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Biology of Reproduction 66, 1696-1701 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Bovine Immature Oocytes Acquire Developmental Competence During Meiotic Arrest In Vitro1

Shu Hashimoto3,,a, Naojiro Minami2,,b, Ryo Takakuraa, and Hiroshi Imaib

a Embryo Transplantation Laboratory, Snow Brand Milk Products Co. Ltd., 119 Uenae, Tomakomai, Hokkaido 059-1365, Japan b Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To test the hypothesis that oocytes require time to acquire developmental competence during meiotic arrest, we investigated the effects of butyrolactone I (BL I), a potent and specific inhibitor of cyclin-dependent kinase, on the developmental competence of bovine oocytes after in vitro fertilization (IVF) following release from meiotic arrest. In the present study, 4 culture conditions were used: addition of BSA or fetal bovine serum (FBS) under 2 oxygen tensions (5% vs. 20%) during meiotic arrest with 100-µM BL I. The developmental competence to the blastocyst stage was higher (P < 0.01) in oocytes that were arrested in FBS-supplemented medium under 5% O2 (37%) than in oocytes that were arrested under other conditions (5%–24%) or that matured directly following follicle aspiration (23%). The time course of nuclear maturation of BL I-treated oocytes was also examined. The results demonstrated that oocytes treated with BL I start germinal vesicle (GV) breakdown and reach the metaphase II stage 5.5–6.0 h earlier than nonarrested oocytes. The developmental rates to the blastocyst stage of BL I-treated oocytes matured for 15.5 and 21 h were higher (P < 0.05) than those of nontreated oocytes matured for 21 and 26.5 h, respectively. These results demonstrate that bovine immature oocytes, which were arrested at the GV stage with BL I in FBS-supplemented medium under low oxygen tension, acquire higher developmental competence during meiotic arrest.

early development, follicle, in vitro fertilization, meiosis, oocyte development


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Fully grown, prophase I-arrested oocytes, which are competent to resume meiotic maturation, are maintained in meiotic arrest within ovarian follicles by inhibitory factors produced by the follicle. When oocytes are removed from Graafian follicles and cultured in vitro under suitable conditions, they resume meiosis spontaneously and progress to the metaphase II (MII) stage. The ability of bovine oocytes matured in vitro to develop to the morula/blastocyst stage is less than that of in vivo-matured oocytes [1, 2]. The decrease in the developmental competence of in vitro-matured oocytes may be due to insufficient cytoplasmic maturity [1–3].

To improve the developmental competence of bovine immature oocytes, various approaches have been attempted. Several studies have examined the effects of holding oocytes at the germinal vesicle (GV) stage before in vitro maturation, because oocytes might require time to acquire developmental competence during meiotic arrest [4–6]. This idea is based on the fact that mammalian oocytes are arrested at the diplotene stage until the GnRH surge occurs and meiotic maturation resumes. On the other hand, oocytes aspirated from follicles resume meiotic maturation spontaneously. Furthermore, the developmental competence of oocytes collected from large follicles has been shown to be higher than that of oocytes collected from small follicles [7–9].

Various agents have been shown to inhibit GV breakdown (GVBD) of bovine oocytes. Such agents include drugs to elevate intracellular cAMP [10, 11], inhibitors of protein synthesis or phosphorylation [4, 12–14], follicular fluid [10, 15], granulosa or theca cells [15–18], follicle hemisections [19, 20], and follicle wall [21]. Oocytes cultured in intact follicles for 48 h appeared to acquire a greater developmental competence than those that matured directly following aspiration [22]. However, we are unaware of any reports that the developmental competence of bovine immature oocytes in vitro can be improved by arresting them at the GV stage using drugs.

The GVBD of oocytes is accompanied by major changes in protein phosphorylation in several species, including Xenopus [23], starfish [24], mice [25, 26], sheep [27], and goat [28]. The p34cdc2 protein kinase is activated in association with this burst of phosphorylation, is the catalytic subunit of maturation-promoting factor (MPF) [29], and is believed to be a key factor regulating the G2/M transition in cells, including oocytes. The activation of MPF is controlled in two phases. In the first phase, p34cdc2 protein kinase associates with the regulatory subunit, cyclin B, which is already synthesized and accumulated during interphase [30]. In the second phase, different sites of p34cdc2 are phosphorylated and dephosphorylated [31–35]. Butyrolactone I (BL I), which acts as a competitive inhibitor of ATP binding, is a potent and specific inhibitor of cyclin-dependent kinase and has few inhibitory effects on other protein kinases [36, 37]. Bovine oocytes treated with BL I have low MPF activity [38, 39], but MPF activity is restored following the release from BL I [39]. In addition, BL I-treated oocytes have the same developmental competence as nontreated oocytes [5].

The partial pressure of oxygen in follicular fluid ranges from 22 to 97 mm Hg (3–13%) [40]. Moreover, we have demonstrated that low oxygen tension during in vitro maturation improves the developmental competence of bovine oocytes due to the decrease in generation of reactive oxygen species (ROS) in the oocytes [41].

In the present study, we examined whether oocytes acquire developmental competence during meiotic arrest. To do this, we investigated the effects of different culture conditions during meiotic arrest by 100 µM BL I on the developmental competence of bovine oocytes after in vitro maturation and in vitro fertilization (IVF) following the release from meiotic arrest. Culture conditions were varied by adding BSA or fetal bovine serum (FBS) to the media and by using different oxygen tensions (5% vs. 20%). We also assessed the kinetics of nuclear maturation of BL I-treated oocytes following the release from meiotic arrest. The ability of arrested oocytes to develop to the blastocyst stage was compared with that of nonarrested oocytes at 2 times after the onset of GVBD (15.5 and 21 h).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Oocyte Collection and Inhibition of Meiotic Resumption

Bovine ovaries were obtained from Holstein cows and heifers at a local slaughterhouse and were transported in saline for 5–8 h at 18–21°C. Bovine oocytes were collected from follicles (diameter, 2–5 mm), and oocytes with intact cumulus cells and evenly granulated cytoplasms (COCs) were selected and randomly assigned to each treatment. The COCs were washed in m-TCM 199 [42] supplemented with 100 µM BL I (arrest medium; YE-0003-00; Funakoshi, Tokyo, Japan). m-TCM 199 consists of 25 mM Hepes and 25 mM bicarbonate-buffered TCM 199 (Gibco, Grand Island, NY), 0.05% (w/v) polyvinyl alcohol (PVA; P-8136; Sigma Chemical Co., St. Louis, MO), 0.5 mM sodium pyruvate (Nacalai Tesque, Inc., Kyoto, Japan), 0.02 AU/ml of FSH (Antrin, Denka, Kanagawa, Japan), 1 µg/ml of estradiol-17ß (E-8875; Sigma), and 1% (w/v) antibiotic-antimycotic solution (Gibco). BL I was prepared as 50 mM stock solution in dimethyl sulfoxide. Each group of 10 COCs was introduced into a 50-µl droplet of arrest medium with or without 3 mg/ml of BSA (A-4378; Sigma) or 10% (w/v) FBS (16140-014; Gibco) in a plastic dish covered with mineral oil (M-8416; Sigma). The COCs were cultured for 18–21 h at 39°C under 5% CO2 in air or 5% CO2, 5% O2, and 90% N2 with high humidity.

In Vitro Maturation

To allow the arrested oocytes to resume meiotic maturation, 10 oocytes were placed in 100-µl droplet of m-TCM 199 in a plastic dish. The dishes were gently shaken for 10–20 sec and then placed for 5 min on a 39°C heated-plate. This procedure was repeated five times to avoid carry-over of BL I into the oocyte maturation medium. The washed 10 COCs were cultured in 50-µl m-TCM 199 for 15.5 or 21 h at 39°C under 5% CO2 in air as previously described [42]. Before in vitro maturation, 9–10 oocytes were fixed and stained for assessment of meiotic arrest. Following in vitro maturation, 16–20 oocytes were fixed and stained for assessment of nuclear maturation. For a control, COCs that were recovered following follicle aspiration were cultured similarly for 21 or 26.5 h.

In Vitro Fertilization

IVF was carried out as previously described [43]. Briefly, frozen-thawed spermatozoa were washed with a discontinuous Percoll solution (Pharmacia, Uppsala, Sweden). Matured oocytes were inseminated with the washed spermatozoa (1 x 106 cells/ml) in a glucose-free defined medium [43] supplemented with 2 µg/ml of heparin (H-3393; Sigma). Oocytes were then completely freed from attached spermatozoa using vortex agitation 6 h after IVF (IVF), and 20 of them were fixed to assess fertilization. IVF was performed at 39°C under 5% CO2 in air at high humidity.

In Vitro Culture

In vitro culture of in vitro maturation/IVF embryos was carried out as previously described [42]. In short, denuded embryos were cultured in bicarbonate-buffered SOFaa [44] supplemented with 3 mg/ml of BSA (A-4378; Sigma), 0.05% (w/v) PVA, and 1% (w/v) antibiotic-mycotic solution. Then, 20 of these embryos were placed in 50 µl of SOFaa and cultured under 5% CO2, 5% O2, and 90% N2 with high humidity.

Development to the blastocyst stage was examined under a stereomicroscope (60x) at 168 h (Day 7) and 192 h (day 8) after IVF.

The number of cells per blastocyst was estimated as previously described [45]. Briefly, 168 h after IVF, the embryos were immersed in acid Tyrode solution (pH 2.5) to remove the zona pellucida. The blastocysts were fixed in ethanol:acetic acid (3:1 [v/v]), stained with 0.24% (v/v) basic fuchsin (B-0904; Sigma), and then examined under phase-contrast microscopy to count the number of cells.

Statistical Analysis

The frequencies of nuclear maturation, fertilization, and development to the blastocyst stage were compared using the Fisher protected least significant difference (PLSD) test following ANOVA. Mean cell numbers of blastocysts were compared using the Scheffe test following ANOVA. The data are shown as the mean percentage ± SEM. A P value less than 0.05 was considered to be significant. The kinetics of nuclear maturation was determined with three replicates using 20 oocytes per replicate. The onset of GVBD was estimated by extrapolating a regression line.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Oocytes were cultured in arrest medium containing 100 µM BL I in the presence of different combinations of supplements and under different oxygen tensions (Table 1). Under the 5 conditions tested, the proportions of oocytes that were arrested at the GV stage ranged from 70% to 87%. These values were not significantly different from one another. However, the proportion of oocytes that reached the MII stage following culture in arrest medium was affected by the arrest medium itself: the rate for oocytes cultured in arrest medium without protein or serum (37.5%) (Table 1) was significantly lower (P < 0.05) than the rates for oocytes cultured with protein or serum (73%–88%). No difference was observed in the sperm penetration rates of oocytes matured following the release from meiotic arrest (83%–87%) or in the female and male pronuclear formation rates (67%–75%) among the BL I treatment groups. However, the proportion of the embryos that developed to the blastocyst stage at Day 7 after IVF of oocytes that were arrested in FBS-supplemented medium under 5% O2 (37%) (Fig. 1) was higher (P < 0.01) than those of the other groups (5%–24%). Of the oocytes that were arrested in FBS-supplemented medium under 5% O2, 44% developed to the blastocyst stage at Day 8 after IVF (Fig. 1). This rate was significantly higher (P < 0.01) than those achieved by the oocytes arrested under other conditions (8%–31%). No difference was observed in mean cell number of blastocysts among treatments (P > 0.05, 105.8–152.3 cells/blastocyst) (Fig. 1).


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  		TABLE 1. Proportions of oocytes at the GV stage cultured for 19–21 h in the presence of BL-I in different culture media and of oocytes at MII stage matured for 21 h following release from meiotic arrest



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  		FIG. 1. Developmental competence of bovine oocytes after in vitro maturation and IVF following the release from meiotic arrest in BSA- or FBS-supplemented medium. Control: oocytes were matured directly following follicle aspiration. BSA: oocytes were cultured in arrest medium supplemented with BSA under 5% CO2 in air. FBS: oocytes were cultured in arrest medium supplemented with FBS under 5% CO2 in air. LOW BSA: oocytes were cultured in arrest medium supplemented with BSA under 5% CO2, 5% O2, and 90% N2. LOW FBS: oocytes were cultured in arrest medium supplemented with FBS under 5% CO2, 5% O2, and 90% N2. Data were obtained from six replications with 20 embryos. The numbers of blastocysts used for the estimation of cell number are shown in parentheses. a,b,c,d,e,fDifferent superscripts differ significantly (P < 0.01 by Fisher PLSD following ANOVA) in each developmental stage

The proportion of oocytes that underwent GVBD after release from meiotic arrest was 0.102 + 0.229x (r2 = 0.983) between 0 and 4 h, where x is the time of culture (Fig. 2). Similarly, the proportion of oocytes that reached the MII stage after release from meiotic arrest was found to be -1.015 + 0.11x (r2 = 0.996) between 10 and 15 h. The x-axis intercepts of these lines thus give the start times of GVBD (-0.44 h after the start of the culture for maturation) and extrusion of the polar body 1 (9.2 h), respectively. The proportion of oocytes that underwent GVBD directly following follicle aspiration was -0.992 + 0.179x (r2 = 1.0) between 6 and 10 h. Similarly, the proportion of oocytes that were cultured directly following follicle aspiration and that reached MII stage was -1.897 + 0.128x (r2 = 0.991) between 15 and 21 h. The x-axis intercepts of these lines thus give the start times of GVBD (5.5 h after the start of the culture for maturation) and extrusion of the polar body 1 (14.8 h). The difference in the start time of GVBD between oocytes cultured after the release from meiotic arrest and oocytes cultured directly after follicle aspiration was 5.9 h. The difference in the start time of the extrusion of polar body 1 between these 2 groups of oocytes was 5.6 h.



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  		FIG. 2. Time sequence of nuclear maturation of bovine oocytes following the release from meiotic arrest with BL I. A) Proportion of oocytes that underwent germinal vesicle breakdown. B) Proportion of oocytes that reached the MII stage. BL I oocytes were cultured in FBS-supplemented arrest medium under 5% CO2, 5% O2, and 90% N2 for 18 h and cultured in maturation medium. Control oocytes were cultured in maturation medium directly following follicle aspiration

The times required for GVBD and nuclear maturation in BL I-treated oocytes were 5.5–6.0 h less than those required in nontreated oocytes (Fig. 2). Thus, the developmental competence to the blastocyst stage of oocytes cultured after release from meiotic arrest was compared with that of nontreated oocytes, which were cultured for 5.5 h longer than BL I-treated oocytes. No difference was observed between arrested oocytes and nonarrested oocytes in sperm penetration rates (75–82%) or in female and male pronuclear formation rates (60–69%). However, among oocytes that were released from meiotic arrest and then matured for another 15.5 or 21 h, the proportion of oocytes that developed to the blastocyst stage at 7 days after IVF was 40% or 42%, respectively (Fig. 3). These rates were significantly higher (P < 0.05) than the rates of the blastocysts developed from oocytes matured for 21 and 26.5 h directly following follicle aspiration (24% and 23%, respectively). Among oocytes that were released from meiotic arrest and then incubated for another 15.5 h, 49% reached the blastocyst stage at 8 days after IVF (Fig. 3). This rate was significantly higher (P < 0.05) than the rate of oocytes matured for 21 h directly following follicle aspiration (33%). At Day 7 after IVF, 41% of the BL I-treated oocytes developed to the blastocyst stage, whereas only 23.5% of the nontreated oocytes reached this stage. Similarly, at Day 8 after IVF, 47.5% of the BL I-treated oocytes developed to the blastocyst stage, whereas only 33.5% of the nontreated oocytes reached this stage. These differences were significant (P < 0.001). In addition, meiotic arrest by BL I increased the mean cell number of the blastocysts (P < 0.01; BL I: 15.5 h, 147 ± 7; 21 h, 147 ± 8; control: 21 h, 102 ± 10) (Fig. 3).



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  		FIG. 3. Effects of 1) meiotic arrest and 2) length of in vitro maturation following meiotic arrest on the developmental competence of bovine oocytes. Oocytes that had been subjected to meiotic arrest were released from meiotic arrest and allowed to mature in vitro for 15.5 h (BL I 15.5 h) or 21 h (BL I 21 h). Control oocytes were matured for 21 h (control 21 h) or 26.5 h (control 26.5 h) directly following follicle aspiration. Data were obtained from five replications with 20 embryos. The numbers of blastocysts used for the estimation of cell number are shown in parentheses. a,b,c,dDifferent superscripts differ significantly (P < 0.05 by Fisher PLSD following ANOVA) in each developmental stage; e,fP < 0.01 by Scheffe test following ANOVA


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present results clearly demonstrate that bovine oocytes acquire a higher developmental competence during meiotic arrest. Previous studies have shown that oocytes collected from follicles of larger diameter have a greater developmental competence [7–9]. This finding suggests that oocytes acquire developmental competence progressively during follicular growth. Thus, it has been inferred that the oocytes collected from small follicles require time to acquire developmental competence. Furthermore, the levels of RNA transcription in oocytes at the diplotene stage are similar to those observed in oogonia and are higher than those contained in ovulated oocytes [46, 47]. Oocytes accumulate mRNAs for their development until the onset of zygotic gene activation [46]. BL I, which was used for meiotic arrest of bovine oocytes in the present study, is a potent and specific inhibitor of cyclin-dependent kinase and has few inhibitory effects on other protein kinases [36, 37]. Recently, Marchal et al. [48] have shown that immature porcine oocytes synthesize some proteins during meiotic arrest by roscovitine, a potent inhibitor of cyclin-dependent kinase [49]. Therefore, translation or posttranslational modification of proteins or transcription of mRNAs itself might increase during meiotic arrest induced by BL I.

In the present study, addition of FBS to the media during meiotic arrest resulted in a higher developmental competence of oocytes than did addition of BSA. Sera contain many components, including hormones, trace elements, and growth factors. Addition of hormones or growth factors to the maturation medium has been shown to enhance the developmental competence of oocytes after IVF (LH [50], GH [51], and epidermal growth factor [52, 53]). These results suggest that components contained in sera improve the environments of oocytes during meiotic arrest.

Results of the present study demonstrate that low oxygen tension during meiotic arrest in vitro improves the developmental competence of the oocytes after IVF. Oxygen at the atmospheric level has been shown to be detrimental to mammalian embryos [54–56] and to bovine oocytes [41], possibly due to the generation of ROS [57]. A factor termed hypoxia-inducible factor I (HIF I) has been shown to induce the expression of erythropoietin under low oxygen tension in human hepatoblastoma cells [58]. Subsequently, transient transfection studies have revealed that HIF I-binding sites are involved in the regulation of a number of hypoxically inducible genes, such as genes encoding glycolytic enzymes [59–61], glucose transporters [62, 63], tyrosine hydroxylase [64], vascular endothelial growth factor (VEGF) [65–68], and platelet-derived endothelial cell growth factor [69]. In addition, under low oxygen tension, the hypoxia-inducible VEGF gene is not only transcribed, its mRNA stability increases [70]. VEGF is a major angiogenic factor; that is, it stimulates endothelial cell mitogenesis and capillary proliferation [65]. Human oocytes collected from follicles that contain a higher concentration of VEGF have a higher viability [71, 72]. These results imply that transcripts of genes that are expressed during meiotic arrest under low oxygen tension play beneficial roles in the subsequent development of oocytes.

Our results demonstrate that the nuclear maturation of BL I-treated oocytes starts 5–6 h earlier than that of nontreated oocytes. BL I has been shown to increase the proportion of GV-IV-stage oocytes, in which fully condensed chromosome bivalents are seen within intact GV [39]. We also found that the proportion of GV-IV-stage oocytes increased by BL I treatment (data not shown). MPF, the activity of which is inhibited by BL I, acts as a lamin kinase, phosphorylating lamins on mitotic phosphorylation sites and causing nuclear lamina disassembly [73]; the disassembly of nuclear lamina, in turn, is an essential prerequisite for the process of nuclear envelope breakdown [74, 75]. Based on these observations, the cell cycle of bovine oocytes treated with BL I might proceed to the stage before the nuclear envelope breakdown. Previous studies have shown that oocytes proceed to this stage in the presence of an inhibitor of protein synthesis [76–79].

The results of the present study revealed that the time required for nuclear maturation of oocytes treated with BL I was shorter than the time required for nontreated control oocytes. We found that the developmental competence of oocytes treated with BL I was higher than that of control oocytes (nontreated oocytes that were cultured for 5.5 h longer than BL I-treated oocytes) (Fig. 3). These results clearly indicate that bovine oocytes treated with BL I in FBS-supplemented medium under low oxygen tension acquire developmental competence during meiotic arrest.

The results of the present study indicate that immature oocytes require time to acquire greater developmental competence before meiotic maturation. A combination of FBS supplementation into the medium and a decrease of oxygen tension during meiotic arrest provided the favorable conditions to enable developmentally incompetent oocytes to acquire developmental competence. However, further molecular and genetic analyses will be needed to understand the mechanism of this improvement.


   FOOTNOTES
 
First decision: 18 December 2001.

1 Part of this work was supported by a grant from the Japan Society for the Promotion of Science (JPS-RFTF 97L00905 to N.M.). Back

2 Correspondence. FAX: 81 75 753 6329; naojiro{at}kais.kyoto-u.ac.jp Back

3 Current address: Research & Development Center for Dairy Farming, Chuo-ku, Sapporo 060-0003, Japan Back

Accepted: December 27, 2001.

Received: November 16, 2001.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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