Early postimplantation embryolethality in mice following in utero inhibition of adenosine deaminase with 2'-deoxycoformycin.
Adenosine deaminase (ADA) catalyzes the hydrolytic deamination of adenosine (or 2'-deoxyadenosine) to inosine (or 2'-deoxyinosine). Previously, we have shown that ADA activity is subject to strong cell-specific developmental regulation in placental tissues of mice between days 6 and 11 of gestation (Knudsen et al.:Biology of Reproduction 39:937-951, 1988). In the present study, we examined the effects of intrauterine exposure to 2'-deoxycoformycin (dCF; pentostatin), a potent irreversible inhibitor of ADA, on early postimplantation development. Deoxycoformycin was administered to pregnant ICR mice as a single intraperitoneal injection at a dose of 5 mg/kg on one of days 6 through 11 of gestation (plug day 0). A marked increase in the incidence of implantation site resorptions was observed following treatment specifically on days 7 (61% resorbed) or 8 (78% resorbed). No effect was observed following treatment on days 6, 9, 10, or 11. ADA-immunoreactive protein was shown, by ABC-immunoperoxidase staining on days 7 or 8 of gestation, to be present at high levels in decidual cells of the antimesometrial region but at below-detectable levels in the embryo. Treatment of pregnant dams with dCF on day 7 produced a complete (greater than 99%) inhibition of ADA activity in the antimesometrial decidua by 30 min, induced excessive cell death in the prospective neural plate and primary mesenchyme of the trilaminar disc by 6 h, and arrested embryonic development at an early somite stage. These results suggest that the antimesometrial decidua plays a protective role in preventing an inappropriate accumulation of endogenous ADA substrates in the implantation site.
Knudsen
T B
TB
Department of Anatomy, James H. Quillen College of Medicine Johnson City, Tennessee 37614.
Gray
M K
MK
Church
J K
JK
Blackburn
M R
MR
Airhart
M J
MJ
Kellems
R E
RE
Skalko
R G
RG
D000243:Adenosine Deaminase / Q000502:physiology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D005865:Gestational Age; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D008813:Mice, Inbred ICR / Q000196:embryology*; D009700:Nucleoside Deaminases / Q000502:physiology*; D015649:Pentostatin / Q000633:toxicity*; D011247:Pregnancy
D015649:Pentostatin; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase