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Polycystic ovarian syndrome is accompanied by repression of gene signatures associated with biosynthesis and metabolism of steroids, cholesterol and lipids.

Salilew-Wondim D, Wang Q, Tesfaye D, Schellander K, Hoelker M, Hossain MM, Tsang BK - J Ovarian Res (2015)

Bottom Line: Functional annotation of the dysregulated genes revealed that biosynthesis and metabolism of steroids, cholesterol and lipids to be the most top functions enriched by the repressed genes.However, cell differentiation/proliferation, transcriptional regulation, neurogenesis, cell adhesion and blood vessel development processes were enriched by activated genes.The dysregulation of genes associated with biosynthesis and metabolism of steroids, cholesterol and lipids, cell differentiation/proliferation in DHT- treated ovaries could be a molecular clue for abnormal steroidogenesis, estrous cycle irregularity, abnormal folliculogenesis, anovulation and lipid metabolism in PCOS patients.

View Article: PubMed Central - PubMed

Affiliation: Institute of Animal Science, Animal Breeding and Husbandry Group, University of Bonn, Endenicher Allee 15, Bonn, 53115, Germany. dsal@itw.uni-bonn.de.

ABSTRACT

Background: Polycystic ovarian syndrome (PCOS) is a spectrum of heterogeneous disorders of reproduction and metabolism in women with potential systemic sequel such as diabetes and obesity. Although, PCOS is believed to be caused by genetic abnormalities, the genetic background that can be associated with PCOS phenotypes remains unclear due to the complexity of the trait. In this study, we used a rat model which exhibits reproductive and metabolic abnormalities similar to the human PCOS to unravel the molecular mechanisms underlining this complex syndrome.

Methods: Female Sprague-Dawley rats were randomly assigned to DHT and control (CTL) groups. Rats in the DHT group were implanted with a silicone capsule continuous-releasing 83 μg 5α-dihydrotestosterone (DHT) per day for 12 weeks to mimic the hyperandrogenic state in women with PCOS. The animals were euthanized at 15 weeks of age and the pairs of ovaries were excised and the ovarian cortex tissues were used for gene expression analysis. Total RNA was from the ovarian cortex was amplified, labeled and hybridized to the Affymetrix GeneChip® Rat Genome 230 2.0 Array. A linear model system for microarray data analysis was used to identify genes affected in DHT treated rat ovaries and the molecular pathway of those genes were analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis tool.

Results: A total of 573 gene transcripts, including CPA1, CDH1, INSL3, AMH, ALDH1B1, INHBA, CYP17A1, RBP4, GAS6, GAS7 and GATA4, were activated while 430 others including HSD17B7, HSD3B6, STAR, HMGCS1, HMGCR, CYP51, CYP11A1 and CYP19A1 were repressed in DHT-treated ovaries. Functional annotation of the dysregulated genes revealed that biosynthesis and metabolism of steroids, cholesterol and lipids to be the most top functions enriched by the repressed genes. However, cell differentiation/proliferation, transcriptional regulation, neurogenesis, cell adhesion and blood vessel development processes were enriched by activated genes.

Conclusion: The dysregulation of genes associated with biosynthesis and metabolism of steroids, cholesterol and lipids, cell differentiation/proliferation in DHT- treated ovaries could be a molecular clue for abnormal steroidogenesis, estrous cycle irregularity, abnormal folliculogenesis, anovulation and lipid metabolism in PCOS patients.

No MeSH data available.


Related in: MedlinePlus

Ovarian transcriptome profile differences between DHT-treated and CTL rat groups. (A) The number of annotated (with known gene symbol) and non-annotated (unknown gene symbol) dysregulated genes in DHT rat groups. (B) The fold change (FC) distribution of dysregulated genes. (C) The heatmap showing the expression pattern of differentially expressed genes within and between biological replicates. DHT represents biological replicates in DHT-treated rat groups while CTL represents biological replicates in rats received an empty silastic capsule. Heatmap was generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red indicating the activated transcript level while the green color shows repressed expression pattern of a specific gene.
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Fig1: Ovarian transcriptome profile differences between DHT-treated and CTL rat groups. (A) The number of annotated (with known gene symbol) and non-annotated (unknown gene symbol) dysregulated genes in DHT rat groups. (B) The fold change (FC) distribution of dysregulated genes. (C) The heatmap showing the expression pattern of differentially expressed genes within and between biological replicates. DHT represents biological replicates in DHT-treated rat groups while CTL represents biological replicates in rats received an empty silastic capsule. Heatmap was generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red indicating the activated transcript level while the green color shows repressed expression pattern of a specific gene.

Mentions: This study was a part of our previously published results and thus a detailed description of the PCOS phenotypic data has been provided [23]. The DHT- treated rats had higher body weight, oestrous cycle irregularity and reduced insulin sensitivity. Ovaries from these rats had lower weight and exhibited absence of corpus luteum, higher percentage of follicle cysts, relatively thin membrane granulosa and theca hyperplasia. Thus, to unravel the genes that are abnormally activated or repressed due to PCOS, the ovarian transcriptome profile of DHT-treated and CTL rats were compared using the GeneChip @rat Genome array. The genes of which the pattern of expression was different between the DHT and CTL groups were identified by a linear model described in the LIMMA pipeline and bioconductor packages. 1774 of the 31046 gene transcripts available in GeneChip® Rat Genome 230 2.0 A array showed ≥ 2 fold change dysregulation in DHT-treated rat ovaries compared to CTL group (data not shown). However, using a stricter selection criteria (fold change ≥ 2, p ≤ 0.01 and false discovery rate (FDR) ≤ 10%), a total of 1003 transcripts were dysregulated in DHT-treated compared to CTL group (Figure 1A and B). Hierarchical clustering of the dysregulated genes exhibited a similar expression pattern within biological replicates and distinct differences between the groups (Figure 1C).Figure 1


Polycystic ovarian syndrome is accompanied by repression of gene signatures associated with biosynthesis and metabolism of steroids, cholesterol and lipids.

Salilew-Wondim D, Wang Q, Tesfaye D, Schellander K, Hoelker M, Hossain MM, Tsang BK - J Ovarian Res (2015)

Ovarian transcriptome profile differences between DHT-treated and CTL rat groups. (A) The number of annotated (with known gene symbol) and non-annotated (unknown gene symbol) dysregulated genes in DHT rat groups. (B) The fold change (FC) distribution of dysregulated genes. (C) The heatmap showing the expression pattern of differentially expressed genes within and between biological replicates. DHT represents biological replicates in DHT-treated rat groups while CTL represents biological replicates in rats received an empty silastic capsule. Heatmap was generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red indicating the activated transcript level while the green color shows repressed expression pattern of a specific gene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4414284&req=5

Fig1: Ovarian transcriptome profile differences between DHT-treated and CTL rat groups. (A) The number of annotated (with known gene symbol) and non-annotated (unknown gene symbol) dysregulated genes in DHT rat groups. (B) The fold change (FC) distribution of dysregulated genes. (C) The heatmap showing the expression pattern of differentially expressed genes within and between biological replicates. DHT represents biological replicates in DHT-treated rat groups while CTL represents biological replicates in rats received an empty silastic capsule. Heatmap was generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red indicating the activated transcript level while the green color shows repressed expression pattern of a specific gene.
Mentions: This study was a part of our previously published results and thus a detailed description of the PCOS phenotypic data has been provided [23]. The DHT- treated rats had higher body weight, oestrous cycle irregularity and reduced insulin sensitivity. Ovaries from these rats had lower weight and exhibited absence of corpus luteum, higher percentage of follicle cysts, relatively thin membrane granulosa and theca hyperplasia. Thus, to unravel the genes that are abnormally activated or repressed due to PCOS, the ovarian transcriptome profile of DHT-treated and CTL rats were compared using the GeneChip @rat Genome array. The genes of which the pattern of expression was different between the DHT and CTL groups were identified by a linear model described in the LIMMA pipeline and bioconductor packages. 1774 of the 31046 gene transcripts available in GeneChip® Rat Genome 230 2.0 A array showed ≥ 2 fold change dysregulation in DHT-treated rat ovaries compared to CTL group (data not shown). However, using a stricter selection criteria (fold change ≥ 2, p ≤ 0.01 and false discovery rate (FDR) ≤ 10%), a total of 1003 transcripts were dysregulated in DHT-treated compared to CTL group (Figure 1A and B). Hierarchical clustering of the dysregulated genes exhibited a similar expression pattern within biological replicates and distinct differences between the groups (Figure 1C).Figure 1

Bottom Line: Functional annotation of the dysregulated genes revealed that biosynthesis and metabolism of steroids, cholesterol and lipids to be the most top functions enriched by the repressed genes.However, cell differentiation/proliferation, transcriptional regulation, neurogenesis, cell adhesion and blood vessel development processes were enriched by activated genes.The dysregulation of genes associated with biosynthesis and metabolism of steroids, cholesterol and lipids, cell differentiation/proliferation in DHT- treated ovaries could be a molecular clue for abnormal steroidogenesis, estrous cycle irregularity, abnormal folliculogenesis, anovulation and lipid metabolism in PCOS patients.

View Article: PubMed Central - PubMed

Affiliation: Institute of Animal Science, Animal Breeding and Husbandry Group, University of Bonn, Endenicher Allee 15, Bonn, 53115, Germany. dsal@itw.uni-bonn.de.

ABSTRACT

Background: Polycystic ovarian syndrome (PCOS) is a spectrum of heterogeneous disorders of reproduction and metabolism in women with potential systemic sequel such as diabetes and obesity. Although, PCOS is believed to be caused by genetic abnormalities, the genetic background that can be associated with PCOS phenotypes remains unclear due to the complexity of the trait. In this study, we used a rat model which exhibits reproductive and metabolic abnormalities similar to the human PCOS to unravel the molecular mechanisms underlining this complex syndrome.

Methods: Female Sprague-Dawley rats were randomly assigned to DHT and control (CTL) groups. Rats in the DHT group were implanted with a silicone capsule continuous-releasing 83 μg 5α-dihydrotestosterone (DHT) per day for 12 weeks to mimic the hyperandrogenic state in women with PCOS. The animals were euthanized at 15 weeks of age and the pairs of ovaries were excised and the ovarian cortex tissues were used for gene expression analysis. Total RNA was from the ovarian cortex was amplified, labeled and hybridized to the Affymetrix GeneChip® Rat Genome 230 2.0 Array. A linear model system for microarray data analysis was used to identify genes affected in DHT treated rat ovaries and the molecular pathway of those genes were analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis tool.

Results: A total of 573 gene transcripts, including CPA1, CDH1, INSL3, AMH, ALDH1B1, INHBA, CYP17A1, RBP4, GAS6, GAS7 and GATA4, were activated while 430 others including HSD17B7, HSD3B6, STAR, HMGCS1, HMGCR, CYP51, CYP11A1 and CYP19A1 were repressed in DHT-treated ovaries. Functional annotation of the dysregulated genes revealed that biosynthesis and metabolism of steroids, cholesterol and lipids to be the most top functions enriched by the repressed genes. However, cell differentiation/proliferation, transcriptional regulation, neurogenesis, cell adhesion and blood vessel development processes were enriched by activated genes.

Conclusion: The dysregulation of genes associated with biosynthesis and metabolism of steroids, cholesterol and lipids, cell differentiation/proliferation in DHT- treated ovaries could be a molecular clue for abnormal steroidogenesis, estrous cycle irregularity, abnormal folliculogenesis, anovulation and lipid metabolism in PCOS patients.

No MeSH data available.


Related in: MedlinePlus