Early postimplantation embryolethality in mice following in utero inhibition of adenosine deaminase with 2′-deoxycoformycin

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Abstract
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 (>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.

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