a variety of “off-target” effects as well. PPARalpha-null and wild-type male mice at 6-9 months of age were dosed by gavage for 7 consecutive days with either 0, 3, or 10 mg/kg PFOS (potassium salt) in 0.5% Tween 20. Five biological replicates consisting of individual animals were included in each dosage group. Data were compared to results previously published by our group for PFOA and Wy-14,643, a commonly used agonist of PPARalpha (Rosen et al., Toxicol Pathol. 36:592-607, 2008; GSE9796)

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Transcriptomic single-cell analysis of murine neonatal growth plate with conditional G6PDH deletion

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