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Pregnancy-specific transcriptional changes upon endotoxin exposure in mice - PubMed

  • ️Wed Jan 01 2020

Pregnancy-specific transcriptional changes upon endotoxin exposure in mice

Kenichiro Motomura et al. J Perinat Med. 2020.

Abstract

Objectives Pregnant women are more susceptible to certain infections; however, this increased susceptibility is not fully understood. Herein, systems biology approaches were utilized to elucidate how pregnancy modulates tissue-specific host responses to a bacterial product, endotoxin. Methods Pregnant and non-pregnant mice were injected with endotoxin or saline on 16.5 days post coitum (n=8-11 per group). The uterus, cervix, liver, adrenal gland, kidney, lung, and brain were collected 12 h after injection and transcriptomes were measured using microarrays. Heatmaps and principal component analysis were used for visualization. Differentially expressed genes between groups were assessed using linear models that included interaction terms to determine whether the effect of infection differed with pregnancy status. Pathway analysis was conducted to interpret gene expression changes. Results We report herein a multi-organ atlas of the transcript perturbations in pregnant and non-pregnant mice in response to endotoxin. Pregnancy strongly modified the host responses to endotoxin in the uterus, cervix, and liver. In contrast, pregnancy had a milder effect on the host response to endotoxin in the adrenal gland, lung, and kidney. However, pregnancy did not drastically affect the host response to endotoxin in the brain. Conclusions Pregnancy imprints organ-specific host immune responses upon endotoxin exposure. These findings provide insight into the host-response against microbes during pregnancy.

Keywords: acute chorioamnionitis; fetal inflammation; funisitis; host immune response; infection; inflammation; maternal inflammation; preterm birth; preterm labor; systemic inflammation.

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Conflict of interest statement

Declaration of Interests Statement

The authors have no conflicts of interest to declare.

Figures

Figure 1.
Figure 1.. The transcriptome of the uterine tissues in pregnant and non-pregnant mice in response to endotoxin

(A) Mice were injected with either 15 μg of lipopolysaccharide (LPS) (Pregnant n = 9, non-pregnant n = 8) or sterile 1X phosphate-buffered saline (PBS) (Pregnant n = 10, non-pregnant n = 11). (B) An unsupervised Principal Component Analysis based on the expression of all genes on the array. (C) A clustered heatmap based on the top 200 most varying genes. (D) A Venn diagram representing overlap between differentially expressed genes (DEGs) as detected by comparison between LPS- and PBS-injected pregnant mice (pink) and non-pregnant mice (blue). (E) A volcano plot showing the interaction between the pregnant and non-pregnant states when comparing DEGs in the uterus from LPS- or PBS-injected mice. (F) The list of pathways enriched by the analysis of pregnancy-specific genes.

Figure 2.
Figure 2.. The transcriptome of the cervix in pregnant and non-pregnant mice in response to endotoxin

(A) Mice were injected with either 15 μg of lipopolysaccharide (LPS) (Pregnant n = 10, non-pregnant n = 9) or sterile 1X phosphate-buffered saline (PBS) (Pregnant n = 10, non-pregnant n = 11). (B) An unsupervised Principal Component Analysis based on the expression of all genes on the array. (C) A clustered heatmap based on the top 200 most varying genes. (D) A Venn diagram representing overlap between differentially expressed genes (DEGs) as detected by the comparison between LPS- and PBS-injected pregnant mice (pink) and non-pregnant mice (blue). (E) A volcano plot showing the interaction between the pregnant and non-pregnant states when comparing DEGs in the cervix from LPS- or PBS-injected mice. (F) The list of pathways enriched by the analysis of pregnancy-specific genes.

Figure 3.
Figure 3.. The transcriptome of the liver in pregnant and non-pregnant mice in response to endotoxin

(A) Mice were injected with either 15 μg of lipopolysaccharide (LPS) (Pregnant n = 10, non-pregnant n = 9) or sterile 1X phosphate-buffered saline (PBS) (Pregnant n = 10, non-pregnant n = 11). (B) An unsupervised Principal Component Analysis based on the expression of all genes on the array. (C) A clustered heatmap based on the top 200 most varying genes. (D) A Venn diagram representing overlap between differentially expressed genes (DEGs) as detected by the comparison between LPS- and PBS-injected pregnant mice (pink) and non-pregnant mice (blue). (E) A volcano plot showing the interaction between the pregnant and non-pregnant states when comparing DEGs in the liver from LPS- or PBS-injected mice. (F) The list of pathways enriched by the analysis of pregnancy-specific genes.

Figure 4.
Figure 4.. The transcriptome of the adrenal glands in pregnant and non-pregnant mice in response to endotoxin

(A) Mice were injected with either 15 μg of lipopolysaccharide (LPS) (Pregnant n = 10, non-pregnant n = 9) or sterile 1X phosphate-buffered saline (PBS) (Pregnant n = 10, non-pregnant n = 11). (B) An unsupervised Principal Component Analysis based on the expression of all genes on the array. (C) A clustered heatmap based on the top 200 most varying genes. (D) A Venn diagram representing overlap between differentially expressed genes (DEGs) as detected by the comparison between LPS- and PBS-injected pregnant mice (pink) and non-pregnant mice (blue). (E) A volcano plot showing the interaction between the pregnant and non-pregnant states when comparing DEGs in the adrenal glands from LPS- or PBS-injected mice. (F) The list of pathways enriched by the analysis of pregnancy-specific genes.

Figure 5.
Figure 5.. The transcriptome of the kidney in pregnant and non-pregnant mice in response to endotoxin

(A) Mice were injected with either 15 μg of lipopolysaccharide (LPS) (Pregnant n = 10, non-pregnant n = 9) or sterile 1X phosphate-buffered saline (PBS) (Pregnant n = 10, non-pregnant n = 11). (B) An unsupervised Principal Component Analysis based on the expression of all genes on the array. (C) A clustered heatmap based on the top 200 most varying genes. (D) A Venn diagram representing overlap between differentially expressed genes (DEGs) as detected by the comparison between LPS- and PBS-injected pregnant mice (pink) and non-pregnant mice (blue). (E) A volcano plot showing the interaction between the pregnant and non-pregnant states when comparing DEGs in the kidney from LPS- or PBS-injected mice. (F) The list of pathways enriched by the analysis of pregnancy-specific genes.

Figure 6.
Figure 6.. The transcriptome of the lung in pregnant and non-pregnant mice in response to endotoxin

(A) Mice were injected with either 15 μg of lipopolysaccharide (LPS) (Pregnant n = 10, non-pregnant n = 9) or sterile 1X phosphate-buffered saline (PBS) (Pregnant n = 10, non-pregnant n = 11). (B) An unsupervised Principal Component Analysis based on the expression of all genes on the array. (C) A clustered heatmap based on the top 200 most varying genes. (D) A Venn diagram representing overlap between differentially expressed genes (DEGs) as detected by the comparison between LPS- and PBS-injected pregnant mice (pink) and non-pregnant mice (blue). (E) A volcano plot showing the interaction between the pregnant and non-pregnant states when comparing DEGs in the lung from LPS- or PBS-injected mice. (F) The list of pathways enriched by the analysis of pregnancy-specific genes.

Figure 7.
Figure 7.. The transcriptome of the brain in pregnant and non-pregnant mice in response to endotoxin

(A) Mice were injected with either 15 μg of lipopolysaccharide (LPS) (Pregnant n = 10, non-pregnant n = 9) or sterile 1X phosphate-buffered saline (PBS) (Pregnant n = 10, non-pregnant n = 11). (B) An unsupervised Principal Component Analysis based on the expression of all genes on the array. (C) A clustered heatmap based on the top 200 most varying genes. (D) A Venn diagram representing overlap between differentially expressed genes (DEGs) as detected by the comparison between LPS- and PBS-injected pregnant mice (pink) and non-pregnant mice (blue). (E) A volcano plot showing the interaction between the pregnant and non-pregnant states when comparing DEGs in the brain from LPS- or PBS-injected mice. (F) The list of pathways enriched by the analysis of pregnancy-specific genes.

Figure 8.
Figure 8.. Overall analysis of the transcriptome in pregnant mice

(A, B) UpSet plots of (A) upregulated and (B) downregulated differentially expressed genes (DEGs) in pregnant mice based on the transcriptome of the uterus, cervix, lung, liver, kidney, adrenal glands, and brain. (C, D) Venn diagrams representing the shared (C) upregulated and (D) downregulated DEGs in pregnant mice based on the transcriptome of the uterus, cervix, liver, adrenal glands, kidney, lung, and brain.

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