Reduction of Drug-Induced Cleft Palate in Mice

Szabo, K. T.; Brent, RobertL.

doi:10.1016/s0140-6736(75)92580-5

Cited by 42 publications

(6 citation statements)

References 4 publications

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“…Thus, the single-day infusion data and in vitro embryo exposure data are consistent with the hypothesis that the early developing invVYS was the target organ for HBOC-201 toxicity. Reduced nutrition/starvation of pregnant rat [22] and mouse embryos [23,24] during the early period of organogenesis has previously been linked to the production of malformations in these species, which is also consistent with the findings in HBOC-treated litters in this report. Additionally, interference with invVYS function during the remainder of gestation would be expected to diminish transfer of some nutrients into the embryo, which could account for the fetal weight decrements seen in HBOC-treated groups.…”

Section: Discussionsupporting

confidence: 92%

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

Stump

Holson

Harris

et al. 2015

Reproductive Toxicology

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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.

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Section: Discussionsupporting

confidence: 92%

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

Stump

Holson

Harris

et al. 2015

Reproductive Toxicology

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“…Furthermore, reduction in nutrition to rat (Ellington, 1980) and mouse embryos (Szabo and Brent, 1975;Hemm et al, 1977) during the early period of organogenesis has been linked to the production of malformations in these species, which is consistent with the findings in HBOC-treated litters. While identifying the likely target organ is an important step in assessing developmental toxicity, it is also important to understand the probable MOA to apply the knowledge gained to other potential developmental toxicants.…”

supporting

confidence: 86%

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

Holson

Stump

Pearce

et al. 2005

Critical Reviews in Toxicology

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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 (approximately 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.

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“…During earlier stages of gestational events (up to day 7), it might be possible that ConA entering the blood stream might be taken up by the yolk sac placenta, where it remains and adversely affect the nutrient transport functions during this critical period. Reduced embryonic nutrition has been shown to be toxic in mice (Szabo and Brent, 1975;Hayasaka and Hoshino, 1979;Hayasaka et al, 1986) and rabbits (Clark et al, 1986). However, in the case of a glucose biosensor, even if the total amount of ConA in the sensor were to enter the blood stream, the concentration of ConA would only be approximately 1.5 g/l, which is almost 7 orders of magnitude lower than the tested ConA concentration in rabbits.…”

Section: Teratogenicitymentioning

confidence: 98%