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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 expression pattern of genes involving in sex steroid biosynthesis pathway in DHT-treated rat ovaries. (A) A modified steroid biosynthesis pathway from [53]. The intermediate and final products performed by dysregulated genes in DHT-treated ovaries are indicated in white box while the number in red or green circle corresponds the genes (enzymes) indicated in Figure B. (B) The heatmap displaying the expression pattern of repressed and activated genes involving in steroid biosynthesis in DHT compared to CTL. FC indicates the average fold change gene expression reduction or activation in DHT compared to CTL. P value: the significant levels.
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Fig8: The expression pattern of genes involving in sex steroid biosynthesis pathway in DHT-treated rat ovaries. (A) A modified steroid biosynthesis pathway from [53]. The intermediate and final products performed by dysregulated genes in DHT-treated ovaries are indicated in white box while the number in red or green circle corresponds the genes (enzymes) indicated in Figure B. (B) The heatmap displaying the expression pattern of repressed and activated genes involving in steroid biosynthesis in DHT compared to CTL. FC indicates the average fold change gene expression reduction or activation in DHT compared to CTL. P value: the significant levels.

Mentions: One of the major functions of the ovary is the production of steroid hormone [35]. Here, we identified dysregulation of several genes associated with steroidogenesis in ovaries of DHT-treated rats, including repression of cytochrome P450s, STAR and 3β-hydroxysteroid dehydrogenases (Figure 8). The repression of STAR in DHT-treated group suggests a reduced level of cholesterol influx for downstream steroidogenesis. In addition, the down-regulation of CYP11A1 and CYP19A1 in DHT-treated ovaries was consistent with our previous publication showing decreased aromatase expression and estradiol secretion in granulosa cells from DHT-treated rats [36]. Therefore, the dysregulation of genes associated with steroidogenesis in DHT-treated rats could result in abnormal sex hormone levels and ultimately PCOS phenotypes, including cycle irregularity, abnormal folliculogenesis and anovulation.Figure 8


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 expression pattern of genes involving in sex steroid biosynthesis pathway in DHT-treated rat ovaries. (A) A modified steroid biosynthesis pathway from [53]. The intermediate and final products performed by dysregulated genes in DHT-treated ovaries are indicated in white box while the number in red or green circle corresponds the genes (enzymes) indicated in Figure B. (B) The heatmap displaying the expression pattern of repressed and activated genes involving in steroid biosynthesis in DHT compared to CTL. FC indicates the average fold change gene expression reduction or activation in DHT compared to CTL. P value: the significant levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig8: The expression pattern of genes involving in sex steroid biosynthesis pathway in DHT-treated rat ovaries. (A) A modified steroid biosynthesis pathway from [53]. The intermediate and final products performed by dysregulated genes in DHT-treated ovaries are indicated in white box while the number in red or green circle corresponds the genes (enzymes) indicated in Figure B. (B) The heatmap displaying the expression pattern of repressed and activated genes involving in steroid biosynthesis in DHT compared to CTL. FC indicates the average fold change gene expression reduction or activation in DHT compared to CTL. P value: the significant levels.
Mentions: One of the major functions of the ovary is the production of steroid hormone [35]. Here, we identified dysregulation of several genes associated with steroidogenesis in ovaries of DHT-treated rats, including repression of cytochrome P450s, STAR and 3β-hydroxysteroid dehydrogenases (Figure 8). The repression of STAR in DHT-treated group suggests a reduced level of cholesterol influx for downstream steroidogenesis. In addition, the down-regulation of CYP11A1 and CYP19A1 in DHT-treated ovaries was consistent with our previous publication showing decreased aromatase expression and estradiol secretion in granulosa cells from DHT-treated rats [36]. Therefore, the dysregulation of genes associated with steroidogenesis in DHT-treated rats could result in abnormal sex hormone levels and ultimately PCOS phenotypes, including cycle irregularity, abnormal folliculogenesis and anovulation.Figure 8

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