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Contents

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References

Maternal communication with gametes and embryo remains to be an important research subject in reproductive biology. This is mainly because of the central role that events taking place during this period play in establishment of pregnancy and creation of an offspring. The benefits of understanding how gametes and embryo communicate with maternal tract are not limited to improving conception rates or better fertility. It is apparent that gametes and embryo interactions form the basis of the periconceptional environment. These events play a major role in forming the epigenetic profile of an individual, influencing its development and health in adulthood. In this paper, I will describe some ideas and opinions on the new strategies and tools needed for further understanding of maternal communication with gametes and embryo.


What is this Paper About?

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References

In recent years, many investigations have been carried out to understand the events taking place during maternal communication with gametes and embryo. My aim in this paper is not to review all recent developments in the field or provide the reader with an up to date summary of what has happened in the field. Some good and recent reviews for updating your knowledge are mentioned here for the reader (Bauersachs et al. 2008; Van Soom et al. 2010; Mor et al. 2011).

In this paper, I will focus on summarizing some of the work carried out in understanding the local responses of maternal tract to gametes and embryo in my laboratory. In contrast to other investigations regarding maternal interaction with gametes and embryo that have looked and compared alterations in the female reproductive tract between pregnant and non-pregnant individuals or mated/inseminated and non-mated/inseminated women, we have tried to investigate alterations in the female reproductive tract in response to the presence of gametes and embryo in the maternal tract of an individual. Hence, we have hoped to create an experimental model to allow study of the local effects of the presence of gametes and embryo in the female reproductive tract without the interference of other variables such as hormones, nutritional and environmental factors. Finally, I will explain the necessity of application of computational system biology approaches for understanding the process involved in maternal interactions with gametes and embryo.

Where We Were and Where We Are Now

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References

Much prenatal mortality occurs in all mammals. In the human, it has been estimated that as many as two-thirds of pregnancies fail in healthy women attempting to conceive (Smart et al. 1982). An even higher amount of embryonic wastage occurs following in vitro fertilization and embryo transfer (Liu et al. 1988). The majority of these losses occur prior to or during implantation. Consequently, menstrual cycle length is not extended and the failure of the pregnancy goes unnoticed. In sheep and cattle, embryonic losses are also relatively high, with most occurring in the first 3 weeks of pregnancy (Nancarrow 1994; Zavy 1994). In litter-bearing species, such as the pig, between 30% and 40% of conceptuses are lost during the 114-day gestation, but wastage is again highest in the early stages before placentation is fully established (Pope 1994).

This is a quotation from a review paper published by Michael Roberts and his colleagues 15 years ago (Roberts et al. 1996). I do not think life has changed much today compared to those days. Currently, the true incidence of early pregnancy losses in humans may reach as high as 70%. As many cases of pregnancy loss remains undetected before menses in a large proportion of women (Wilcox et al. 1988; Chard 1991; Zinaman et al. 1996). Despite rapid progress in assisted reproductive technology, the average implantation rate is still approximately 25% (de los Santos et al. 2003), and the rate of implantation failure after IVF (in vitro fertilization) may reach 80–90% (Ezra and Schenker 1995; de Mouzon et al. 1998). The situation in livestock breeding is not much better. While in 1980, the expected early embryonic death in inseminated British Friesian cattle was 28%, by 2006, this figure increased to 43% in Holstein Friesian cattle (Diskin and Morris 2008).

Interestingly, the remedy which scientists suggested for this problem 15 years ago remains unchanged (Roberts et al. 1996). We need to understand the events and signals exchanged between the mother and the offspring at very early stages of pregnancy. Malfunction of communication between mum and embryo at this stage of life is leading to implantation failure and rejection of the embryo. Hence, from the moment the gametes encounter the female reproductive tract, their interaction starts creating the periconceptional milieu which forms the optimum environment for the conception and for early embryonic development. Recent findings suggest that the alteration of the periconceptional environment results in changes of the epigenomic profiles of offsprings (Heijmans et al. 2009). These may even influence the offspring’s health and development in adulthood (Gluckman and Hanson 2006; Watkins and Fleming 2009). In summary, the maternal interaction with gametes and embryo not only has a profound effect on the creation of an offspring but also determines its destiny and maybe even its health in later life.

Local Maternal Responses to Gametes and Embryo

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References

Sex hormones play a major role in orchestrating the maternal milieu and its responses to embryo and gametes (King and Critchley 2010). The female reproductive tract reacts to systemic stimulation by sex hormones undergoing major changes at tissue and cellular levels, leading to proteomic and genomic alterations in the maternal tract (Bauersachs et al. 2008). In the past, we have hypothesized that the extent and severity of alterations in response to systemic signals produced by hormones would mask the local changes in gene expression and protein production in the maternal tract in response to gametes and embryo. Hence, separating the exact responses produced by the maternal tract in reaction to gametes and embryo compared with those created in reaction to systemic sex hormone changes between pregnant and non-pregnant individuals is essential for understanding local responses of the mother to gametes and embryo. This task (separating responses to local and systemic stimuli) has proven very difficult and in need of carful experimental design. Nearly in all the cases, our design has been tailored towards, for example comparing gene expression profiles or proteomic profiles of parts of the maternal tract in direct contact with gametes and/or embryo to that not in direct contact with gametes and embryo in the same individual. In this way, one can be sure that systemic stimuli such as hormonal variations and other potential variables that may affect gene expression or protein production in maternal tissue have been the same in all the samples.

Taking this point into account, the earliest example of such an approach for studying maternal communication with gametes and embryo is the paper published by Lee et al. in 2002 that clearly pointed to the direct local effect that oocyte and embryo produce in the maternal tract. The authors compared gene expressions in the oviduct which contained the embryo with the oviduct which contained the oocytes in the same mice. The embryos at one-cell stage were transferred to pseudo-pregnant mouse oviducts, and the oocytes were transferred to contralateral oviducts of the same women. Forty-eight hours later, the three-cell or four-cell stage embryos were flushed out of oviducts. Finally, RNA was extracted from the oviductal tissues, and the gene expression profiles of the oviducts in contact with embryos or oocytes were compared. They found a number of genes and clones (identities of many of these transcripts were not known at that time) that were differentially expressed in the oviduct in response to the embryo and the oocyte.

This particular study (Lee et al. 2002) encouraged us and other investigators (Bauersachs et al. 2003; Fazeli et al. 2004; Georgiou et al. 2005, 2007b; Alminana et al. 2009) to carry out further experiments to confirm that the female reproductive tract was capable of sensing the presence of the spermatozoa, the oocyte and the embryo. In addition it seemed that the female reproductive tract produced specific responses to spermatozoa, oocytes and embryo (Bauersachs et al. 2003; Georgiou et al. 2005, 2007a; Alminana et al. 2009). In the last few years, we have followed this line of investigations in our laboratory and have established in vivo and in vitro models for studying various aspects of maternal interaction with gametes and embryo. Unfortunately, it is impossible to detail all of our experiments and results in this short communication, but the reader is directed to following publications from our laboratory for more information (Georgiou et al. 2005, 2007a, 2011; Sostaric et al. 2006; Seytanoglu et al. 2008). Many of these studies have been carried out in close collaboration with the research group of Professor Emilio Martinez at the University of Murcia. Our joint investigations into the maternal interaction with gametes and embryos have painted a rich and comprehensive picture of various genes and proteins involved in the production of local responses of the maternal tract to the gametes and the developing embryo, leading us to develop and propose a new concept in maternal communication with gametes and embryo.

Maternal Communication with Gametes and Embryo is a Dynamic Process

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References

The major outcome of our investigations is that maternal tract milieu is actively being regulated both by systemic stimuli such as hormones and by local stimuli such as gametes and embryo. The notion that gametes or embryo themselves can modulate the oviductal environment extends the concept of regulatory mechanisms within the female reproductive tract beyond hormonal regulatory systems. It presents a mechanism by which gametes and embryo have immediate and local control of their environment. For example, in an in situ experiment (Georgiou et al. 2005) exposing oviductal tissue to spermatozoa and oocytes, we noted that most of the oviductal secretory proteins altered by gametes were regulators of protein folding and stability, such as various chaperones, protein isomerases and proteolytic enzymes. Most of these identified proteins were uniquely regulated by the presence of either sperm or oocyte in the oviduct with a potential function on gamete maturation, viability and function, hence potentially pointing to the ability of maternal tract to prepare its environment in anticipation of the arrival of the zygote.

The other important point to consider is the fact that as the maternal communication with gametes and embryo is an active and ongoing progressive process, depending on which stage of this process we sample and analyse the maternal milieu, we would see an ever-changing picture. This is not surprising. All events taking place in the maternal tract leading to conception and establishment of the pregnancy happen in a short period of time between the arrival of the gametes in the oviduct/Fallopian tubes and the translocation of the early embryo to the uterus. These distinct intervening processes require unique microenvironment and optimum conditions. It is therefore logical that the maternal tract opts for a dynamically changing environment capable of satisfying the requirements of these events in the maternal tract. So far, what we have been able to understand from this process is just static snapshots of a vibrant movie. We need to look at the fluidity and the dynamism of these processes from a new point of view to be able to grasp the whole picture.

Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References

Accepting maternal communication with gametes and embryo as a dynamic process that is regulated not only by systemic stimuli such as sex hormones but also at local level by gametes and embryo would have a number of consequences for our understanding of physiology of reproduction. Here, I will try to explain two of these points briefly.

Existence of gametes and embryo recognition systems in the maternal tract

It seems that arrival of either gametes or embryo activates a cell-type-specific signalling pathway within the maternal tract, which leads directly to specific alterations of maternal tract milieu. This indicates the existence of a gamete and embryo recognition system in the oviduct and uterus that can alert women to the presence of the either gametes or embryo in their reproductive tract. Such a system for the recognition of gametes and embryo is comparable to that of Toll-like receptors (Kawai and Akira 2010) for recognition of non-self entities. We speculate that a comparable system exists in the female reproductive tract for recognition of gametes and embryo that has yet to be discovered.

A need to apply computational modelling approaches to studies of maternal communication with gametes and embryo

So far, the picture painted of maternal communication with gametes and embryo emphasizes the importance, complexity and dynamic nature of this process. The snap shots we and others (Lee et al. 2002; Bauersachs et al. 2003, 2008; Georgiou et al. 2005, 2007b; Fazeli 2008) have taken from this process reveal a diverse family of genes and proteins, playing key roles in the process. To compile a full picture by taking into consideration all these factors and their interactions is very difficult. For decades, reproductive biologists, rather than trying to amalgamate their efforts and look at the interaction of all these molecules, opted for a reductionist approach, studying the function of a gene or a molecule at a time. Fortunately, this is not a unique problem associated only with our field. Many other physiological systems and phenomena have a similarly complex nature, and investigators have traditionally opted for a reductionist approach rather than opting for a systemic look at the complete picture (Hester et al. 2011). Hence, to address this issue, nowadays, scientist more and more often involve the use of computational or in silico models to understand complex biological systems (Edelman et al. 2011; Teusink et al. 2011; Trayanova 2011).

We have made initial attempts in developing a 3-D model of the oviduct of pigs and mice (Fazeli et al. 2009). Using agent-based modelling principles, we have designed preliminary simulations and models for sperm movement and transport within the oviduct (Van Soom et al. 2010). We intend to continue this work and add many more factors, which can potentially influence these processes, to our in silico model. We hope this modelling and simulation practice will provide us with new insights in understanding the processes involved in maternal communication with gametes and embryo.

Concluding Remarks

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References

Advances in genomic and proteomic technologies give us the ability to detect minute changes in biological systems. One of the fields, which was revolutionized by these new technologies, is reproductive physiology. Using these advanced methods, we have been able to detect alterations in the genomic and proteomic profiles of the female reproductive tract in response to gametes and embryo. In addition to maternal diet, sex hormones and immune system, which all can modulate and profoundly change periconceptional environment, gametes and embryo also affect this environment and modify it to their own benefit. The diversity of factors and the rapid changes in the modulated periconceptional environment necessitate approaches which can take into account the large number of variables involved. This is why we are in need of developing computational or in silico models to further understand how maternal environment is regulated at periconception.

The benefits of understanding how periconceptional milieu is regulated are not limited to higher conception rates or better fertility any longer. The periconceptional environment also plays a major role in forming the epigenetic profile of an individual, influencing its development and health in adulthood. Nature may use this strategy to enhance the offspring’s adaptation and survival abilities in a new environment even before birth. If we understand how it happens, we may be able to do the same and increase reproductive success which not only manifests itself in a higher number of offspring but also equips them with better physiological well-being and health. The same way nature has always done it.

References

  1. Top of page
  2. Contents
  3. What is this Paper About?
  4. Where We Were and Where We Are Now
  5. Local Maternal Responses to Gametes and Embryo
  6. Maternal Communication with Gametes and Embryo is a Dynamic Process
  7. Looking at Maternal Communication with Gametes and Embryo as an Active Process, What Would be the Consequences of this New Look?
  8. Concluding Remarks
  9. Conflict of interest
  10. Author contributions
  11. References