{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T19:25:14Z","timestamp":1760383514727},"reference-count":81,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2001,8,14]],"date-time":"2001-08-14T00:00:00Z","timestamp":997747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratology"],"published-print":{"date-parts":[[2001,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Treatment of pregnant mice with 2\u2010chloro\u20102\u2032\u2010deoxyadenosine (2CdA) on day 8 of gestation induces microphthalmia through a mechanism coupled to the p53 tumor suppressor gene. The present study defines 2CdA dosimetry with respect to exposure (pharmacokinetics), p53 protein induction, and disease (microphthalmia).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pregnant CD\u20101 mice dosed with 0.5\u201310.0 mg\/kg 2CdA on day 8 provided fetuses for teratological evaluation; 2CdA was measured by HPLC in the antimesometrium through 180 min postexposure, and p53 was assessed with immunostaining of the embryo through 270 min. 5\u2032\u2010\/3\u2032\u2010RACE was used to sequence the candidate gene for 2CdA bioactivation from target cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Microphthalmia appeared first in the dose\u2010response curve. The highest 2CdA dose having no observable adverse effect (NOAEL) was 1.5 mg\/kg; the benchmark dose that produced an extra 5% risk of microphthalmia (BMD<jats:sub>5<\/jats:sub>) was 2.5 mg\/kg, and the lower confidence limit (BMDL) was 2.0 mg\/kg. Pharmacokinetic parameters for doses encompassing the threshold (1.5\u20132.5 mg\/kg) were modeled at 1.0\u20131.8 \u03bcM (C<jats:sub>max<\/jats:sub>) and 30\u201380 \u03bcM\u2010min (AUC). The p53 response was not detected below the BMDL; however, a low\u2010grade response appeared 4.5 hr after a teratogenic dose (5.0 mg\/kg), and high\u2010grade induction followed an embryolethal dose (10.0 mg\/kg). RACE identified a novel splice variant of mitochondrial deoxyguanosine kinase, dGK\u20103, as the likely candidate for 2CdA bioactivation in the embryo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Microphthalmia represented the critical effect malformation of 2CdA. The findings suggest a mitochondrial mechanism for 2CdA bioactivation, leading to an embryonic p53 response only after 2CdA elimination and implying pharmacodynamic coupling to the exposure\u2013disease continuum. Teratology 64:154\u2013169, 2001. 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