Inverted Yolk Sac Placenta Research Articles

The road (not) taken - Placental transfer and interspecies differences.

Species differences are among the main reasons for the high failure rate of preclinical studies. A better awareness and understanding of these differences might help to improve the outcome of preclinical research. In reproduction, the placenta is the central organ regulating fetal exposure to a substance circulating in the maternal organism. Exact information about placental transfer can help to better estimate the toxic potential of a substance. From an evolutionary point of view, the chorioallantoic placenta is the organ with the highest anatomical diversity among species. Moreover, frequently used animal models in reproduction belong to rodents and lagomorphs, two groups that are characterized by the generation of an additional type of placenta, which is crucial for fetal development, but absent from humans: the inverted yolk sac placenta. Taken together, the translatability of placental transfer studies from laboratory animals to humans is challenging, which is supported by the fact that numerous species-dependent toxic effects are described in literature. Thus, reliable human-relevant data are frequently lacking and the toxic potential of chemicals and pharmaceuticals for humans can hardly be estimated, often resulting in recommendations that medical treatments or exposure to chemicals should be avoided for safety reasons. Although species differences of placental anatomy have been described frequently and the need for human-relevant research models has been emphasized, analyses of substances with species-dependent placental transfer have been performed only sporadically. Here, we present examples for species-specific placental transfer, including that of nanoparticles and pharmaceuticals, and discuss potential underlying mechanisms. With respect to the COVID 19-pandemic it might be of interest that some antiviral drugs are reported to feature species-specific placental transfer. Further, differences in placental structure and antibody transfer may affect placental transfer of ZIKA virus.

Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac.

HBOC-201 is a bovine-derived, cross-linked, and stabilized hemoglobin (250kDa) in physiological saline. Daily intravenous infusions of HBOC (1.95, 3.90, or 5.85g/kg/day) during gestational days (GDs) 6-18 in Sprague-Dawley rats caused fetal mortality, reduced birth weight, and malformations. Subsequent single-day infusions (5.85g/kg/day) showed that developmental toxicity was limited to GDs 7-9 when histiotrophic nutrition via the inverted visceral yolk sac (invVYS) is essential. Histiotrophic nutrition is receptor-mediated endocytosis of bulk maternal proteins and subsequent lysosomal degradation providing amino acids and other nutrients for embryonic growth. Controls for protein content, oncotic properties, and hemoglobin content indicated that toxicity was due to hemoglobin. Rat whole embryo cultures verified HBOC interference with invVYS transport capacity and resultant deficient embryonic nutrition. These mechanisms of action are not expected to impact human development based on differences in VYS morphology and function, although a complete understanding of early human embryonic nutrition is lacking.

Comparative placentation in the spiny rat Thrichomys laurentinus (Rodentia, Hystricognathi, Echimyidae)

Comparative placentation in the spiny rat Thrichomys laurentinus (Rodentia, Hystricognathi, Echimyidae)

Chorioallantoic and yolk sac placentation in Thrichomys laurentinus (Echimyidae) and the evolution of hystricognath rodents

The evolutionary history of Hystricognathi is associated with major transformations in their placental system. Data so far indicate that key characters are independent from size dimensions in medium to very large species. To better understand the situation in smaller species, we analyzed placental development in a spiny rat, Thrichomys laurentinus. Fourteen individuals ranging from early implantation to near term were investigated by histology, immunohistochemistry, proliferation activity and electron microscopy. Placentation in Thrichomys revealed major parallels to the guinea pig and other hystricognath rodents with respect to the early and invasive implantation, the process of trophoblast invasion, the internal organization of the labyrinth and the trophospongium as well as the establishment of the complete inverted yolk sac placenta. In contrast to systematically related small-sized species, the placental regionalization in Thrichomys was characterized by a remarkable lobulated structure and associated growing processes. Reverse to former perspectives, these conditions represented ancient character states of hystricognaths. The subplacenta was temporarily supplied by both the maternal and fetal blood systems, a rare condition among hystricognaths. The extraplacental trophoblast originating from the subplacenta was partly proliferative in mid gestation. In conclusion, the presented results indicated that only minor variations occurred in small-sized hystricognath species, independent of their systematic interrelationships. Previous views were supported that placentation in hystricognaths followed an extraordinary stable pattern, although the group had distinct habitats in South America and Africa that were separated 30-40 million years ago.

Development of the Inverted Visceral Yolk Sac in Three Species of Caviids (Rodentia, Caviomorpha, Caviidae)

Guinea pig related rodents possess numerous derived placental characters. We attempt to identify diversity within the visceral yolk sac and its association with the chorioallantoic placenta in three species of caviids, two of them possessing a capsule formed by the decidua that covers the chorioallantoic placenta. The results verify that in early pregnancy all three species have an inverted yolk sac placenta. In advanced pregnancy the species differ: Galea spixii, as representative without a capsule, bear a yolk sac in apposition to the chorioallantoic placenta with signs of exchange activity until term. Galea is similar to other caviomorphs in this respect. In Dasyprocta leporina and Cuniculus paca, the representatives possessing a capsule, the yolk sac endoderm lacks signs of substance exchange. Evidently, the presence of a capsule prevents such an interaction. The variations established here must be considered if animal models for human placentation are required which have restricted access to the chorioallantoic placenta from the outside.

Placentation in the paca (Agouti paca L)

BackgroundThe paca is a South American rodent with potential as a commercial food animal. We examined paca placenta as part of a wider effort to understand the reproductive biology of this species.MethodsThirteen specimens between midgestation and term of pregnancy were studied by light and transmission electron microscopy.ResultsThe placenta is divided into several lobes separated by interlobular trophoblast. Maternal arterial channels and fetal veins are found at the centre of each lobe. In the labyrinth, maternal blood flows through trophoblast-lined lacunae in close proximity to the fetal capillaries. The interhaemal barrier is of the haemomonochorial type with a single layer of syncytiotrophoblast. Caveolae occur in the apical membrane of the syncytiotrophoblast and recesses in the basal membrane, but there is no evidence of transtrophoblastic channels. The interlobular areas consist of cords of syncytiotrophoblast defining maternal blood channels that drain the labyrinth. Yolk sac endoderm covers much of the fetal surface of the placenta. The subplacenta comprises cytotrophoblast and syncytiotrophoblast. There are dilated intercellular spaces between the cytotrophoblasts and lacunae lined by syncytiotrophoblast. In the junctional zone between subplacenta and decidua, there are nests of multinucleated giant cells with vacuolated cytoplasm. The entire placenta rests on a pedicle of maternal tissue. An inverted yolk sac placenta is also present. The presence of small vesicles and tubules in the apical membrane of the yolk sac endoderm and larger vesicles in the supranuclear region suggest that the yolk sac placenta participates in maternal-fetal transfer of protein.ConclusionThe paca placenta closely resembles that of other hystricomorph rodents. The lobulated structure allows for a larger exchange area and the development of precocial young.

Mode of Action: Yolk Sac Poisoning and Impeded Histiotrophic Nutrition—HBOC-Related Congenital Malformations

Rodents form an early inverted yolk sac placenta (invYSP) by apposing the yolk sac to the uterine wall. The invYSP supplies nutrients via histiotrophic nutrition involving pinocytosis of materials from uterine gland secretions, lysosomal degradation, and transfer of the products to the embryo. Interference with histiotrophic trafficking through the invYSP by high-molecular-weight molecules (such as trypan blue) causes malformations and resorptions. Later in gestation, rodents form a definitive chorioallantoic placenta (CAP). By contrast, humans and dogs never develop an invYSP, relying exclusively on the CAP. Given their large size (∼ 250 kD), hemoglobin-based oxygen carriers (HBOC), being developed as blood substitutes, could be expected to interfere with histiotrophic trafficking through the invYSP. During initial toxicity testing, intravenous infusions of HBOC caused pronounced developmental toxicity in rats exposed during the pre-CAP period. Assuming that HBOC interfered with invYSP function, we hypothesized that these findings would not apply to humans or dogs, which lack an invYSP. Subsequent extensive developmental toxicity studies in dogs produced no developmental toxicity after intravenous infusion at the maximum tolerated dose. In view of the existing species-specific placental differences and HBOC's demonstrated, exclusive interference with invYSP histiotrophic nutrition, HBOC is not expected to cause abnormal development in humans or other mammals that do not develop an invYSP.

The rate of blood flow through the inverted yolk sac placenta of the anaesthetized guinea-pig

The rate of blood flow through the yolk sac placenta of late gestation guinea-pig fetuses was estimated by an indirect approach: radionuclide-labelled microspheres were injected in a saphenous vein and the ratio of radioactivity in the yolk sac to that in one of several reference organs was calculated. The ratio was then multiplied by a constant derived from separate experiments in which blood flows to the fetal abdominal organs and chorioallantoic placenta were determined. Stomach blood flow was positively correlated to arterial oxygen content (r = 0.74, P < 0.05), as was the weight-specific splenic blood flow (r = 0.66, P < 0.05). Perfusion of the small and large bowel, kidneys and chorioallantoic placenta was not related to arterial pH or oxygen content and these organs were used as references for the estimation of vitelline blood flow. A positive correlation was found between yolk sac blood flow and arterial oxygen content (r = 0.91, P < 0.01). In normoxaemic guinea-pig fetuses, yolk sac blood flow is 100-300 microliters per min.

The trophotaenial placenta of a viviparous goodeid fish. II. Ultrastructure of trophotaeniae, the embryonic component.

Embryos of the viviparous goodeid fish Ameca spendens develop within the ovarian lumen, where they establish a placental association with the maternal organism and undergo a 15,000% increase in embryonic dry weight. The placenta consists of an embryonic component, the trophotaeniae, and a maternal component, the internal ovarian epithelium. Examination with light microscopy and with transmission and scanning electron microscopy reveals that trophotaeniae of A. splendens are extraembryonic membranes consisting of five ribbon-like processes originating from a tube-like mass of tissue that extends outward from the perianal region of developing embryos. There are two sets of lateral processes and a longer single median process. Trophotaeniae possess an outer epithelium that surrounds a highly vascularized core of loose connective tissue. Epithelial cells possess apical microvilli and a pronounced endocytotic apparatus. Cells of the trophotaenial epithelium are either tightly apposed along their lateral margins or separated by enlarged intercellular spaces. Regions of the trophotaenial epithelium possessing enlarged intercellular spaces are distributed in patches. The trophotaenial epithelium is continuous with the embryonic hindgut epithelium and is considered to be derived from it. Comparison of trophotaenial morphology in A. splendens with that reported in Xenotoca eiseni reveals differences in histological organization. The former possess unsheathed trophotaeniae, whereas the latter are sheathed. We postulate that the apposition of trophotaenial epithelium to the internal ovarian epithelium constitutes a placental association equivalent to a noninvasive, epithelioform of an inverted yolk sac placenta. Structural relationships of embryonic and maternal tissues of the trophotaenial placenta are discussed in relation to maternal-embryonic nutrient transfer processes.

The fine structure of the chinchilla placenta.

The structure of the placental labyrinth, interlobular or "coarse" syncytium, visceral (splanchnopleuric) yolk sac, giant cells and subplacenta of the chinchilla was studied with the electron microscope. The fine structure of the interhemal membrane of the placental labyrinth was found to be hemomonochorial, consisting of a single layer of syncytial trophoblast. In this respect, the placental labyrinth was similar to that of another caviomorph rodent, the guinea pig. The labyrinthine trophoblast had pinocytotic vesicles as well as larger vaculoes and multivesicular bodies. The interlobular syncytium contained granular endoplasmic reticulum, and in one case from early in gestation there were intracisternal granules in the ER. The visceral endodermal cells of the inverted yolk sac placenta had a well-developed system of apical vesicles and tubules as well as larger cytoplasmic vacuoles. Their appearance was similar to that of endodermal cells found in other rodents which are known to absorb proteins and other substances from the uterine lumen. Towards term the giant cells were often vacuolated and contained large deposits of glycogen as well as lipid droplets. The syncytial trophoblast of the subplacenta contained numerous moderately electron-dense granules which may be secretory in function; cytotrophoblastic cells lacked these granules. The subplacental syncytium often surrounded spaces or lacunae which contained an electron-dense granular material.

The formation of the allantoic placenta in the golden hamster (Mesocricetus auratus).

The processes of attachment, implantation and placentation in the golden hamster (Mesocricetus auratus) have been re-examined. Blastocyst attachment occurs at 4.0 days P.C. and complete interstitial implantation is attained by 5.5 days P.C. At 6.15 days P.C. the trophoblast of the trager breaks into the uterine lumen which becomes filled with blood clot. The advancing trager uses this blood clot as a bridge to reach the decidua basalis, lying on the opposite side of the uterine cavity, at 8.5 days P.C. Thus the uterine lumen becomes obliterated opposite each conceptus by the formation of the allantoic placentas which are vascularised by 8.5 days P.C. Non-glandular extensions of the glandular interlocular lumina penetrate between the decidua capsularis and the muscularis of the antimesometrial wall of the uterus from the 8th day P.C. onwards. On the 14th day P.C. the parietal wall of the yolk sac and its thin covering layer of decidua capsularis disappear to form a completely inverted yolk sac placenta. This places the yolk sac cavity in continuity with the non-glandular extensions of the uterine lumen and re-establishes complete continuity of the uterine lumen.

Histochemical distribution of some hydroxysteroid dehydrogenases in the placenta, foetal membranes and uterine mucosa of the mouse.

SUMMARY The placenta, foetal membranes and uterine mucosa of mice (pregnant for 8–17 days) have been investigated by histochemical methods for NAD-dependent 3β-hydroxysteroid dehydrogenase (3β-HSDH), and for NAD-and NADP-dependent 17α- and 17β-hydroxysteroid dehydrogenases (17α- and 17β-HSDH), 11α- and 11β-hydroxysteroid dehydrogenases (11α- and 11β-HSDH), and 20β-hydroxysteroid dehydrogenase (20β-HSDH). 3β-HSDH was found to be distributed in the trophoblastic giant cells of the first generation with both pregnenolone and DHA as substrates, and in the giant cells of the second generation and of the labyrinth and the endodermal cells of the inverted yolk sac placenta, but only with DHA as substrate. 17α-HSDH and 17β-HSDH, NAD-dependent, were present in both the first and second generation giant cells and in the giant cells of the labyrinth as well as in the endodermal cells of the inverted yolk sac placenta. With NADP as cofactor, 17α-HSDH and 17β-HSDH were weakly positive with all the substrates used in the giant cells of the second generation and of the labyrinth, while NADP-dependent 17β-HSDH was present in the first generation giant cells and in the endodermal cells of the inverted yolk sac placenta but only with oestradiol-17β as substrate. The histochemical reaction for 11α-HSDH, both NAD- and NADP-dependent, was limited to trophoblastic giant cells of the second generation and of the labyrinth; 11β-HSDH, both NAD- and NADP- dependent, was distributed in the giant cells of the second generation and of the labyrinth, the epithelial cells of the uterine mucosa and the decidua basalis. The histochemical reaction for 20β-HSDH, NAD- and NADP-dependent, was weakly positive in the giant cells of the first generation only.

Nomograms for correction of blood Po2, Pco2, pH, and base excess for time and temperature.

Nomograms for correction of blood Po2, Pco2, pH, and base excess for time and temperature.

Development of structure and function in the mammalian yolk sac: I. Developmental morphology and vitamin B 12 uptake of the rat yolk sac

Morphological and physiological aspects of differentiation have been analyzed in the visceral splanchnopleure of the inverted yolk sac placenta of the albino rat between 13 days and term. The visceral yolk sac is known to be involved in the transfer of antibodies from the maternal to the fetal blood. The absorptive cells of the visceral endoderm possess ultrastructural features characteristic of protein-absorbing cells. The appearance of the free surface of these simple columnar cells suggests motility. It is primarily modified to form long, branching microvilli that often seem to be fusing. Invaginations of the free surface originate between microvilli, and most probably connect with an extensive canalicular system of smooth membranes located in the superficial cytoplasm. The inner surface of both the invaginations and the canaliculi possesses a filamentous coat that may represent a vast internal surface for the attachment of proteins. Morphological and physiological evidence suggests that large absorptive vacuoles arise as dilatations of the canaliculi. The content of the more deeply located vacuoles is more condensed, and they may be called absorptive droplets. Thus, a superficial system of smooth membranes is directly involved in the uptake of macromolecules, such as antibodies and other proteins. During this period of gestation various morphological changes occur that may affect absorptive activity considerably. As gestation proceeds, the microvilli become shorter and less branched; the smooth membrane system is altered; and intercellular associations change as large dilatations appear in the intercellular space of the absorptive epithelium. In addition, there is a thickening of the placental barrier that intervenes between the yolk sac (or uterine cavity) and the vitelline circulation. The present findings indicate that the visceral yolk sac possesses a highly specific mechanism for accumulating considerable vitamin B 12 and B 12-intrinsic factor complex in vitro. The parietal wall lacks this mechanism. The capacity to concentrate vitamin B 12 and B 12-intrinsic factor both in vivo and in vitro is greater at 13 days than near term when determined on the basis of radioactivity per unit weight. This suggests a decrease in absorptive capacity per cell as gestation proceeds. The reduced absorptive activity of each cell is, however, more than counterbalanced by a seventyfold increase in the mass of this placental membrane. Microscopic examination revealed that the morphology of the visceral yolk sac is well preserved during a 60-minute period of in vitro incubation. Experimental findings in vitro indicate that although the visceral splanchnopleure can accumulate a large macromolecular complex, such as vitamin B 12-IF, it lacks the capacity to concentrate small molecules, such as l-valine and α-methylglucoside, against a concentration gradient. This evidence suggests that this placental membrane in the rat may be highly specialized for the transfer of macromolecules.

Histochemical distribution of 3-beta-hydroxysteroid dehydrogenase and 17-alpha-and 17-beta-hydroxysteroid dehydrogenases in the placenta and foetal membranes of the rat.

SUMMARY The placenta and the foetal membranes of rats (pregnant 5–21 days) have been assayed by histochemical methods for 3β-hydroxysteroid dehydrogenase (3β-HSDH), NAD-dependent, and 17α- and 17β-hydroxysteroid dehydrogenases (17α- and 17β-HSDH), both NAD and NADP-dependent. 3β-HSDH was limited to the trophoblastic giant cells of the first generation, whereas 17α- and 17β-HSDH were present in both the first- and second-generation giant cells and also in the endodermal cells of the inverted yolk sac placenta.

Surgical investigation of the function of the inverted yolk sac placenta in the rat

Surgical investigation of the function of the inverted yolk sac placenta in the rat