Interspecific pregnancy (literally pregnancy between species, also called interspecies pregnancy or xenopregnancy) [1] is the pregnancy involving an embryo or fetus belonging to another species than the carrier. [1] Strictly, it excludes the situation where the fetus is a hybrid of the carrier and another species, thereby excluding the possibility that the carrier is the biological mother of the offspring. Strictly, interspecific pregnancy is also distinguished from endoparasitism, where parasite offspring grow inside the organism of another species, not necessarily in the womb.
It has no known natural occurrence, but can be achieved artificially by transfer of embryos of one species into the womb of another.
Potential applications include carrying human fetuses to term as a potential yet ethically controversial alternative to human surrogate mothers or artificial uteri for gay male couples, [3] mothers with damaged uteri or heterosexual couples that do not want to risk childbirth. It would also provide a sober, drug-free and nonsmoking carrier that is less expensive than human surrogates. [3] For animals, it could be a valuable tool in preservation programs of endangered species, providing a method of ex situ conservation. [4] [5] It could also avail for recreation of extinct species. There have been both successful and unsuccessful examples of interspecific pregnancy in a multitude of different animals: “alpaca and lama (Godke 2001), cow (Bos taurus) and zebu (Bos indicus; Summers et al. 1983), banteng (Bos javanicus) and cow (Bos taurus; Solti et al. 2000), horse, donkey, Przewalski’s horse and Grant’s zebra (Summers et al. 1987; Allen et al. 1993), moflon (Ovis gmelina musimon) and sheep (Ovis aries; Dixon et al. 2007), Spanish ibex (Capra pyrenaica) and domestic goat (Capra hircus; Fernandez-Arias et al. 1999) and Indian desert cat (Felis silvestris) and domestic cat (Felis catus; Pope et al. 1993).” [6]
Mus musculus - Mus caroli Interspecific Pregnancy
In the case of these two species of mice embryo transfer was somewhat successful. M. caroli embryos were transferred into M. musculus mice. [6] This produced very low rates of success. It was later discovered that development for the first 9 and a half days appeared normal, but then hemorrhaging would occur. [6] This same hemorrhaging was observed in horse-donkey interspecific pregnancy. [6] Researchers believe that this is the body’s immunological response to the incompatibility between the two species. [6] What is interesting though is that though embryos from M. caroli fail to develop in the M. musculus females, but embryos from M. musculus can survive in M. caroli females. [6] Another important aspect of this research is the use of chimeras (an organism or tissues that contains two sets of DNA). [7] With the use of chimeras, it was found that hemorrhaging was less likely to occur, and “postnatal tissue-specific differential growth” occurred. Research suggests that the death of these interspecific fetuses is most likely tied to maternal immune responses and “failure of local immunoregulation.” [6]
Camelids - Bactrian camel calves (Camelus bactrianus) from dromedary camels (Camelus dromedarius)
Bactrian camel (an Old-World endangered camelid) embryos were transferred into dromedary camels. [5] The researcher’s selected dromedary camels were selected for this task due to its similarities to the Bactrian camel: 37 pairs of chromosomes, similar placentas, similar gestation periods, similar reproductive physiology, comparable body size, and successful examples of hybridization. [5] Four healthy Bactrian camels were born without any complications out of the ten transferred embryos. [5] Through this research, we gained a lot of knowledge about interspecific pregnancy, specifically what causes it to succeed and fail. [5] Researchers believe that success depends upon the binding of sperm to an oocyte. [5] Without this successful binding, pregnancy failure is more likely to occur after interspecies embryo transmission. [5] They also concluded that in camel’s non-immunological embryo reduction does not occur when more than one embryo is in the uterus. [5] Demonstrating that conception rates may increase if more than one embryo is present in a camel’s uterus. [5] With these findings, the researchers believe that they can save the endangered Bactrian and relocate them to areas where other camelids are. [5]
Overview
Overall, the many experiments involving interspecific pregnancy help us to better understand the immunological influence of failed interspecific pregnancies. These immunological influences include: trophoblast (cells formed on the outer layer of a blastocyst (which provides nutrients to an embryo), rejection due to a cell-mediated immunological response, inappropriate interactions between trophoblasts and endometrium (site where blastocysts are implanted or the uterine lining), etc. [8] [9]
Immunologically, an embryo or fetus of an interspecific pregnancy would be equivalent to xenografts rather than allografts, [1] putting a higher demand on gestational immune tolerance in order to avoid an immune reaction toward the fetus. [1] Some mice experiments indicate an imbalance between Th1 and Th2 helper cells with a predominance of Th1 cytokines. [10] However, other mice experiments indicate that an immune response towards xeno-fetuses does not belong to classical cytotoxic T lymphocyte or natural killer cell pathways. [11]
Interspecies compatibility is related to the type of placentation, as mothers of species having the more invasive hemochorial placentation (such as humans) must create a stronger downregulation of maternal immune responses, and are thereby more receptive to fetuses of other species, compared to those with endotheliochorial (e.g. cats and dogs) or epitheliochorial placentation (e.g. pigs, ruminants, horses, whales), where there is no contact between the maternal blood and the fetal chorion. [1] [12]
Other potential hazards include incompatibility of nutrition or other support system. Notably, there is a risk of inappropriate interactions between the trophoblast of the fetus and the endometrium of the mother. [6] Trophoblasts are cells that form the outer layer of the blastocyst and develop into a large portion of the placenta. [8] They also are crucial for attaching an embryo to the uterine lining of a female. [8] Due to their high importance, trophoblasts play a key role in interspecific pregnancy success. [8] For example, the placental glycosylation pattern at the fetomaternal interface should optimally be similar to that of the host species. [13]
Yet, for some species, such as a Bactrian camel embryo inside a dromedary, pregnancy can be carried to term with no other intervention than the embryo transfer. [1] [5] This is possible for gaur embryos inside cattle as well, but with severe intrauterine growth restriction, with uncertainty of how much is caused by the IVF procedure itself, and how much is caused by interspecies incompatibility. [2]
The ability of one species to survive inside the uterus of another species is in many cases unidirectional; that is, pregnancy would not necessarily be successful in the inverse situation where a fetus of the other species would be transferred into the uterus of the first one. For example, horse embryos survive in the donkey uterus, but donkey embryos perish in the uterus of an untreated mare. [1] [6] Deer mouse embryos survive in the uterus of the white-footed mouse, but the reciprocal transfer fails. [1] [6]
Methods to artificially stimulate gestational immune tolerance towards a xeno-fetus include intercurrently introducing a component of a normal allogeneic pregnancy. For example, embryos of the species Spanish ibex are aborted when inserted alone into the womb of a goat, but when introduced together with a goat embryo, they may develop to term. [4] This technique has also been used to grow panda fetuses in a cat, but the cat mother died of pneumonia before she completed term. [14] Also, murine embryos of Ryukyu mouse (Mus caroli) will survive to term inside the uterus of a house mouse (Mus musculus) only if enveloped in Mus musculus trophoblast cells. [15] Goat fetuses have likewise been successfully grown in sheep wombs by enveloping the goat inner cell mass in sheep trophoblast. [16] Such envelopment can be created by first isolating the inner cell mass of blastocysts of the species to be reproduced by immunosurgery, wherein the blastocyst is exposed to antibodies toward that species. Because only the outer layer, that is, the trophoblastic cells, are exposed to the antibodies, only these cells will be destroyed by subsequent exposure to complement. The remaining inner cell mass can be injected into a blastocele of the recipient species to acquire its trophoblastic cells. [17] It has been theorized that the allogeneic component prevents the production of maternal lymphocytes and cytotoxic anti-fetal antibodies, but the mechanism remains uncertain. [6]
On the other hand, immune suppression with ciclosporin has shown no effect for this purpose. Pre-transfer immunization with antigens from the species providing the embryo has promoted more rapid and uniform failure of the interspecies pregnancy in mice, [11] but increased survival in horse-donkey experiments. [18]
Embryos may be created by in vitro fertilization (IVF) with gametes from a male and female of the species to be reproduced. They may also be created by somatic cell nuclear transfer (SCNT) into an egg cell of another species, creating a cloned embryo that transferred into the uterus of yet another species. This technique was used for the experiment of panda fetuses in a cat mentioned in techniques for overcoming rejection. [14] In this experiment, nuclei from cells taken from abdominal muscles of giant pandas were transferred to egg cells of rabbits and, in turn, transferred into the uterus of cat together with cat embryos. Concomitant use of SCNT and interspecific pregnancy has also been speculated to potentially recreate the mammoth species, for example by taking genetic material from mammoth specimens preserved in permafrost and transferring it into egg cells and subsequently the uterus of an elephant. [19] [20]
Although there have been many examples of successful interspecific pregnancies, there are still many researchers who question if this is ethical. Experimenting on animals is already brings in questions about an animals welfare, adding pregnancy on top of that only complicates things further. For animal research to be considered as ethical, there cannot be any other options in terms of research (i.e. there is no easier form of research) and the data gathered will be so beneficial, the infringement of the animal’s wellbeing is worth it (a lesser of the two evils). [21] Based on this framework, and the fact that this research has already taken place (as an ethics committee must agree the research reaches the criteria), this research is considered ethical. [21]
In mammals, pregnancy is the period of reproduction during which a female carries one or more live offspring from implantation in the uterus through gestation. It begins when a fertilized zygote implants in the female's uterus, and ends once it leaves the uterus.
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate maternal and fetal circulations, and is an important endocrine organ, producing hormones that regulate both maternal and fetal physiology during pregnancy. The placenta connects to the fetus via the umbilical cord, and on the opposite aspect to the maternal uterus in a species-dependent manner. In humans, a thin layer of maternal decidual (endometrial) tissue comes away with the placenta when it is expelled from the uterus following birth. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.
In genetics and developmental biology, somatic cell nuclear transfer (SCNT) is a laboratory strategy for creating a viable embryo from a body cell and an egg cell. The technique consists of taking a denucleated oocyte and implanting a donor nucleus from a somatic (body) cell. It is used in both therapeutic and reproductive cloning. In 1996, Dolly the sheep became famous for being the first successful case of the reproductive cloning of a mammal. In January 2018, a team of scientists in Shanghai announced the successful cloning of two female crab-eating macaques from foetal nuclei.
The amniotic sac, also called the bag of waters or the membranes, is the sac in which the embryo and later fetus develops in amniotes. It is a thin but tough transparent pair of membranes that hold a developing embryo until shortly before birth. The inner of these membranes, the amnion, encloses the amniotic cavity, containing the amniotic fluid and the embryo. The outer membrane, the chorion, contains the amnion and is part of the placenta. On the outer side, the amniotic sac is connected to the yolk sac, the allantois, and via the umbilical cord, the placenta.
Blastulation is the stage in early animal embryonic development that produces the blastula. In mammalian development, the blastula develops into the blastocyst with a differentiated inner cell mass and an outer trophectoderm. The blastula is a hollow sphere of cells known as blastomeres surrounding an inner fluid-filled cavity called the blastocoel. Embryonic development begins with a sperm fertilizing an egg cell to become a zygote, which undergoes many cleavages to develop into a ball of cells called a morula. Only when the blastocoel is formed does the early embryo become a blastula. The blastula precedes the formation of the gastrula in which the germ layers of the embryo form.
The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the embryoblast which subsequently forms the embryo, and an outer layer of trophoblast cells called the trophectoderm. This layer surrounds the inner cell mass and a fluid-filled cavity or lumen known as the blastocoel. In the late blastocyst, the trophectoderm is known as the trophoblast. The trophoblast gives rise to the chorion and amnion, the two fetal membranes that surround the embryo. The placenta derives from the embryonic chorion and the underlying uterine tissue of the mother. The corresponding structure in non-mammalian animals is an undifferentiated ball of cells called the blastula.
The trophoblast is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the placenta. They form during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg to become extraembryonic structures that do not directly contribute to the embryo. After blastulation, the trophoblast is contiguous with the ectoderm of the embryo and is referred to as the trophectoderm. After the first differentiation, the cells in the human embryo lose their totipotency because they can no longer form a trophoblast. They become pluripotent stem cells.
An artificial womb or artificial uterus is a device that would allow for extracorporeal pregnancy, by growing a fetus outside the body of an organism that would normally carry the fetus to term. An artificial uterus, as a replacement organ, would have many applications. It could be used to assist male or female couples in the development of a fetus. This can potentially be performed as a switch from a natural uterus to an artificial uterus, thereby moving the threshold of fetal viability to a much earlier stage of pregnancy. In this sense, it can be regarded as a neonatal incubator with very extended functions. It could also be used for the initiation of fetal development. An artificial uterus could also help make fetal surgery procedures at an early stage an option instead of having to postpone them until term of pregnancy.
Prenatal development involves the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal development until birth.
"Cytotrophoblast" is the name given to both the inner layer of the trophoblast or the cells that live there. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo.
Implantation, also known as nidation, is the stage in the mammalian embryonic development in which the blastocyst hatches, attaches, adheres, and invades into the endometrium of the female's uterus. Implantation is the first stage of gestation, and, when successful, the female is considered to be pregnant. An implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow.
Decidualization is a process that results in significant changes to cells of the endometrium in preparation for, and during, pregnancy. This includes morphological and functional changes to endometrial stromal cells (ESCs), the presence of decidual white blood cells (leukocytes), and vascular changes to maternal arteries. The sum of these changes results in the endometrium changing into a structure called the decidua. In humans, the decidua is shed during childbirth.
Human embryonic development or human embryogenesis is the development and formation of the human embryo. It is characterised by the processes of cell division and cellular differentiation of the embryo that occurs during the early stages of development. In biological terms, the development of the human body entails growth from a one-celled zygote to an adult human being. Fertilization occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic material of the sperm and egg then combine to form the single cell zygote and the germinal stage of development commences. Human embryonic development covers the first eight weeks of development, which have 23 stages, called Carnegie stages. At the beginning of the ninth week, the embryo is termed a fetus. In comparison to the embryo, the fetus has more recognizable external features and a more complete set of developing organs.
Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously "unexplained infertility" or recurrent miscarriage.
Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign in the body, as can happen in cases of spontaneous abortion. It is studied within the field of reproductive immunology.
The fetal membranes are the four extraembryonic membranes, associated with the developing embryo, and fetus in humans and other mammals. They are the amnion, chorion, allantois, and yolk sac. The amnion and the chorion are the chorioamniotic membranes that make up the amniotic sac which surrounds and protects the embryo. The fetal membranes are four of six accessory organs developed by the conceptus that are not part of the embryo itself, the other two are the placenta, and the umbilical cord.
Hormonal regulation occurs at every stage of development. A milieu of hormones simultaneously affects development of the fetus during embryogenesis and the mother, including human chorionic gonadotropin (hCG) and progesterone (P4).
Choriogonadotropin subunit beta (CG-beta) also known as chorionic gonadotrophin chain beta is a protein that in humans is encoded by the CGB gene.
Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies.
Preimplantation factor(PIF) is a peptide secreted by trophoblast cells prior to placenta formation in early embryonic development. Human embryos begin to express PIF at the 4-cell stage, with expression increasing by the morula stage and continuing to do so throughout the first trimester. Expression of preimplantation factor in the blastocyst was discovered as an early correlate of the viability of the eventual pregnancy. Preimplantation factor was identified in 1994 by a lymphocyte platelet-binding assay, where it was thought to be an early biomarker of pregnancy. It has a simple primary structure with a short sequence of fifteen amino acids without any known quaternary structure. A synthetic analogue of preimplantation factor (commonly abbreviated in studies as sPIF or PIF*) that has an identical amino acid sequence and mimics the normal biological activity of PIF has been developed and is commonly used in research studies, particularly those that aim to study potential adult therapeutics.
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