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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 (250 kDa) in physiological saline. Daily intravenous infusions of HBOC (1.95, 3.90, or 5.85 g/kg/day) during gestational days (GDs) 6–18 in Sprague-Dawley rats caused fetal mortality, reduced birth weight, and malformations. Subse...

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Autores principales: Stump, D.G., Holson, J.F., Harris, C., Pearce, L.B., Watson, R.E., DeSesso, J.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Published by Elsevier Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127137/
https://www.ncbi.nlm.nih.gov/pubmed/25617809
http://dx.doi.org/10.1016/j.reprotox.2015.01.005
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author Stump, D.G.
Holson, J.F.
Harris, C.
Pearce, L.B.
Watson, R.E.
DeSesso, J.M.
author_facet Stump, D.G.
Holson, J.F.
Harris, C.
Pearce, L.B.
Watson, R.E.
DeSesso, J.M.
author_sort Stump, D.G.
collection PubMed
description HBOC-201 is a bovine-derived, cross-linked, and stabilized hemoglobin (250 kDa) in physiological saline. Daily intravenous infusions of HBOC (1.95, 3.90, or 5.85 g/kg/day) during gestational days (GDs) 6–18 in Sprague-Dawley rats caused fetal mortality, reduced birth weight, and malformations. Subsequent single-day infusions (5.85 g/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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spelling pubmed-71271372020-04-08 Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac Stump, D.G. Holson, J.F. Harris, C. Pearce, L.B. Watson, R.E. DeSesso, J.M. Reprod Toxicol Article HBOC-201 is a bovine-derived, cross-linked, and stabilized hemoglobin (250 kDa) in physiological saline. Daily intravenous infusions of HBOC (1.95, 3.90, or 5.85 g/kg/day) during gestational days (GDs) 6–18 in Sprague-Dawley rats caused fetal mortality, reduced birth weight, and malformations. Subsequent single-day infusions (5.85 g/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. Published by Elsevier Inc. 2015-04 2015-01-21 /pmc/articles/PMC7127137/ /pubmed/25617809 http://dx.doi.org/10.1016/j.reprotox.2015.01.005 Text en Copyright © 2015 Published by Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Stump, D.G.
Holson, J.F.
Harris, C.
Pearce, L.B.
Watson, R.E.
DeSesso, J.M.
Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac
title Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac
title_full Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac
title_fullStr Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac
title_full_unstemmed Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac
title_short Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac
title_sort developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127137/
https://www.ncbi.nlm.nih.gov/pubmed/25617809
http://dx.doi.org/10.1016/j.reprotox.2015.01.005
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