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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

The most significantly molecular functions enriched by genes activated in DHT-treated ovaries. The direction of the arrow shows the significant level of the gene ontology terms. The heatmaps describe the expression pattern of clusters of genes involving in selected functions. Heatmaps were generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red in DHT group indicating the activated transcript level while the green color in CTL shows repressed expression pattern of a specific gene. DHT and CTL on the bottom of the heatmaps represent biological replicates in DHT-treated rat ovaries and rats which receive an empty silastic capsule, respectively
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Fig6: The most significantly molecular functions enriched by genes activated in DHT-treated ovaries. The direction of the arrow shows the significant level of the gene ontology terms. The heatmaps describe the expression pattern of clusters of genes involving in selected functions. Heatmaps were generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red in DHT group indicating the activated transcript level while the green color in CTL shows repressed expression pattern of a specific gene. DHT and CTL on the bottom of the heatmaps represent biological replicates in DHT-treated rat ovaries and rats which receive an empty silastic capsule, respectively

Mentions: Gene set enrichment analysis showed 18 candidate biological processes, including cell differentiation/proliferation, transcriptional regulation/gene expression, neurogenesis, cell adhesion, RNA metabolism, macromolecule biosynthesis and blood vessel development processes to be affected in DHT-treated ovaries due to gene activation (Figure 6). Moreover, the activated genes known to be involved in selective and non-covalent binding of zinc ions, receptors, growth factors, protein phosphatases, DNA secondary structure and peptide antigens. In addition, some of the activated genes are known to be involved in growth factor activity, initiating for cell growth or proliferation and transcription corepressor activity (Table 2).Figure 6


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)

The most significantly molecular functions enriched by genes activated in DHT-treated ovaries. The direction of the arrow shows the significant level of the gene ontology terms. The heatmaps describe the expression pattern of clusters of genes involving in selected functions. Heatmaps were generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red in DHT group indicating the activated transcript level while the green color in CTL shows repressed expression pattern of a specific gene. DHT and CTL on the bottom of the heatmaps represent biological replicates in DHT-treated rat ovaries and rats which receive an empty silastic capsule, respectively
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: The most significantly molecular functions enriched by genes activated in DHT-treated ovaries. The direction of the arrow shows the significant level of the gene ontology terms. The heatmaps describe the expression pattern of clusters of genes involving in selected functions. Heatmaps were generated using normalized log2 transformed values and the normalized log2 transformed expression values are described by pseudo color scale with red in DHT group indicating the activated transcript level while the green color in CTL shows repressed expression pattern of a specific gene. DHT and CTL on the bottom of the heatmaps represent biological replicates in DHT-treated rat ovaries and rats which receive an empty silastic capsule, respectively
Mentions: Gene set enrichment analysis showed 18 candidate biological processes, including cell differentiation/proliferation, transcriptional regulation/gene expression, neurogenesis, cell adhesion, RNA metabolism, macromolecule biosynthesis and blood vessel development processes to be affected in DHT-treated ovaries due to gene activation (Figure 6). Moreover, the activated genes known to be involved in selective and non-covalent binding of zinc ions, receptors, growth factors, protein phosphatases, DNA secondary structure and peptide antigens. In addition, some of the activated genes are known to be involved in growth factor activity, initiating for cell growth or proliferation and transcription corepressor activity (Table 2).Figure 6

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