title: Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac.
abstract: 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.
authors.affiliation: WIL Research Laboratories, Ashland, OH, United States.
authors.forename: D G
authors.initials: DG
authors.lastname: Stump
authors.affiliation: Ashland, OH, United States.
authors.forename: J F
authors.initials: JF
authors.lastname: Holson
authors.affiliation: University of Michigan, Ann Arbor, MI, United States.
authors.forename: C
authors.initials: C
authors.lastname: Harris
authors.affiliation: Biologics Consulting Group, Alexandria, VA, United States.
authors.forename: L B
authors.initials: LB
authors.lastname: Pearce
authors.affiliation: SNBL USA, Everett, WA, United States.
authors.forename: R E
authors.initials: RE
authors.lastname: Watson
authors.affiliation: Exponent, Inc., Alexandria, VA, United States; Georgetown University School of Medicine, Washington, DC, United States. Electronic address: jdesesso@exponent.com.
authors.forename: J M
authors.initials: JM
authors.lastname: DeSesso
mesh_terms: D000818:Animals; D005260:Female; D011247:Pregnancy; D051381:Rats; D000014:Abnormalities, Drug-Induced; D001802:Blood Substitutes; D046149:Embryo Culture Techniques; D047108:Embryonic Development / Q000187:drug effects; D005313:Fetal Death / Q000209:etiology; D005865:Gestational Age; D006454:Hemoglobins / Q000008:administration & dosage / Q000633:toxicity; D023421:Models, Animal; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D015017:Yolk Sac / Q000187:drug effects / Q000502:physiology
chemical_list: D001802:Blood Substitutes; C096798:HBOC 201; D006454:Hemoglobins
keywords: Hemoglobin-based oxygen carrier; Histiotrophic; Placenta; Visceral yolk sac; Whole embryo culture