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

Stump, Donald G.; Holson, Joseph F.; Harris, Craig; Pearce, L. Bruce; Watson, Rebecca; DeSesso, John M.

doi:10.1016/j.reprotox.2015.01.005

Cited by 9 publications

(6 citation statements)

References 36 publications

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“…It is known that human yolk sac does not function as a placenta in the sense of being able to transfer nutrients between the maternal and embryonic circulations (Boyd, 2012;DeSesso et al, 2012). In addition, it is reported that the HBOC-201 (hemoglobinbased oxygen carriers)-induced embryo toxicity is indeed due to the damage of the yolk sac, and is not expected to impact human development (Stump et al, 2015). Therefore, the embryo toxicity induced by dysfunction of the yolk sac in rats cannot likely be extrapolated to humans.…”

Section: Discussionmentioning

confidence: 99%

Effect of dibutyltin on placental and fetal toxicity in rat

et al. 2017

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-In order to elucidate the effect of chorioallantoic and yolk sac placenta on the embryonic/fetal toxicity in dibutyltin dichloride (DBTCl)-exposed rats, we examined the histopathological changes and the tissue distribution of dibutyltin in the placentas and embryos. DBTCl was orally administered to the groups at doses of 0 mg/kg during gestation days (GD)s 7-9 (control group) and 20 mg/kg during GDs 7-9 (GD7-9 treated group), and GDs 10-12 (GD10-12 treated group). The total fetal mortality was increased, and malformations characterized by craniofacial dysmorphism were detected in the GD7-9 treated group. The embryonic/fetal weight and placental weight showed a decrease in both DBTCl-treated groups. Histologically, some embryos on GD 9.5 in the GD7-9 treated group underwent apoptosis without any changes of yolk sac. In the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS), tin was detected in the embryo, allantois, yolk sac, ectoplacental cone and decidual mass surrounding the conceptus on GD 9.5 in the GD7-9 treated group. Thus, it is considered that the embryo in this period is specifically sensitive to DBTCl-induced apoptosis, compared with other parts. The chorioallantoic placentas in both DBTCl-treated groups showed the developmental delay and hypoplasia in the fetal parts of placenta, resulting from apoptosis and mitotic inhibition. Thus, it was speculated that the DBTCl-induced malformations and fetal resorption resulted from the apoptosis in the embryo caused by the direct effect of DBTCl. The DBTCl-induced lesions in the chorioallantoic placenta were a non-specific transient developmental retardation in the fetal parts of placenta, leading to intrauterine growth retardation.

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Section: Discussionmentioning

confidence: 99%

Effect of dibutyltin on placental and fetal toxicity in rat

et al. 2017

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“…Researchers currently think that the optimal particle size for HBOCs is 128 kD or higher [33], but there is no consensus as to the appropriate range of their molecular weights. For example, the average molecular weight of HBOC-201 (Biopure Co. Ltd, Cambridge, MA) is 250 kD and that of Zero-link (oxyVita Inc.) is higher than 20 MD [34,35].…”

Section: Discussionmentioning

confidence: 99%

Glutaraldehyde-polymerized hemoglobin and tempol (PolyHb-tempol) has superoxide dismutase activity that can attenuate oxidative stress on endothelial cells induced by superoxide anion

Feng

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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A Tempol compound with an amine group (4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, NH-Tempol) was cross-linked to hemoglobin in a one-step polymerization reaction to produce a novel hemoglobin-based oxygen carrier (HBOC) designated PolyHb-Tempol. The reaction parameters, including the reaction time, pH, temperature, and ratio of reactants, were optimized, and the physiochemical properties of the resulting product were characterized. PolyHb-Tempol didn't show any toxicity towards endothelial cells. Furthermore, from observations of cell morphology and viability, PolyHb-Tempol showed a significant ability to inhibit or eliminate oxidative stress induced by superoxide free radicals. These results suggest that PolyHb-Tempol may potentially be suitable as an HBOC.

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“…9). It is thought that the human yolk sac does not function as a placenta in the sense of being able to transfer nutrients between maternal and embryonal circulations 86 , 88 , 89 . Therefore, embryo toxicity induced by yolk sac dysfunction during the period before chorioallantoic placenta formation in rats cannot necessarily be extrapolated to humans.…”

Section: Comparison With Human Placentamentioning

confidence: 99%

“…Thus, an animal model that does not rely upon an inverted yolk sac for embryonic nutrition should be used to elucidate any potential risk of developmental toxicity caused by chemicals in humans. 89…”

Section: Comparison With Human Placentamentioning

confidence: 99%

Morphology and physiology of rat placenta for toxicological evaluation

2019

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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.

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

Cited by 9 publications

References 36 publications

Effect of dibutyltin on placental and fetal toxicity in rat

Effect of dibutyltin on placental and fetal toxicity in rat

Glutaraldehyde-polymerized hemoglobin and tempol (PolyHb-tempol) has superoxide dismutase activity that can attenuate oxidative stress on endothelial cells induced by superoxide anion

Morphology and physiology of rat placenta for toxicological evaluation

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