Abstract
Gene expression is required in all steps of embryonic development and therefore heat stress is known to reduce developmental competence after direct exposure of oocytes and embryos to different conditions of heat shock, by decreasing protein synthesis. Moreover, as in somatic cells, the heat stress befuddles the integration of RNA and posttranscriptional modification of RNA, the assumption was that during meiotic maturation heat shock may mutate RNA within oocytes, with the possibility of altering the surrounding cumulus cells, causing, thus, reductions in development. Heat shock proteins (HSP) are among the first proteins produced during embryonic development and are crucial to cell function. The HSP70 (HSPA14 gene) is an important part of the cell’s machinery for folding, unfolding, transport, localization of proteins and differentiation, regulation of the embryonic cell cycle and helping to protect cells from stress. Therefore, HSPA14 is an apoptotic gene induced by heat shock is associated with embryonic loss, playing an important role of control mechanism of processes involved in growth, cellular differentiation, and embryonic development. In addition the connexin proteins (e.g. Cx43), related to gap junctions, are expressed in numerous tissues including gonads, act as a mediator of heat stress effect on cells. In the present review, the effect of heat stress on bovine embryonic development in a physiologic and genetic point of view is fully discussed.
Keywords
- heat stress
- oocyte
- maturation
- gene expression
- HSPA14
- Cx43
- real‐time PCR
1. Introduction
Climate changes influence the biogeography and phenology of animals, thus affecting their reproduction, physiological development, and metabolism [1]. The global warming refers to the continued increase of the earth's temperature and ecosystems change, as when the sun heats the earth, the earth radiates only some of the sun's energy into space, while some energy is trapped by atmospheric gases, such as carbon dioxide and water vapor. This energy builds up in the earth's atmosphere, the earth gradually becomes hotter and leads to increase in the temperature, and hence heat stress can happen [2]. Depending on the proportion of CO
2. Ovarian physiology: folliculogenesis, oocytes growth, and development: oocytes growth and development
The fertilization of mature oocyte occurs in the oviduct and there are three distinct phases that can be divided during this process. During the first phase (the oocyte growth phase), the developmental competence of the oocyte and cell structure is generated, when oocyte growth accompanies follicular growth from the primordial to the small (2–3 mm) tertiary (antral) follicle. When follicles in a cohort reach a diameter of about 3–5 mm, one dominant follicle is selected during the antral phase. During the third phase, the oocyte undergoes to change (oocyte maturation) almost 24 hours between the peak ovulation and the rise of LH.
2.1. Oogenesis
The mature oocytes are differentiated, released, and established in mammalian ovaries to undergo oogenesis process for fertilization. The ovaries have individual follicles consisting of an innermost oocyte, surrounding granulosa cells, and outer layers of thecal cells, controlled by the endocrine system. Moreover, mammalian ovary produces steroids and peptide growth factors, which allow the development of female secondary sexual characteristics and support pregnancy [20]. The oocytes and surrounding granulosa cells have amiable connections together to support oocyte viability and growth mediated by the gap junctions, which are efficient conduits for low molecular weight substances. The granulosa cells have some metabolized molecules, which play a role in transporting the oocytes. Additionally, the KIT ligands and c‐kit receptor are localized to oocytes and granulosa cells, respectively, to promote oocyte growth and follicular development. Moreover, some of the growth factors derived from oocytes, such as GDF‐9 and BMP‐15, contribute in follicular development by regulating the differentiation of surrounding somatic cells, as these communications are important for oocyte growth and follicular development [21]. The occurrence of events of oogenesis are concomitantly with folliculogenesis, as oogenesis can be explained as the process of formation and maturation of the egg by development and differentiation of the female gamete during the meiotic division, and this is the first phase of progress for the fetus. Thus, female ovaries have fixed number of oocytes, which decreases by time passing with several years, without potential to renew. During the ovarian start to deplete the auxiliary of oocytes, it evolves to a senescence/aging stage born with a fixed number of oocytes, which through several years reduce, without potential to renew. When the ovarian start to deplete the auxiliary of oocytes, it evolves to a senescence stage, leading the female to menopause [22]. During meiosis, mammalian oocytes undergo two consecutive asymmetric cell divisions, which are essential for the formation of a functional female gamete, without an intermediate replicative phase. Each division must ensure accurate segregation of the maternal genome and highly asymmetric partition of the cytoplasm, further that a tiny polar body and a large oocyte are generated. It leads to an asymmetric organization (or polarization) of the egg, which determines the geometry and the success of fertilization. Asymmetric divisions are tightly controlled by microtubule and microfilament cytoskeletons. During the beginning of the first meiotic division, this process allows the separation of the duplicated centrosomes and therefore to the gathering of a bipolar spindle formed by microtubules. Thus, it is referred to as the process that produces gametes with half of the number of chromosomes from the parent cells. For the position of spindle surrounding the oocytes and tossing the first polar body in parallel with separation of chromosome, the microfilaments are carried out in meiosis I. The microtubule spindle is positioned at the surrounding of the oocytes until fertilization, causing the emission of the second polar body during second meiotic division (meiosis II). Additionally, the loss of asymmetry is a mark of low‐quality oocytes and a signature of pre‐ and postovulatory aging [23].
2.2. Folliculogenesis
Meiotic prophase consists of several temporary stages: preleptotene, leptotene, zygotene, pachytene, and the diplotene stage in which the first meiotic division of the ovarian follicles begin to develop as primordial structure that oocyte arrested. Primordial follicle activation is characterized by the possession of complete layer of 11–20 granulosa cells around the oocytes. Secondary follicle stage starts to show features of a second layer of granulosa cells. Zona pellucid is the initial deposition material around the oocyte, and at the same time, cortical granules are formed within the oocyte cytoplasm. It is at this point of development that follicles appear to become responsive to gonadotrophins [24]. The progress of ovarian follicle is a combination of many sides of a compound process that starts with the foundation of limited pool of primordial follicles and attains in either atretic degradation of the follicle or liberation of mature oocytes for fertilization. Through the primary, preantral and antral stages, the primordial follicles must be grown during these stages before reaching to the preovulatory stage where they are eligible to release oocytes for starting the fertilization stage. The corpus luteum structure (CL) is formed from the differentiation of the residual of granulosa and thecal cells after ovulation [25]. Large stock of oocytes is enclosed in primordial follicles in mammalian ovaries, and some of these follicles initiate growth toward a possible ovulation undergoing activity of the ovarian cycle. Additionally, most of these follicles end their growth at any moment and degenerate through atresia. During the growth of follicles, only a subset of oocytes is capable to support meiosis, fertilization, and early embryo development to the blastocyst stage. This proportion of eligible oocytes depends on the size of the follicular cell. Developing lines of evidence propose that the competent oocytes increase the storage of gene production leading to the determinant to support the precocious stages of developmental embryos, before the activation of embryonic genome. Thus, these transcripts may be stored during early folliculogenesis as the oocyte grows and displays high transcription activity [26]. Young and McNeilly [27] classified the system into five types: type I represents the primordial follicles, which are a resting stage before their activity begins. In this stage, follicles have only one layer of granulosa cells and this is the follicle transitioning through the primary stage, when the granulosa cells become cuboidal. The second type of follicles includes one layer of cuboidal granulosa cells. While antral follicles include two to four layers of granulosa cells going to the third type. At this stage, the large preantral follicles consists of four to six layers of granulosa cells, considering this stage as the fourth stage, increasing the number of layers, thus reaching the fifth type. Then, the
2.3. Oocytes morphology and classification
2.4. Oocyte maturation
Immature oocytes begin to develop in the ovaries, with each oocyte possessing a large nucleus that is referred to as the germinal vesicle (GV). Therefore, immature oocytes start to give response and undergo maturation process, which starts the nucleus of oocyte to have disassembly during a sequence called germinal vesicle breakdown (GVBD). After this stage, the immature oocyte turns into mature being eligible for developing until fertilization. Moreover, regardless of the timing of GVBD relative to fertilization and at the end, all oocytes must be matured enough to be able to consequently develop to continue to proceed normally [31]. During dictyate stage of prophase I, the oocytes are arrested, which can be identified by the presence of a germinal vesicle (GV). Additionally, meiosis I is marked by germinal vesicle breakdown (GVBD) following which bivalents are brought to alignment at the spindle equator by metaphase I. Anaphase I then ensues when chromosomes segregate between the secondary oocyte and the polar body. Following first polar body extrusion (PBE), oocytes progress without a hiatus into meiosis II where they are arrested for a second time at metaphase II [32]. During the maturation process, mammalian oocytes accompany a comprehensive, extensive rearrangement of the cytoskeleton and associated proteins. In oocytes, during the MI takes nearby 6-11 hours and the spindle migration toward the egg cortex occurs at this time. When the chromosome-spindle complex moves to the egg cortex, it involves a spindle pole close to the cortex [33]. Spindle movement induces a cortical differentiation performed by the accumulation of actin filaments and a scarcity of microvilli. After polar body extrusion, chromosomes realign progressing to metaphase II.
2.4.1. Nuclear and cytoplasmic maturation
The oocytes for bovine with an inside zona diameter smaller than 95 μm are unable to start meiosis
The diameter of the follicle increases depending on the number of Golgi apparatus present in the oocyte. The change in location of cortical granules constitutes the most obvious ultrastructure sign of cytoplasmic maturation. According to the oocytes in the GV stage, cortical granules are distributed in clusters throughout the cytoplasm. However, as the oocytes progress to metaphase I stage, the cortical granules translocate to the periphery of the oocyte and become attached to the plasma membrane. At the end of the maturation period, when these oocytes reach the MII stage, the granules are distributed through the inner surface close to the plasma membrane [37]. The mitochondria make a homogeneous distribution throughout the cytoplasmic and are more common at the germinal vesicle (GV) stage, while heterogeneous distribution is more commonly observed in the oocyte of metaphase I or II. During oocyte maturation, the mitochondria disperse distribution throughout the cytoplasm, until reaching metaphase II (MII), when the central position in the cell operates in the mitochondria because high‐energy supply around the nucleus is very important during embryonic development. It is also observed that morphologically poor quality embryos are only characterized by the homogenous distribution of the mitochondria [38]. Additionally, the cytoplasmic maturation describes both the ultrastructural changes that take place in the oocyte from the germinal vesicle (GV) to the metaphase II (MII) stage and the possession of developmental competence of the oocyte. Mammalian oocyte's cytoplasmic maturation can be described as the ability of a mature egg to undergo regular fertilization stage, all stages of cleavage, and further development of the blastocyst. Other indirect morphological parameters considered to evaluate cytoplasmic maturation include cumulus cell expansion, polar body expulsion, and increased perivitelline space (PVS) of Ref. [39].
3. RNA synthesis and molecular maturation
The molecular maturation coincides with the maturation and growth of oocyte corresponding with transcription and mRNAs expression by genes of oocytes. In mammalians ovaries, meiosis occurs mainly in two steps: during foetal life (step 1) and through the period of preovulatory life (step 2). The genetic information must be stored in advance because of nuclear instructions, when the chromosomes are the subjects of transformation. Thus, in the form of mRNA, the chromosomes arrive and are silenced at the resumption of meiosis. After DNA synthesis at double helix, the chromosomes are partially condensed and rearranged by the process of crossing over. The chromatin then reaches a special conformation that is an intermediate between chromatin condensation and interphase, the dictyate phase. Additionally, in some species during that special prophase period, the oocyte remains static and the chromosome appearance changes little. When an oocyte begins to grow in the primordial follicle, the uncondensed loops of chromatin in the dictyate state ensure the transcription of required elements. Thus, the mRNA produced is either translated immediately [40]. Through the
4. Production of embryos in vitro
There are many reasons for interest in
In Figure 2, it can be observed different stages of embryonic development from day 0 to day 7, monitored by our team. Following fertilization, embryos undergo a series of mitotic cell divisions. Hence, the embryo compacts to form a morula that comprises of cells in a compact cluster including the pellucid zone (i.e., comprising of glycoproteins envelope of mammalian oocytes, which beset the embryo). Then, the blastocyst is formed and finally “hatches” from the zona pellucid. Besides, in humans, all this process takes about 1 week [48], and in cows, it can take up to 10 days.
5. Effects of heat stress on animal fertility
During summer, heat shock reduces pregnancy, conception rates, and leads to low fertility in lactating dairy cow. Progesterone secretion by luteal cells is decreased and this is reflected in plasma progesterone concentration, the endometrial function, and alters its secretory activity by high temperature, which leads to the termination of pregnancy. Moreover, heat shock impedes oocytes quality and embryo development and increases the mortality rate of embryos [49]. Therefore, there are different factors that lead to the decrease of fertility in cattle. The most important are the increased humidity and temperature that result in a decreased expression of overt estrus and a reduction in appetite and dry matter intake. During the postnatal period “puerperium,” the exposure to extreme heat stress prolonged, leading to negative energy balance and increase in the calving pregnancy interval. Heat stress influences by decreasing the dominance of the selected follicle and this decreases the steroidogenic ability of its granulose cells and theca cells, which declines the estradiol concentrations in blood. The elevation or reduction of the plasma progesterone levels can be relied on whether it is severe or chronic, and on the cattle metabolism state. The reduction of follicular activity and the alteration of ovulatory pattern execute endocrine changes, leading to the reduction of oocytes and the quality of embryos [50]. Moreover, oocyte’s maturation from the meiotic stage of germinal vesicle (GV) to MII is affected by heat stress and it has been shown that high temperatures affect also the cattle cumulus‐oocyte complexes (COCs), zona pellucida hardening, fertilization, and further cleavage of putative zygotes after fertilization [51]. In cattle, genes exist for regulation of body temperature and for cellular resistance to elevated temperature. These genes offer possibility for their incorporation into dairy cow through cross breeding or on an individual‐gene basis and the physiological and genetic manipulation of the cow to improve embryonic resistance to high environmental temperature, which reduces fertility in lactating dairy cows, and as a result, pregnancy, oocyte, and early embryo are affected by heat stress [52]. Therefore, heat stress reduces gonadotropin secretion and the ovarian pool of oocytes and impairs fertility. Additionally, heat stress has immediate effects on follicle and its enclosed oocyte, follicular function, and follicular growth and disrupts steroidogenesis [53]. Heat stress has an impact on the reproductive function, that is, it reduces the intensity of the behavioral estrus and leads to low fertility in female and compromised sperm output and increased sperm abnormalities in male. The pregnancy rate and the embryos at earlier stages of development during heat stress are affected [54]. Furthermore, oocyte susceptibility to heat shock can be detected during the germinal vesicle (GV) and oocyte maturation periods. The bovine oocytes’ exposure to high temperature
6. Regulation of the cell cycle and oocyte maturation
Several mechanisms are involved in the activation of translationally inactive mRNA. These mechanisms involve the phosphorylation of many factors that initiate translation. Therefore, according to this model, polyadenylation (the addition of adenine) of the 3’ terminal portion of the cytoplasmic mRNA would stimulate the release of repressor molecules linked to the 5’ portion, thus beginning translation. The transport of this mRNA to the cytoplasm occurs through a characteristic splicing of the poly‐(A) tail, which, after reaching the cytoplasmic compartment, becomes smaller and heterogeneous in size. The cytoplasmic elongation of the poly‐(A) tail has been associated to the translation activation, meaning that during addition of adenine to mRNA in the cytoplasmic of oocyte through maturation leads to deadenylations, leading to the degradation of the particular mRNA. For this reason, protein synthesis starts when the two ribosomal subunits are linked onto the mRNA. This stimulates the degradation of particular mRNA which, when oocytes are acquiring developmental competence, the fundamental transcripts produced encode regulators of the cell cycle such as “maturation promoting factor” (MPF), the protein of the c-mos pro-oncogene (MOS), and mitogen-activated protein kinase (MAPK) [37]. In mitotic cells, S‐phase always precedes M‐phase in order to maintain euploidy. Additionally, the maturation (M‐phase) promoting factor (MPF) plays a pivotal role in oocytes during their maturation. During the mitotic cell cycle, MPF activity shows different stages of vacillation and steadiness, i.e., MPF activity wobbles positively and negatively in time with the beginning and ending of M‐phase in succession, while being precisely regulated during the two cell divisions of meiosis. MPF is a heterodimer protein kinase complex consisting of two subunits: the catalytic subunit CDK1 and the regulatory subunit cyclin B1. As phosphorylation is required by CDK1, cyclin B is the main determinant for CDK1 and this is a necessary factor for certain processes during cell cycle as (1) initiating germinal vesicle breakdown (GVBD) through phosphorylation of nucleoporin—a components of nuclear pore complex—among many protein components of nuclear envelope and (2) with a large protein complex termed as condensing that helps in supercoiling the DNA during mitosis. The kinase activity requires more than binding of CDK1 to cyclin B1. MPF, the heterodimer protein, is held in an inactive state termed as PRE‐MPF by wee1 kinase that causes inhibitory phosphorylation of CDK1 (p34
7. Regulation of mammalian oocyte gene expression at transcription level
There are six Obox (oocyte‐specific homeobox) family transcripts and Obox‐1, 2, 3, and 5 mRNA they have been detected in oocytes from growing primary follicles [67], playing then an important role in early embryogenesis [68, 69] by orchestrating gene transcription, either ubiquitously or in a tissue‐specific manner. Mice lacking the Obox6 gene grow without morphological abnormalities and with normal fertility, indicating a functional redundancy among the Obox family members [70]. Moreover, several genes play key roles in oogenesis, folliculogenesis, or early embryonic development. In particular, GDF‐9 and BMP‐15 are necessary for folliculogenesis beyond primary follicles in mouse and sheep, respectively. Gene expression in oocyte is quite different from those in somatic cells. The messenger RNAs produced by these cells are not only required to support germ cell development but, in the case of oocytes, they are also used for maturation, fertilization, and early embryogenesis. It is very important to understand the oocyte mechanisms and transcription factors that play a role in the regulation of the transcriptional activity of the oocyte dictating its ultimate acquisition of developmental competence. The oocyte genome has evolved specialized transcription machinery to ensure proper activation of gene that is required for oocyte growth and early embryonic development [71].
8. Gene expression and the role of the Cx43 and HSPA14 genes during the embryonic development
8.1. The HSPA14 gene
Experiments developed by our team show that exposing cumulus oocyte complexes (COCs) to 41°C did not alter the number of embryos that cleaved but reduced significantly the percentage of development in the blastocyst stage [9]. Additionally, the exposure of bovine embryos to heat shock during oocyte maturation leads to embryos with reduced development and induced alterations in protein synthesis and possibly gene expression as early as the two‐cell embryos. In addition, cumulus cells are removed before maturation, which affects and reduces the protein synthesis at 42°C exposure oocytes and COCS. On the other hand, the developed oocytes at 39°C created heat shock protein 70 kDa but oocytes exposure to 42°C did not increase synthesis of any of these proteins, which was shown after examining the methionine‐ and cysteine‐labeled proteins—by two‐dimensional SDS‐PAGE and fluorography. It has also been noticed that the reduction of protein synthesis caused a prominent decrease in the percentage of protein synthesis in oocytes with intact cumulus compared to those bared oocytes. Therefore, the heat shock increases the steady‐state amounts of mRNA for the inducible form of heat shock protein 70 (HSP70) in embryos. The
8.2. The Cx43 gene
Connexins (CXs) are a family of transmembrane proteins with molecular masses varying from 26 to 60 kD;
9. Methods for studying differential gene expression
Several techniques have been developed for the screening of genomic alterations at the mRNA level, including subtractive hybridization, differential display‐PCR, expressed sequence tag (EST), serial analysis of gene expression (SAGE), and microarray hybridization. Some of these techniques have been used to investigate changes in gene expression at oocyte cell development and differentiation [93]. In addition, the effective and simple methods for identifying and isolating those genes that are differentially expressed in various cells or under altered conditions. Advantages of the technique include the ability to isolate genes with no prior knowledge of their sequence or identity and the use of common molecular biology techniques that do not require specialized equipment or analyses, its abilities to compare multiple experimental samples for any number of treatment conditions, phenotypes, or genotypes simultaneously, and to identify genes that are either up‐ or downregulated in one sample relative to another [94]. The differential display include as first step is reverse transcription of mRNA to cDNA using one of anchor primers (which is usually poly T oligonucleotide with one or two additional bases, e.g., T
Acknowledgments
The authors thank Dr. Sofia Quadros and Mr. Filipe António for their precious collaboration in this review. CITA‐A is also fully acknowledged. The second author is partially supported by the Azorean Agency for Science and Technology, grant BD M3.1.2/F/044/2011.
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