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Chronically elevated androgen and/or consumption of a Western-style diet impairs oocyte quality and granulosa cell function in the nonhuman primate periovulatory follicle

  • Reproductive Physiology and Disease
  • Published:
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Abstract

Purpose

To investigate the impact of chronically elevated androgens in the presence and absence of an obesogenic diet on oocyte quality in the naturally selected primate periovulatory follicle.

Methods

Rhesus macaques were treated using a 2-by-2 factorial design (n = 10/treatment) near the onset of menarche with implants containing either cholesterol (C) or testosterone (T, 4–5-fold increase above C) and a standard or “Western-style” diet alone (WSD) or in combination (T+WSD). Following ~ 3.5 years of treatment, females underwent controlled ovulation (COv, n = 7–10/treatment) cycles, and contents of the naturally selected periovulatory follicle were aspirated. Follicular fluid (FF) was analyzed for cytokines, chemokines, growth factors, and steroids. RNA was extracted from luteinizing granulosa cells (LGCs) and assessed by RNA-seq.

Results

Only healthy, metaphase (M) I/II-stage oocytes (100%) were retrieved in the C group, whereas several degenerated oocytes were recovered in other groups (33–43% of T, WSD, and T+WSD samples). Levels of two chemokines and one growth factor were reduced (p < 0.04) in FF of follicles with a MI/MII oocyte in WSD+T (CCL11) or T and WSD+T groups (CCL2 and FGF2) compared to C and/or WSD. Intrafollicular cortisol was elevated in T compared to C follicles (p < 0.02). Changes in the expression pattern of 640+ gene products were detected in LGC samples from follicles with degenerated versus MI/MII-stage oocytes. Pathway analysis on RNAs altered by T and/or WSD found enrichment of genes mapping to steroidogenic and immune cell pathways.

Conclusions

Female primates experiencing hyperandrogenemia and/or consuming a WSD exhibit an altered intrafollicular microenvironment and reduced oocyte quality/competency, despite displaying menstrual cyclicity.

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Acknowledgments

The outstanding efforts of the NCTRI NHP Core members Emily Mishler, M.S., Corrine Wilcox, B.S., Kise Bond, P.S.M., and Andrea Calhoun, M.S. under the direction of Ov Slayden, Ph.D. as well as Diana Takahashi, M.S., were critical for the successful execution of all protocols and are greatly appreciated. In addition, the efforts of the staff of the ONPRC Endocrine Technology Support Core contributed to the success of this project. RNA sequencing was performed by the OHSU Massively Parallel Sequencing Shared Resource. Analysis of the RNA-seq data was performed by the ONPRC’s Biostatistics & Bioinformatics Core under the direction of Lucia Carbone, Ph.D. and Suzanne Fei, Ph.D. with statistical analyses performed by Lina Gao, Ph.D. and Byung Park, Ph.D. We greatly appreciate the core’s analysis pipelines that utilize OHSU’s Exacloud compute cluster.

Funding

Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under Award Number P50HD071836 (to RLS). Additional funding was provided by NIH Award Number P51OD011092 (Support for National Primate Research Center and Cores).

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Authors and Affiliations

  1. Division of Reproductive & Developmental Sciences, Oregon Health & Science University, Beaverton, OR, USA

    Cecily V. Bishop, Taylor E. Reiter, Carol B. Hanna, Brittany L. Daughtry, Shawn L. Chavez, Jon D. Hennebold & Richard L. Stouffer

  2. Department of Animal and Rangeland Sciences, Oregon State University, Corvallis, OR, 97331, USA

    Cecily V. Bishop

  3. Endocrine Technologies Core, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA

    David W. Erikson

  4. Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, 97239, USA

    Shawn L. Chavez, Jon D. Hennebold & Richard L. Stouffer

  5. Department of Physiology & Pharmacology, Oregon Health & Science University, Portland, OR, 97239, USA

    Shawn L. Chavez & Jon D. Hennebold

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  1. Cecily V. Bishop
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All procedures involving rhesus monkeys were reviewed and approved by the ONPRC/Oregon Health and Science University (OHSU) Institutional Animal Care and Use Committee (IACUC) in accordance with the U.S. Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals.

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Electronic Supplementary Material

Supplemental Figure 1:

Examples of estradiol (E2) and progesterone (P4) patterns and oocyte/ fertilization outcomes from several T-treated females. E2 and P4 patterns were not associated with oocyte stage or fertilization success. A premature rise of P4 >0.5ng/ml before hCG administration (orange arrow, bottom graph and image) was associated with follicle rupture (ovulated). (PNG 2249 kb)

High Resolution Image (TIF 4905 kb)

Supplemental Figure 2:

Additional Venn Diagram Analyses comparing all pairwise comparisons from LGC transcriptome analyses. Numbers of RNAs in each contrast and overlap between C vs T (yellow ellipse), C vs WSD (red ellipse) C vs T+WSD (purple ellipse), T vs T+WSD (green ellipse) and WSD vs T+WSD (blue ellipse). Panel A) All RNAs in dataset. Panel B) Only up-regulated RNAs in pairwise comparisons. Panel C) Only down-regulated RNAs in pairwise comparisons. See Methods for details of statistical analyses and Table 7 for total RNAs significantly up-regulated and down-regulated identified by each contrast. (PNG 807 kb)

High Resolution Image (TIF 1543 kb)

Supplemental Figure 3:

The Top Regulator Effect Networks identified by IPA for pairwise comparison C vs T (Supplemental Table 4). Genes in top row are transcription factors by which changes in activity could lead to the observed changes in gene product expression in the center row. Processes identified in the bottom row are the predicted cellular outcomes of the observed changes to gene expression. Red colors indicate activated and green indicate inhibited molecules, while orange/yellow lines indicate direction of predicted activation and blue lines indicate directed of predicted inhibition (dashed lines indicate lower level of confidence for predictions, grey lines indicate those predictions that do not reach statistical significance). (PNG 1862 kb)

High Resolution Image (TIF 2913 kb)

Supplemental Figure 4:

The Top Regulator Effect Networks identified by IPA for pairwise comparison C vs WSD (Supplemental Table 4). Genes in top row are transcription factors by which changes in activity could lead to the observed changes in gene product expression in the center row. Processes identified in the bottom row are the predicted cellular outcomes of the observed changes to gene expression. Red colors indicate activated and green indicate inhibited molecules, while orange/yellow lines indicate direction of predicted activation and blue lines indicate directed of predicted inhibition (dashed lines indicate lower level of confidence for predictions, grey lines indicate those predictions that do not reach statistical significance). (PNG 3593 kb)

High Resolution Image (TIF 5048 kb)

Supplemental Figure 5:

The Top Regulator Effect Networks identified by IPA for pairwise comparisons C vs T+WSD (Panel A) and T vs T+WSD (Panel B; Supplemental Table 4). Genes in top row are transcription factors by which changes in activity could lead to the observed changes in gene product expression in the center row. Processes identified in the bottom row are the predicted cellular outcomes of the observed changes to gene expression. Red colors indicate activated and green indicate inhibited molecules, while orange/yellow lines indicate direction of predicted activation and blue lines indicate directed of predicted inhibition (dashed lines indicate lower level of confidence for predictions, grey lines indicate those predictions that do not reach statistical significance). (PNG 1220 kb)

High Resolution Image (TIF 2232 kb)

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Bishop, C.V., Reiter, T.E., Erikson, D.W. et al. Chronically elevated androgen and/or consumption of a Western-style diet impairs oocyte quality and granulosa cell function in the nonhuman primate periovulatory follicle. J Assist Reprod Genet 36, 1497–1511 (2019). https://doi.org/10.1007/s10815-019-01497-8

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