Domestic Rabbit

Oryctolagus cuniculus

Order: Lagomorpha
Family: Leporidae

1) General zoological data of species

The domestic rabbit, often erroneously assumed to be synonymous with the New Zealand White Rabbit, is widely used in research laboratories. There are now, however, numerous other strains of domestic rabbit, and many feral rabbits occur as well.

Rabbits belong to one of the two families of Lagomorpha (the Leporidae), the other being the pikas (Ochotonidae). Their genetic relationship was reviewed by Stock (1976) and by Dave et al. as well (1965). The domestic rabbit is considered to have been derived from the wild rabbits of England, Oryctolagus cuniculus. There are well over 50 "breeds" of rabbits. They vary widely in size, genetic makeup, and in coloration (Miller, 1999). Rabbits possess three (or four) upper incisor teeth, rather than the two incisors found in rodents. Like the teeth in rodents, they continue to grow throughout life in rabbits. Domestic rabbits weigh between 2 and 6 kg and have a life expectancy of about 6 years. Two comprehensive reviews of the biology and diseases of rabbits have been published, one by Kraus et al. (1984), and the other by Miller (1999).

Gotch (1979) described the origin of the term "oryctolagus" as deriving from the Greek (orukter = tool for digging; lagos = a hare; cuniculus = a rabbit).

 2) General gestational data

The length of gestation in rabbits is 31-32 days; ovulation occurs about 10 hours after coitus, following a complex endocrine cascade.The rabbit is thus a reflex ovulator (Fox & Laird, 1970). As many as 10 offspring may be produced, more often there are 4-6. The weight at birth is 50-60 g. The average placental weight is 4 g (Mårtensson, 1984), and puberty occurs at 4-6 months. The tubal transport of fertilized ova and blastocysts was studied by Tsutsumi et al. (1975). They showed that "alien" eggs catch up with the transport of normal eggs rapidly and they reached the uterus within 6 hours. The rabbit has an "uterus duplex" (completely separate horns) and the placental implantation is superficial, with inversion of the yolk sac (Mossman, 1987). It develops a discoid, labyrinthine, chorio-allantoic placenta, with a hemodichorial feto-maternal interface.

3) Implantation

Following the initial observations by Amoroso (1961), Miller (1999) showed that a mucin coat is placed on the surface of the developing embryo as it passes through the tubal isthmus. At the time of its initial implantation (day 7-8 p.c.), the blastocyst is much enlarged, and the zona pellucida has disappeared. Implantation of the symmetrical pair of "placental folds" that exist on the blastocyst surface takes place antimesometrially. Amoroso (1961) described the finer details of these early contacts and of blastocyst invasion beautifully. There are two folds on the blastocyst surface, not only at the antimesometrial side where the disks develop, but also on the opposite side (the "ob-placental region"), where the yolks sac contact with the endometrium takes place, with the subsequent development of many multinucleated giant cells of trophoblastic origin. The definitive placenta, however, develops mesometrially and it is essentially bilobed. One prominent feature of rabbit implantation is the development of numerous multinucleated giant cells in the endometrium. They reach their maximal development by day 17 and, thereafter, they gradually disappear. These were first interpreted as being of endometrial derivation, but later they were considered to have a trophoblastic origin, which is also the current view. Petry & Kühnel (1966) depicted these giant cells in the "chorion laeve" as well. They suggested the possibility that these cells accomplish much protein transport to the fetus. Because of the complexity of the ensuing development, and because of the unusual nomenclature employed in descriptions of rabbit placentation, two diagrams of Amoroso's (1961) excellent description are shown next.

The exposure of the yolk sac to the uterine lumen is a major aspect of the inverted yolk sac placentation. Much substance transport occurs through these membranes. The compartments of the yolk sac placentation are shown above. They include the avascular omphalopleur (bilaminar - ectoderm and endoderm) and the vascular omphalopleur (trilaminar - ectoderm, endoderm, and mesoderm with vessels). The latter includes the sinus terminalis, as shown above. Note also the folding nature of the amniogenesis.

The rabbit placenta has, in addition to the bidiscoid chorioallantoic portion, a completely inverted yolk sac as is shown above. Please also observe the rather large exocoelomic space and the very small allantoic sac, especially when the latter is compared with the massive size found in some other species. This has suggested to some observers that waste products and fluids are exchanged only through the placenta, rather than involving the allantois. At this "ob-placental" pole of implantation there is much endometrial proliferation and modification of its surface. While this yolk sac placentation flourishes at first, it regresses later in gestation and it probably plays then a less important site of exchange.

Since the initial phases of implantation are likely to be related to the interactions and recognition of surface molecules, Biermann et al. (1997) delineated the carbohydrate ligands of surface lectins of the Fallopian tube, endometrium, and blastocysts in rabbits. Denker & Hafez (1975) showed experimentally that, most likely, some trophoblastic enzymes rather than endometrial factors initiate implantation of the blastocysts.

Implantation in rabbits thus begins on day 7, at the time when Tscheudschilsuren et al. (1999) saw the first strong expression of an arylhydrocarbon receptor and a translocator on the endometrial glandular surface. Grundker & Kirchner (1996) studied the effect of growth factors on rabbit blastocysts. Insulin-like growth factors (IGF-1 and IGF-2), as well as basic fibroblast growth factor (FGF-2), were found in endometrial secretions. FGF-2 became especially plentiful on day seven. IGF-1 was found to enhance blastocyst expansion, while IGF-2 had no effect. FGF-2 caused the development of trophoblastic knobs. Other growth factors were explored by Klonisch et al. (2001). They studied EGF and TGF in the early interaction of rabbit blastocysts with endometrium and found strong evidence that the "ErbB/EGF" system plays a role in the peri-implantation period.

The actual discoid, chorio-allantoic placenta commences its development on about the 12th day p.c., four days after blastocyst attachment and following increased secretion by the uterine glands. A prominent feature of this development is the degeneration of the swollen decidua. Amoroso (1961) described it thus: "The uterine glands are, however, only temporary pathways to the invasion of the trophoblast. They eventually disappear completely and are replaced on the tenth day by multinucleate decidual cells. [It should here be pointed out that the endometrial origin of these cells needs reinvestigation; see Mossman, 1987, p. 216]. The dips thus correspond to the gland orifices and represent the beginnings of so-called villi". Amoroso stated that the endothelial barrier disappears completely by the tenth day. Vascular mesoderm then invades the trophoblastic columns. These are tubes that surround maternal blood channels, and the complexity of these structures increases with advancing gestation considerably so as to forming a typical placental labyrinth. Focal maternal hemorrhages occur at the depth of the disks.

The rabbit trophoblast begins to tap maternal blood vessels on day 9, two days after implantation has taken place (Hoffman et al., 1990). Thereafter, the "labyrinthine hemodichorial, chorioallantoic placenta", with inversion of the permanent yolk sac, develops (Enders & Blankenship, 1999). These authors drew attention to the very irregular thickness of regions in the placenta, with outer syncytium placed over a layer of cytotrophoblast and they diagrammed the hemal interface. As in rodents (see chapter on mouse), antibodies and other proteins are transferred through the inverted yolk sac region. The reader is also directed to the detailed description of rabbit implantation by Hoffman et al. (1999).

Hafez (1964; 1965) superovulated rabbits and transferred an excessively large number of blastocysts to does. While implantation often occurred in the overcrowded uterine horns, there was much resorption after implantation and fewer live pups were born than was the number of blastocysts that were transplanted. Some of the neonates were growth-retarded, some had congenital anomalies. Some placentas were fused because of crowding. Fujimoto et al. (1975) enumerated the number of blastomeres at different days before implantation and also studied their chromosomal complements. On day 4 there were 1,766 cells, on day 6 there were 98,790. The diameter of triploid blastocysts, induced by delayed fertilization, is reduced (Shaver & Carr, 1969). Moreover, triploid ova had a significant mortality.

4) General characteristics of placenta

The rabbit placenta is discoidal when viewed from the fetal surface, but Mossman (1987) pointed out that it is rather more bidiscoidal when sectioned because of the development of a striking "groove" on the fetal surface of the disk in the sagittal plane of the uterus. The bidiscoidal structure is the result of the two surface folds visible already on the blastocyst. There is late, complete inversion of the yolk sac and development of a labyrinthine hemodichorial placental disk. The allantoic sac is relatively small. At term, there is virtually no amnionic fluid and the amnion is extremely thin and apposes the fetal skin directly.

The specimens shown above were kindly donated by Dr. G. Heldt at UCSD. They come from a 27 day gestation of a strain that normally delivers on day 31. There were nine fetuses, each weighing between 30 and 34 g. The placentas, detached from the uterus, weighed between 85 and 88 g. The portion of uterus to which they were attached weighed 11 g. The doe was 4.5 kg.

5) Details of barrier structure

The hemodichorial placental "membrane" of interchange in the rabbit has alternating "thin and thick" regions (Enders & Blankenship, 1999). Both display a layer of cytotrophoblast, above which is syncytium. In some regions, however, the proximity of maternal and fetal blood is very close and seemingly only separated by fetal capillary endothelium. Amoroso (1961) suggested that, here, the trophoblast is deficient and that, basically, a hemo-endothelial relation is formed. In addition, there appear areas of numerous large, polyploid, multinucleated trophoblastic cells in the endometrium. They are now considered to be fetal tissue and to originate from the bilaminar omphalopleur (Mossman, 1987). These cells completely surround the maternal arteries, invade them and, in time, they even reach the myometrium within the maternal vessels. This deep penetration of trophoblastic cells was commented upon in Mossman's last page of his early vascular paper (1926) and will be of further concern in discussions on rodent and guinea pig implantations.

Larsen (1961) has studied the implantation site electronmicroscopically. The vacuoles that were present in the syncytium merged into lacunae that become filled with maternal blood after invasion of her blood vessels, coinciding with the time course provided by Hafez & Tsutsumi (1966). Yolk sac attachment takes place on day 7 p.c., with relatively poor vascular supply in that region.

 6) Umbilical cord

In contrast to rats, rabbit fetuses are said to have already separated from their placenta and membranes at the time of birth (Hudson et al., 1999). Miller (1999), on the other hand, stated that the dam severs the cord by biting and that, thereafter, placentophagy occurs. Parturition is essentially bloodless though, despite the abundance of maternal vessels in the pregnant uterus.
There are two umbilical arteries that pursue a course beside the bladder in the fetus and an umbilical vein passing to the liver. The cord is 2 cm long and has no spirals.

 7) Uteroplacental circulation

The vascularization of the endometrium and of the placenta is complex; moreover, it changes over time. The most comprehensive publication on the topic is that by Mossman (1926). He described in great detail the changing vasculature during development following a protocol of a detailed injection technique. Particularly well studied were the arterial supply to the sinusoidal spaces below the chorionic membrane, the infiltration of the maternal vessels by giant cells, the sinus terminalis of the fetus, and the dissolution of much of the large amount of decidua that develops beneath the fetal cotyledons. His studies suggested that maternal blood is directed to the undersurface of the chorionic membrane into the sinusoids; it then percolates towards the maternal floor through trophoblastic "tubes", to be drained by uterine veins. The fetal blood takes an opposite flow, thus establishing countercurrent blood flows for maximal exchange possibilities. I show next a diagram from Hafez & Tsutsumi (1966) that depicts this complex circulation diagrammatically.

Nucleated red blood cells of the fetus disappeared around day 20-22. Mossman was also much concerned with the large number of leukocytes present in early rabbit implantation. In addition, he wrote detailed accounts of the trophoblastic "tubes". Mossman then still considered that the rabbit placenta was an endothelio-chorial organ. Later studies have disproved this. Hafez & Tsutsumi (1966) have later also analyzed the blood vessels throughout gestation and presented numerous other diagrams of the blood vessels beneath the placenta and between the conceptuses. Their findings suggested that critical vascular changes occur in rabbit gestation around the 20th day. With advancing gestation, the number of endometrial vessels decreases, but they increase in diameters. Other references to studies on uterine and placental blood flows may be found in Mårtensson's publication (1984).

8) Extraplacental membranes

The amnion is avascular, as in other species, and it is extremely thin. No amnionic fluid was present in these placentas, as is usual at this late gestation. The small allantoic sac is only slightly filled with fluid of meso/metanephric origin but its composition changes over time (Krespi & Davies, 1963). These authors have studied the nature, composition, origin and disposition of the fetal fluids in several publications.

 9) Trophoblast external to barrier

There is invasion into the decidua and deep into the myometrium by the giant trophoblastic cells (see Mossman, 1926). These giant cells are also found within maternal blood vessels walls, within the lumens and also in veins. The infiltration is especially prominent in the "subplacental" vessels (next photo). But when deeper levels are studied, within the myometrium the dark color of cells disappears, and they are no longer multinucleate or "giant". They are still endowed with purple cytoplasm and infiltrate to near the uterine serosal surface among muscle bundles. I doubt, however, that they are the same trophoblastic cells; but they are confined to the placental site, not seen next to it, and they are not decidual cells. As is indicated above, future studies need to be directed towards the elucidation of this multitude of specialized cells. They are particularly puzzling in hystricomorph rodents where they are a much larger population of diverse cells.

 10) Endometrium

In contrast to ungulates, the endometrium beneath the implanting placental disk has endometrial glands (Amoroso, 1961). Mossman (1987) described the manner of the abundant decidualization at the base of the rabbit placenta. He contended that the rabbit placenta separates at delivery in a decidual plane, the likes of which are "never more pronounced", he stated. The uterine surface epithelium between the implantation sites enlarges markedly and has the appearance of a secretory tissue. Gray et al. (2001) reviewed the manner of uterine secretion (embryotrophe) of various species, and Miller (1999) reviewed the endometrial changes during implantation.

Mossman (1987) depicted the large, multinucleated giant epithelial cells in the surface of the rabbit endometrium (also in the nonpregnant animal) and concluded that their multiple nuclei or enlarged nuclei result from endomitosis. In his earlier contribution (1926), he showed these giant cells as surrounding the arterial walls of the deeper layer of the implantation site and thence their infiltration into the arterial lumens. There has been much controversy as to the origin of these giant cells, some believing them to derive from decidua, other derive them from trophoblast. Largely because of their lack of glycogen (a characteristic for decidua), Amoroso (1961) firmly decided for a trophoblast derivation.

 11) Various features

Mossman (1987) emphasized in his book on comparative placentation that, in the subplacenta, beneath the groove that develops on the fetal surface of the disk, remnants of uterine epithelium are found. ... "and a uterine cavity of what was the depth of the sulcus between the two mesometrial endometrial folds" (after Mossman, 1926).

12) Endocrinology

Miller (1999) presented a summary of the endocrine parameters of rabbit gestation. Although rabbits are reflex ovulators, ovulation can be induced by hCG. The mechanism by which the corpus luteum is maintained during pregnancy is still poorly understood. Current studies suggest that a mitochondrial protein (StAR) is involved (Miller, 1999). The placenta produces relaxin in its syncytiotrophoblast, but no progesterone is secreted. Hafez (1964) showed that progesterone administration to oophorectomized rabbits maintains the pregnancy. There is also no estrogen production by the rabbit placenta (Mårtensson, 1984). Superovulation with hCG is successful and produces large numbers of blastocysts, often of an increased size (Hafez & Rajakoski, 1968).

In order to understand the possibly adverse effect of glucocorticoids upon fetal development, Hundertmark et al. (2001) studied the localization of 11beta-hydroxysteroid dehydrogenase activity. The enzyme was found in the placenta, colon and kidney of fetal rabbits. The expression of 17beta-hydroxysteroid dehydrogenase was examined by Krusche et al. (2001). They detected it in the placenta, and also in other tissues. Bouraima et al. (2001) examined aromatase-encoding genes and identified promoter-derived transcripts in ovary, fat, and placenta.

The finding that there is no appreciable stimulation of the interstitial compartment of the fetal testes suggests to me that there is little fetal gonadotropin in the fetal circulation.

 13) Genetics

The rabbit has 44 chromosomes, as is attested to by numerous publications (Nichols et al., 1965; Ray & Williams, 1966; Issa et al., 1968; Hsu & Benirschke, 1967). It thus differs from hares and other Lagomorpha which generally have higher chromosome numbers (Dave et al., 1965; Stock, 1976). Hageltorn & Gustavsson (1979) published the findings of chromosome banding studies. The "sex chromatin" or “Barr body” is evident in fibroblasts (Melander, 1962; Hulliger et al., 1963), and early sex determination of blastocysts was thus accomplished by Edwards & Gardner (1967). Initial gene assignments have been reported by Soulié & de Grouchy (1982, 1983). Martin & Shaver (1979) reported on a fertile male rabbit with an extremely small Y-chromosome. Most recently, Korstanje et al. (2003) have established linkages to certain chromosomes with microsatellite markers.(See below).

Spontaneous hybrids between the domestic rabbit and other leporids have not been described. Chang et al. (1964), however, found that artificial insemination of rabbits with semen of the snowshoe hare (Lepus americanus) yielded some fertilized ova, but almost all eventually degenerated before implantation. Only one such hybrid implanted and developed a small embryo. When snowshoe hares were inseminated with rabbit semen and pretreated with hCG, 90% were fertilized and two young were produced (Chang, 1965). Blastocyst transfer failed to induce a normal endometrial response.

Fujimoto et al. (1975) examined the number of blastomeres and chromosomes of superovulated, fertilized rabbit ova. Approximately 9% of these ova were chromosomally abnormal, including exhibiting triploidy. Triploidy can also be induced by delayed fertilization and it is mostly the result of digyny (Shaver & Carr, 1969; see also Austin, 1967). Milde et al. (2001) studied a "proteolipid protein 2 mRNA" expression in embryos. They found this motif, that is similar to PP2/A4 of man, mouse and sheep, to be expressed at the posterior pole of the gastrulating embryo on day 7.

Numerous hereditary diseases have been described in domestic rabbits. They are summarized by Kraus et al. (1984). Omphalocele and gastroschisis are not uncommon, according to Heldt (G. P. Heldt, UC San Diego, Personal communication).

The remarkable overpopulation of rabbits in Australia is legendary. Cooper & Herbert (2001) have recently reviewed its consequences. As few as 13 animals are said to have been the stock from which this expansive population derived. Added to this, in 1950, the myxomatosis virus was intentionally introduced in Australia, with massive deaths but with subsequent gradual resurgence of a resistant strain and modification of the virus. Similarly, calicivirus infection has been unable to significantly reduce the rabbit population in Australia, owing probably to mutations, selection, and transplacental antibody exposure.

"The genetic map of the rabbit is underdeveloped…"stated Korstanje et al. (2001) in a paper on the analysis and mapping of various biochemical markers in two inbred strains of rabbit. They found some polymorphisms, and none in some other systems. The paper provides access to modern genetic studies of rabbit genotypes.

14) Immunology

Early studies of the rabbit placentation were designed to understand the transport of immunoglobulins from mother to fetus (Mossman, 1926). It has since become clear that much of this transport is the result of the inverted yolk sac activity. Because of their gestational characteristics, rabbits have also been used to better understand possible modes for gene therapy (Heikkila et al., 2001). Intravascular, guided catheters were employed for the attempted infection with various gene constructs. No placentitis occurred; adenovirus constructs were the most infective.

Korstanje et al. (2001) studied various immune and serologic markers in inbred strains of rabbits.

15) Pathological features

Two comprehensive reviews of diseases of rabbits have been published, one by Palmer (1978), and the other by Kraus et al. (1984). Most notorious of leporid diseases probably is the nearly 100% fatal myxomatosis. The virus responsible for this infection was introduced into the Australian population in 1950. This was undertaken in an effort to eliminate the rabbit pest experienced in that country (Cooper & Herbert, 2001). Rabbit hemorrhagic disease caused a significant mortality in adult rabbits in Spain (Villafuerte et al., 1994). Calicivirus infection is another serious illness of rabbits. The rabbit has also frequently served as a model for teratogenesis, and for in utero infections. Thus, Qian et al. (2000) showed convincingly that Schistosoma japonicum can be transmitted transplacentally. Likewise, Cere et al. (2000) affirmed that Pneumocystis can be acquired in utero. This organism is the cause of a nearly ubiquitous infection of adult rabbits. Davies et al. (2000) showed that fetal/placental infection occurs when E. coli organisms were placed endocervically during pregnancy. Leslie et al. (2000) followed the cytokine responses of pregnant rabbits that were infected in utero in the third trimester. Likewise, Gibbs et al. (2002) found that rabbit placentas and fetuses can become infected by intracervical injection of E. coli and that antibiotic therapy does not completely eradicate the fetal infection. Rabbits can also become infected, and they are ill after transmission, by the malignant catarrhal fever virus (Buxton & Reid, 1980). Infection with toxoplasma and encephalitozoon was shown by Waller & Bergquist (1982).

Experiments conducted by Kato et al. (2001) with granulocyte colony-stimulating factor showed thrombosis of placental vessels, with necrosis and abortion following. Different results were obtained in rats. Zook et al. (2001) studied the effect of estradiol and levonorgestrel administration to rabbits. They produced decidualization and decidual tumors. These lesions were not confined to female rabbits but occurred (in the spleens) of adult male rabbits as well.

Henderson (1954) was interested in resolving the question of absorption of fetal antigens into the pregnant doe and studied the possible continued placental growth after fetal demise. The latter had been claimed to occur in rhesus monkey pregnancies after fetal demise, but this was later disproved. She caused fetal demise surgically in rabbits or, more rapidly, by stilbestrol administration. Placental growth stopped and, so long as pregnancy continued with some live pups, the uterus did not contract. Leukocytic infiltration ensued and antigen transfer may have occurred after fetal demise.

Numerous genetic errors exist in the many different breeds of rabbit. Some of these errors were summarized by Fox (1975). Palmer (1978) pointed to the large percentage of spontaneous intrauterine resorptions and cautioned that this feature needs to be known when teratogenic studies are conducted, as experimental results may otherwise be misinterpreted.

Kaufmann-Bart & Fischer (2008) have reported a first case of chorocarcinoma in a domestica rabbit with lung metastases. Remarkably, the syncytial cells were immunopositive for anti-human hcg antibody.

16) Physiological data

Miller (1999) has superbly summarized much of what is known about rabbit physiology, reproduction, and endocrinology (see also Kraus et al., 1984). Hudson et al. (1999) observed rabbit and rat parturitions by videography. They found rabbit births to occur much more rapidly than those of rats, and stated that the pups are born already separated from the placenta. This is contrary to the statements by Miller (1999) who described maternal biting of the cord.

Papadopulos et al. (1999) developed fetoscopy in the rabbit model and showed that successful fetoscopic evaluations can be carried out in the rabbit, beginning with the second trimester.

In contrast to so many other mammalian species in which the ovary of newborns has oocytes that have completed their first meiotic division, in rabbits, this maturation occurs mostly postnatally (Teplitz & Ohno, 1963; Kennelly & Foote, 1966). The process of oogenesis peaks on postnatal days 12-14 and is completed on neonatal day 20.

Hagey et al. (1998) have used bile acid structural modifications that have taken place in evolution so as to ascertain disputed relationships among mammals and birds. They showed that rabbits have an unique bile acid form and discussed in this publication the possibility that either the notorious coprophagy of rabbits or their enormous cecum may have contributed to this feature. Glenister (1961) studied trophoblastic maturation of rabbits in organ culture.

17) Other resources

I am indebted to Dr. G. Heldt (UCSD) for these placentas. Cell strains of rabbits and of several Sylvilagus species and of Lepus californicus are available from CRES by contacting Dr. Oliver Ryder at oryder@ucsd.edu.

18) Other relevant features

Rabbits have been used for transporting sheep and cattle blastocysts over long distances. Thus, for instance, Sreean & Scanlon (1968) showed that blastocyst maturation and cleavage of eggs continued when cattle blastocysts were placed into the Fallopian tubes and uteri of pseudopregnant rabbits.

Mossman (1987) suggested that better studies are needed to definitively identify the origin and physiology of the multinucleated giant cells of the rabbit placenta. I believe that the uninucleate cells in the myometrium require study and clarification.

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