DEVELOPING ALLANTOIS IS A PRIMARY SITE OF 2'-DEOXYCOFORMYCIN TOXICITY

In this study, an assessment of normal mouse allantoic development and its sensitivity to 2'-(R)-deoxycoformycin (dCF); Pentostatin) exposur e were examined. Both dissecting microscopy and scanning electron micr oscopy were used to describe the normal growth and morphogenesis of th e mouse allantois over gestational days 7-10 as a preliminary step in evaluating potential abnormal allantoic ontogeny and its effect on umb ilical cord and placental development. Two abnormal allantoic/umbilica l cord phenotypes were observed subsequent to injecting pregnant mice with 5 mg dCF/kg, i.p., on gestational day 7 (GD 7) and evaluating lif ters on 10, 11, and 12. Abnormal phenotypes included: (1) an allantois which extended approximately halfway across the exocoelom but failed to establish a functional contact with the chorion; and (2) a phenotyp e characterized by reduced expansion of the allantois across the chori onic surface, a very thin umbilical cord, and aberrant vascularization throughout the structure. Both abnormal phenotypes exhibited ei ther an agenesis or hypogenesis of the umbilical cord and chorioallantoic p late, respectively. Nei ther abnormal phenotype, however, exhibited er rors in the directionality of allantoic growth toward the chorion nor in the formation of aberrant contacts between allantois and adjacent y olk sac or amnionic mesenchyme. Statistical interpretation of the expe rimental data strongly suggested that ab normalities in allantoic/umbi lical cord development were directly associated with embryolethality a s evidenced by a decline in the frequency of abnormal allantoic/umbili cal cord phenotypes over GD 10-12 (73, 36, acid 4%; respectively) and a con comitant increase in the frequency of implantation site resorpti ons over the same time period (7, 47, and 78%). These results strong s uggest that the developing allantois is very sensitive to the effects of dCF exposure, and that interference with its development leads to e mbryolethality by GD 12. (C) 1996 Wiley-Liss, Inc.