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The Macaque Placenta—A Mini-ReviewSchering-Plough, Department of Toxicology and Drug Disposition, Oss, the Netherlands Correspondence: Eveline P. C. T. de Rijk, Schering-Plough (formerly Organon), Department of Toxicology and Drug Disposition, P.O. Box 20, 5340 BH Oss, the Netherlands; e-mail:eveline.derijk{at}spcorp.com
As part of an overview of the female reproductive organs in the macaque monkey, the present paper presents normal placental development. Although normally not examined in routine toxicologic pathology, the interest in the macaque as a model for reprotoxicity studies is increasing significantly. Based on different classifications, the macaque placenta belongs to the chorioallantoic, (bi)discoid, villous, deciduate, and hemochorial placental type. Within the first fourteen days after fertilization, a large number of events subsequently occur (apposition, adhesion, penetration and traversal of trophoblasts, blood vessel penetration, and development of villi). After this period, the basic placental structure has been laid down in the endometrium, and the initial communication between mother and fetus has been established. Further expansive growth of the placenta and development of anchoring villi are believed to be accomplished by continuous proliferation and migration of the trophoblasts from the trophoblastic shell. Despite the same function of human and macaque placentas, the morphologic structure and developmental timelines are different. Possible toxicological and physiological implications of these differences toward the value of macaques within reprotoxicity studies is discussed at the end of this paper. Besides a transporting role between mother and fetus, the placenta is also an endocrine organ that synthesizes a variety of hormones and cytokines. They influence ovarian and uterine physiology at the start of pregnancy and fetal and mammary physiology during gestation and around labor, respectively. Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. Eveline P. C. T. de Rijk and Eric Van Esch are employed by Schering-Plough. No other competing interests were declared.
Key Words: female reproduction • nonhuman primate • histopathology • placenta • cynomolgus
Within the scope of a physiologic and structural overview of the female reproductive system in macaques, it is inevitable to include a part with a description of the final goal of all the fluctuating cyclic changes in the reproductive system (hormonal levels, hormone receptor levels, and consequent structural changes). As the ultimate goal, reproduction is preceded by implantation of the blastocyst within the endometrium and the development of a placenta. This placentation process is extensively described for humans; literature on monkey placentation is less common, although some excellent papers are available (Carter and Enders 2004; Enders et al. 1985; Enders, 1989, 1993, 2000, 2007; Ramsey et al. 1976). Comparative evaluations of different species demonstrate the existence of a significant variety in all the steps of the placental process and in its morphological structures. Together with the fetal membranes, the placenta forms a barrier against infection and maternal immune attack and transports oxygen and essential nutrients to and waste products from the fetus. The macaque monkey is becoming more and more attractive for use in reprotoxicity studies for several reasons: (1) when the application of the compound is not tolerated in rabbits and rats; (2) when a teratogenic effect is demonstrated in only one of the two species normally used; (3) when compounds are intended to be used by pregnant women; (4) when in rats and rabbits the metabolism is completely different than in humans; (5) when hormonal compounds are tested; and (6) when it is necessary to follow pregnancy by ultrasound imaging techniques. As a consequence, more attention should and will be given to the placental development and structures in this animal. In this manuscript, a concise, general overview of macaque placentation will be given, and differences with the human placenta will be discussed.
General To understand the structure and terminology of the placenta, Ramsey (1982) excellently described the five principal systems of placental classification. These systems are based on: (1) origin (of the embryonic membranes); (2) shape; (3) internal structure; (4) relation to maternal tissues; and (5) composition of the placental membrane. According to these classifications, the macaque placenta is chorioallantoic, mostly bidiscoid, villous, deciduate, and hemochorial. In the next paragraph the classifications will be explained.
Origin-based Classification Prior to implantation, the blastocyst contains a cavity (blastocoele), a clump of cells (the inner cell mass), and a surrounding cell layer, the trophoblasts. At a later stage, both an endodermal and a primitive mesodermal layer cover the inner side of the blastocyst adjacent to the trophoblast layer (Figure 1A). These layers surround a yolk sac (vitelline), which in many oviparous animals serves as a nutrient reservoir. To fulfill not only the need for proteins and lipids, but also for oxygen, the wall becomes vascularized. Since waste products also need to be excreted, another sac with a vascularized wall that communicates with the gut of the embryo is formed (the allantois). The most primitive placenta, the true chorionic placenta, is formed by the fusion of maternal endometrium with the trophoblast/primitive mesodermal wall (this layer is called the chorion or somatopleure). In the choriovitelline placenta, elements of the yolk sac are added to the chorion membrane when fusing with maternal endometrium, whereas the chorioallantoic placenta contains allantois constituents. In Figure 1B, a schematic drawing is given to illustrate the differences of the three placenta types. Not surprisingly, the chorionic placenta is capable of physiological exchange by simple membranous transfer only, as it lacks vascularity. For this reason this type is functional in the early stages of gestation.
Shape-based Classification A more simple classification is by placental shape, which is determined mainly by gross inspection (Ramsey 1982). Placentas may be multiple or single, diffuse, zonary, cotyledonary, or (bi)discoid. The macaque placenta and the human placenta are single and (bi)discoid.
Internal Structure-based Classification
Classification Based on the Relation to Maternal Tissues
Membrane Composition-based Classification
Before implantation, a receptive endometrium should be established. It is known from both human (Fazleabas et al. 1997; Lessey and Castelbaum 2002) and monkey studies (Qin et al. 2003) that interactions between integrins and their extracellular matrix (ECM) ligands play a pivotal role in this process and consequently in a successful implantation. From implantation of the blastocyst to full development of the placenta, a large number of events subsequently occur to establish an optimal environment for fetal growth and an efficient cross-talk between fetus and mother (Enders 1993). Especially in the first seventeen days, the cynomolgus placenta expands exponentially in volume from 0.0036 mm3 to 18.34 mm3, from day 10 until sixteen or seventeen days after fertilization (Enders 2007). At term the placenta weighs around 150 g, and the two disks (bidiscoid) are clearly visible (Figure 2A). The size of the primary discs varies from 7 to 10 cm in diameter, whereas the variability of the secondary disc is extremely high. Gestation time in the cynomolgus monkey is approximately 160 days, whereas in humans gestation is approximately 280 days. The first, second, and third periods in the monkey end around day 53, day 80, and day 120, corresponding with the end of the first, second, and third trimesters in humans around day 84–98, day 140–154, and day 203–224, respectively (Stute 2005).
In general the placentation process is divided in several steps (Enders 2000):
Most of these steps are already in an advanced stage within the first two weeks after fertilization. Since descriptions of these first steps in human placentation are lacking, animal models could be very helpful in unraveling these processes, that is, epithelial penetration can best be studied in marmoset or ferret, and formation of the trophoblastic lacunae in cynomolgus monkey (Enders 2000). Timelines of the most relevant processes have been described for primates by Enders (1993), who nicely demonstrates that, although the processes are similar in macaques and humans at many points, the time frames are slightly different.
Apposition
Adhesion
Penetration of the Uterine Epithelium
The cells of such plaques store large amounts of glycogen and are considered to be an alternative for the stromal decidual reponse on fertilization in humans (Ramsey et al. 1976). Stromal decidualization is very prominent in human endometria during pregnancy (Figure 3B-I) and considerably less visible in macaque endometria (Figure 3B-II).
Stromal and Maternal Blood Vessel Invasion
Establishment of the Communication with Maternal Blood As already mentioned, the trophoblast invasion in humans is less superficial than it is in macaques, because in humans the time that trophoblasts are able to develop before they infiltrate blood vessels is much longer. The lacunar stage is therefore more deeply embedded in the endometrium. The trophoblastic plate in the macaque is a mixture of syncytial and cytotrophoblasts, and as soon as the lacunae are formed, the cytotrophoblasts enter the maternal superficial blood vessels as well, in some cases forming plugs. This process lowers the blood pressure and protects the extraembryonic tissue that is not yet supported by connective tissue. At the end of the lacunar stage, proliferation of the cytotrophoblasts near the blastocyst cavity (in humans) and between the lacunae (in macaques) form the primary villi around days 14–15 (Enders 2007), immediately followed by mesenchymal growth to form secondary villi. In humans, no invasion of maternal arterioles has been reported before this stage. Apart from the developing placental villi, a connecting stalk protecting the main lifeline between mother and fetus (umbilical vessels and allantois) is developed (Figure 3F). Within the first fifteen days, many different processes occur that form the base of the placental structures as they appear at the end of gestation. Literature on the developing placental structures after this time is lacking, and the literature that does exist deals mainly with placental growth (extension of villi). The further growth of the placenta and development of anchoring villi are believed to be accomplished by continuous mitosis and migration of the trophoblasts from the trophoblastic shell (Figure 4). These migrating trophoblasts are often clustered around the septa (Figure 4A) and show high mitotic activity, as is shown after immunohistochemistry using an anti-Ki67 antibody (Figure 4B). The cells also clearly show characteristics of high activity (i.e., large nuclei and nucleoli) (Figure 4C). In contrast to the placenta of the macaque, which contains a very regular shell with relatively small number of loose trophoblasts, the shell in the human placenta is much more irregular, since the stroma is much more heavily invaded by trophoblasts. As the expansion of the villi proceeds, the outer trophoblastic layer becomes more syncytial (Figures 5A–C), with clear clustering of nuclei (Figure 5D). Moreover, increasing amounts of fibrinoid material become visible, sometimes occluding the fetal vasculature (Figure 5B). At later stages these areas will appear as mineralized structures (Figure 5C), becoming rather extensive at the end of pregnancy. The extracellular matrix plays an important role in the process of placental growth, as is demonstrated by several authors (Blankenship 1992; Blankenship and King 1993; King and Blankenship 1994; Qin 2003), by showing significant changes in composition and amount of extracellular matrix expression during the course of gestation in macaques and rhesus monkeys. Similar to the human placenta, in the nonhuman primate placenta two fibrinoid bands can be distinguished: Nitabuch’s stria (junctional zone where fetal and maternal tissue mingle) and Rohr’s stria (direct at base of intervillous space, that is, on the inner fetal border of the trophoblastic shell).
Figure 6 summarizes the morphology of the cynomolgus monkey at term (day 150) and shows the different morphological layers and structures that are normally present at that time. From maternal to fetal side, these layers and structures consist (from bottom to top) of:
Besides the transporting role between mother and fetus, the placenta is also an endocrine organ that synthesizes a variety of hormones and cytokines. These hormones and cytokines mainly influence ovarian, uterine, mammary, and fetal physiology. Both progesterone and estrogens are produced by the placenta and play an important role during gestation. Progesterone supports the endometrium and creates a proper environment for the fetus to survive. The other role of progesterone is to prevent the uterine smooth muscle from contracting (progesterone block). At the end of gestation, this block will be neutralized by the elevating estrogen levels, thereby starting parturition. Without progesterone, the pregnancy would end immediately. The human placenta and the macaque placenta produce several estrogens; in women, the major estrogen is estriol (Diczfalusy 1984). In monkeys a high variation in estriol production has been demonstrated, and its role during pregnancy is less clear. Although in the gorilla, chimpanzee, and orangutan estriol is produced in high quantities, very little to no estriol is found in the old world monkeys (e.g., baboons, rhesus monkey, vervet monkeys, and langur monkeys) and estradiol is the major circulating estrogen (Albrecht and Pepe 1998). Toward the end of gestation, the concentration of estrogen rises. It stimulates the myometrial growth, and as already indicated, antagonizes the progesterone-blocking activity. Besides this important activity, estrogens stimulate, together with other hormones, the growth of mammary gland tissue. Besides steroidal hormones, there are also protein hormones that play an important role in the many processes that occur during placental development and gestation, such as chorionic gonadotropins, placental lactogens, and relaxin. The chorionic gonadotropins are the most well known, and they are produced by the trophoblasts of both human and nonhuman primate placentas. Binding of chorionic gonadotropin to luteinizing hormone receptors prevents regression of the corpus luteum. Placental lactogen is structurally related to growth hormone and prolactin. Its function is still unclear, but it has been suggested that its role is related to the modulation of fetal and maternal metabolism. Another function might be participation in corpus luteum functioning and mammary gland development. Relaxin acts synergistically with progesterone in maintaining pregnancy and enables the relaxation of the pelvic ligaments to aid in parturition. In the macaque, relaxin is produced by both the corpus luteum and the placenta (Shimizu et al. 2002).
Although the macaque monkey is often seen as a good model for human placentation, there are some distinct differences:
In view of these different morphological and developmental aspects of human and macaque placentas, it would be valuable to discuss the possible relevance with respect to the outcome and extrapolation of reproduction toxicology studies with macaques. Differences in the implantation window suggest a slight shift in the most vulnerable period for early pregnancy loss, namely, the differentiation from an unattached blastocyst to rapidly differentiating structure undergoing gastrulation. Some examples from literature show that in both humans and nonhuman primates this period is indeed the most vulnerable stage of fetal development. Besides pregnancy loss, some information is available on drug-related effects on fetal tissues (Hendrickx et al. 1999). In contrast, information on drug-related effects on placental development and/or morphology is lacking for both humans and nonhuman primates. This lack of information makes it difficult to speculate on the relation between drug treatment, placental development, and fetal health. A significant difference in total gestation time (160 days in the cynomolgus monkey versus 280 days in humans) could imply different (total) exposure. As a consequence, this difference could effect further differentiation and maturation of the organs and tissues, although the time of fetal organogenesis is more or less comparable in humans and macaques. In routine reprotoxicity studies, the placenta is largely neglected. To enable a valuable evaluation of the possible role of the placenta in drug-related pregnancy loss/teratogenicity, placental data collection (including thorough histopathological investigation) will be needed. This paper may serve as a trigger for others to recognize the possible importance of sampling and investigating this intriguing organ.
The authors thank all histotechnicians of the toxicology department of Schering-Plough (formerly Organon) for their excellent histotechnical assistance. We are very grateful to Dr. A.C. Enders, Dr. O. Slayden, and Dr. J. Vidal for enabling the presentation of some photographs of the early stages.
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This version was published on December
1, 2008 Toxicologic Pathology, Vol. 36, No. 7 Suppl,
108S-118S (2008)
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Abstract
Introduction
