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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.

ABSTRACT: Purpose: To investigate the impact of chronically-elevated androgens in 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 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 degenerated oocytes were prevalent in other groups (33-43%; overall effect of WSD and T, p=0.1). 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 expression pattern of 640+ gene products were detected in LGC samples from follicles with degenerated oocytes 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE128569 | GEO | 2019/09/05

REPOSITORIES: GEO

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Project description:This study examined the small antral follicles (SAFs) in ovaries of young adult rhesus monkeys following consumption of a western-style diet (WSD), with or without chronically elevated androgen levels since before puberty. Cholesterol or testosterone (T; n=6/group) implants were placed subcutaneously beginning at 1 yr of age, with addition of a WSD (high fat/fructose) at 5.5 yrs. Ovaries from treated females and age-matched controls were collected at 7 yrs of age. Compared to controls, consumption of a WSD, with and without T treatment, increased the numbers of SAFs per ovary (P<0.001), due to the presence of more atretic follicles (P<0.01). Immunostaining for the cellular proliferation markers (pRb and pH3) was greater in granulosa cells of healthy SAFs (P<0.01), while staining for the cell cycle inhibitor (p21) was higher in atretic SAFs (P<0.01). Intense CYP17A1 staining was observed on the theca of SAFs from WSD+/- T groups, compared to controls. Microarray analyses of the transcriptome in SAFs isolated from a subgroup (n=3/grp) of WSD and WSD+T treated females and controls consuming a standard diet, identified mRNA levels for 1944 genes changed >2-fold (p<0.05) among the three groups. Pathway analyses identified several gene pathways altered by WSD and/or WSD+T associated with lipid, carbohydrate and lipid metabolism, plus ovarian processes. Alterations of several SAF mRNAs are similar to those observed in follicular cells from women with PCOS. These data indicate chronic exposure to a WSD in the presence and absence of chronically elevated T alters structure and function of SAFs within primate ovaries. Affymetrix Microarray analyses of the transcriptome in SAFs isolated from ovaries of WSD and WSD+T treated rhesus macaque females and controls consuming a standard diet. Presumptive healthy SAFs were chosen for transcriptome evaluation based on criteria similar to previous studies: the presence of a clear antrum lacking dark oocytes or granulosa cells. Isolated SAFs were pooled by female/ovary (3.7Â±0.3 SAFs/ovary, n=3 ovaries/group), cleaned of extraneous stroma using 30-gauge needles, ruptured, and entire cellular contents (follicle wall/granulosa cells and cumulous-oocyte complex) placed into lysis buffer for RNA isolation (Absolutely RNA Nanoprep Kit, Agilent Technologies, Inc. USA).