Morphology and physiology of rat placenta for toxicological evaluation

Abstract

The placenta plays a pivotal role in fetal growth, and placental dysfunction and injury are associated with embryo/fetal toxicity. Histological examination of the rat placenta for safety evaluation provides valuable clues to the mechanisms of this toxicity. However, the placenta has specific and complex biological features unlike those of other organs, and placental structure dramatically changes depending on the time during the gestation period. Thus, time-dependent histopathological examination of the rat placenta should be performed based on the understanding of normal developmental changes in morphology and function. The placentas of rats and humans are both anatomically classified as discoid and hemochorial types. However, there are differences between rats and humans in terms of placental histological structure, the fetal-maternal interface, and the function of the yolk sac. Therefore, extrapolation of placental toxicity from rats to humans should be done cautiously in the evaluation of risk factors. This review describes the development, morphology, physiology, and toxicological features of the rat placenta and the differences between the rat and human placenta to enable accurate evaluation of reproductive and developmental toxicity in studies.

Keywords: histopathology; human; placenta; rat; reproduction.

Fig. 1.

Time-dependent changes in diameter and thickness of each part of the placenta in rats. Left, placental diameter on GD 15, 17, and 21 in Crl:CD(SD) rats. Error bar represents SD. Right, thickness of each part of the placenta from GD 11 to GD 21 in Wistar Han rats.

Fig. 2.

Biological features of each part of the placenta in rats.

Fig. 3.

Morphology of the embryo on GD 9.5. HE stain. AC, amniotic cavity; Al, allantois; Am, amnion; Ch, chorionic plate; EcC, ectoplacental cone; Em, embryo; ExC, exocoelomic cavity; PDZ, primary decidual zone; PG, primary trophoblastic giant cell; RM, Reichert’s membrane; SDZ, secondary decidual zone; YS, yolk sac.

Fig. 4.

Morphological development of the rat placenta and histological events at each point. BZ, Basal zone; GC, Glycogen cell; ICM, Inner cell mass; LZ, Labyrinth zone; MG, Metrial gland; Tb, Trophoblast; YS, Yolk sac. HE stain.

Fig. 5.

Expression of GLUT1 and GLUT3 in trophoblastic septa. Left, schema of trophoblastic septa. Pathway of glucose via GLUT1 and GLUT3. Upper right, immunohistochemical expression of GLUT1. Bar=100 µm. Lower right, immunohistochemical expression of GLUT3. Bar=100 µm.

Fig. 6.

Morphological development and ultrastructure of trophoblastic septa in the labyrinth zone. Decrease in cellular density in trophoblastic septa and increase in size of cytotrophoblasts with pregnancy progression; HE stain. Bar=100 µm. Lower right, ultrastructure of trophoblastic septa. Bar=15 µm. AV, allantoic vessel; Ct, cytotrophoblast; FV, fetal vessel; MS, maternal sinusoid; St, syncytiotrophoblast; TL, trophectoderm layers.

Fig. 7.

Cellular proliferative activity of each placental layer during pregnancy. Error bar represents SD.

Fig. 8.

Morphology of the basal zone and decidua basalis from GD 13 to GD 21. Regression of the decidua basalis from GD 13. Full development of the basal zone with glycogen islet formation on GD 15 and then gradual regression. Penetration of interstitial trophoblasts through the decidua basalis into the metrial gland from GD 15. HE stain. Bar=500 µm. BZ, basal zone; DB, decidua basalis; GC, glycogen cell; IT, interstitial trophoblast; LZ, labyrinth zone; MG, metrial gland; St, spongiotrophoblast; TG, trophoblastic giant cell.

Fig. 9.

Morphology of the parietal and visceral yolk sac in rats and morphological differences in the yolk sac between rats and humans. a. Parietal yolk sac on GD 9.5 in rats. HE stain. Bar = 50 µm. b. Visceral yolk sac on GD 9.5 in rats. HE stain. Bar = 50 μm. c. Metallothionein expression in the visceral yolk sac on GD 17 in rats. Bar = 50 µm. Lower schema. Morphological differences of yolk sac between humans and rats (early stage and middle/late stage).

Fig. 10.

Transverse sections of the decidua and metrial gland on GD 9.5. Division of the decidua into the decidua capsularis, decidua parietalis, and decidua basalis. The metrial gland in the mesometrial triangle with borders on two smooth muscle layers (arrows). HE stain.

Fig. 11.

Morphology of the metrial gland. a. Invasion of interstitial trophoblasts (arrow) into the metrial gland on GD 15. HE stain. Bar=900 µm. b. Invasion of endovascular trophoblasts into spiral arteries and localization of interstitial trophoblasts around spiral arteries in stroma. HE stain. Bar=100 µm. BZ, basal zone; DB, decidua basalis; ET, endovascular trophoblast; IT, interstitial trophoblasts; LZ, labyrinth zone; MG, metrial gland; SA, spiral artery; NK, uNK cell.

Fig. 12.

Human placenta. a. Macrograph of a placenta at term pregnancy. b. Placental villi. HE stain. Bar=75 µm. c. Surface of the basal plate with extravillous cytotrophoblast invasion and fibrinoid deposition. HE stain. Bar=150 µm. AV, anchoring villus; EC, extravillous cytotrophoblast; Fi, fibrinoid; FV, fetal vessel; IVS, intervillous space; St, syncytiotrophoblast.

Fig. 13.

Pathway of steroid hormone biosynthesis in rats and humans.

Fig. 14.

Relationship between fetal and placental weight. Normal range of weight, mean ± 3 SD.

Fig. 15.

Pathogenesis of placental weight changes. BZ, basal zone; LZ, labyrinth zone; MG, metrial gland.

Fig. 16.

Significance of placental histopathology in reproductive and developmental toxicity studies.