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RNA-seq data of wild-type and Abcb11-deficient mice

ABSTRACT: RNA-seq analysis were applied to elucidate the transcriptional differences of wild-type and Abcb11-deficient mice. Comparison of female Abcb11-/- (Abcb11F) and female C57BL/6J mouse (WTF) livers identified 3,652 RNA species that were differentially expressed (1,809 genes upregulated and 1,843 genes downregulated; Padj < 0.05). Comparison of liver gene expression in Abcb11F versus non-tumor tissue of female Abcb11-/- mice (NTF) revealed 47 differentially expressed genes. Cross-comparison of the lists of differentially expressed genes in Abcb11F versus WTF and in Abcb11F versus NTF revealed 36 genes common to the two data sets.

ORGANISM(S): Mus musculus

PROVIDER: GSE183666 | GEO | 2021/09/10

REPOSITORIES: GEO

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Project description:Intrahepatic cholestasis of pregnancy (ICP) is estimated to impact between 0.4% and 5% of pregnancies worldwide. This disease is associated with elevated maternal bile acids and frequently untoward neonatal outcomes such as respiratory distress and asphyxia. Multiple candidate genes have been implicated, but none have provided insight into the mechanisms of neonatal respiratory distress and death. Herein our studies demonstrate that maternal cholestasis (due to Abcb11 deficiency) produces 100% neonatal death within 24h due to atelectasis producing pulmonary hypoxia, which recapitulates the respiratory distress and asphyxia of human ICP. We show that these neonates have elevated pulmonary bile acids that are associated with disrupted structure of pulmonary surfactant. Maternal absence of Nr1i2 superimposed upon Abcb11 deficiency strongly increased neonatal survival and is directly related to reduced maternal bile acid concentrations. The mechanism accounting for reduced serum bile acids in the mothers deficient in both Nr1i2 and Abcb11 appears related to disrupted reabsorption of intestinal bile acids due to changes in transporter expression. These findings provide novel insights into pulmonary failure by revealing bile acids capability to disrupt the structure of surfactant producing collapsed alveoli, pulmonary failure and ultimately death. These findings have important implications for neonatal health especially when maternal bile acids are elevated during pregnancy and highlight a potential pathway and targets amenable to therapeutic intervention to ameliorate this condition. We used microarrays to measure changes in gene expression profiles in lung tissues from Abcb11+/- lungs after interbreeding C57BL/6 wild-type female or C57BL/6 Abcb11-/- female mice against either C57BL/6 wild-type male mice or C57BL/6 Abcb11-/- male mice to create only heterozygote offspring. We also measured profiles in liver tissues from age-matched C57BL/6 wild-type and C57BL/6 Abcb11-/- mice. Lung tissues were collected from day E17.5, E18.5 and neonatal (N0) mice. Liver tissues were collected from 1.5-month-old C57BL/6 wildtype and Abcb11-/- mice.

Project description:Background - Multiple health effects are associated with moisture damage in buildings. Studies explaining these associations and cell-level mechanisms behind the observed health effects are urgently called for. Objectives - Alongside general toxicological markers, we focused on characterizing gene expression in human airway epithelium after exposure to indoor air particulate matter (PM) sampled from houses with and without moisture damage. Methods - We performed detailed technical building inspections in 25 residential houses and categorized them based on the detection of moisture damages and the probability of occupant exposure. PM sampling was complemented by microbiological and volatile organic compound assessment. We exposed airway constructs to three doses (1:16, 1:8, 1:4) of PM from moisture-damaged (index) and non-moisture-damaged (reference) houses. The RNA of exposed constructs was sequenced targeting toxicology -related genes. We did groupwise comparisons between index and reference houses and pairwise comparisons in matched index/reference houses. We analyzed general toxicological markers and imaged the constructs with electron microscopy. Results - In pairwise comparison, several genes were differentially expressed. Genes related to multiple toxicological pathways were highlighted, while none of the genes was consistently expressed in all the comparisons. In groupwise comparison, CYP1A1 was statistically significantly over-expressed in index houses at all doses (dose 1:16 log2FC = 0.007, padj = 0.03; dose 1:8 log2FC = 0.077, padj = 0.018; dose 1:4 log2FC = 0.270, padj = 0.002) and NFKB1 at the highest dose 1:4 (log2FC = 0.124, padj = 0.029). General toxicological markers did not separate the index/reference houses. Discussion - The exposure to PM from index houses activates toxicology -related genes in airway constructs. While differential expression was not consistent among all the index/reference pairs, possibly due to compositional differences of bioactive particles, our study highlights CYP1A1 and NFKB1 as potential targets in moisture damage -associated cellular responses.

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RNA-seq data of wild-type and Abcb11-deficient mice

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