Original Article

Exposure–disease continuum for 2-chloro-2′-deoxyadenosine, a prototype ocular teratogen. 1. Dose-response analysis †

  1. Judith A. Wubah1,
  2. R. Woodrow Setzer2,
  3. Christopher Lau2,
  4. Jeffrey H. Charlap1,
  5. Thomas B. Knudsen1,*

Article first published online: 14 AUG 2001

DOI: 10.1002/tera.1059

Issue

Teratology

Teratology

Volume 64, Issue 3, pages 154–169, September 2001

Additional Information

How to Cite

Wubah, J. A., Setzer, R. W., Lau, C., Charlap, J. H. and Knudsen, T. B. (2001), Exposure–disease continuum for 2-chloro-2′-deoxyadenosine, a prototype ocular teratogen. 1. Dose-response analysis . Teratology, 64: 154–169. doi: 10.1002/tera.1059

Author Information

  1. 1

    Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107

  2. 2

    National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711

*Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107

  1. †

    This article is a US Government work and, as such, is in the public domain in the United States of America.

Publication History

  1. Issue published online: 14 AUG 2001
  2. Article first published online: 14 AUG 2001
  3. Manuscript Accepted: 7 MAY 2001
  4. Manuscript Received: 28 AUG 2000

Funded by

  • National Institute of Environmental Health Sciences. Grant Number: T32 ES07282
  • NRSA
  • National Institute of Child Health and Human Development. Grant Number: F31 HD08167
  • Environmental Protection Agency. Grant Number: EPA-CR 824 445-01

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Abstract

Background

Treatment of pregnant mice with 2-chloro-2′-deoxyadenosine (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).

Methods

Pregnant CD-1 mice dosed with 0.5–10.0 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′-/3′-RACE was used to sequence the candidate gene for 2CdA bioactivation from target cells.

Results

Microphthalmia appeared first in the dose-response 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 (BMD5) was 2.5 mg/kg, and the lower confidence limit (BMDL) was 2.0 mg/kg. Pharmacokinetic parameters for doses encompassing the threshold (1.5–2.5 mg/kg) were modeled at 1.0–1.8 μM (Cmax) and 30–80 μM-min (AUC). The p53 response was not detected below the BMDL; however, a low-grade response appeared 4.5 hr after a teratogenic dose (5.0 mg/kg), and high-grade induction followed an embryolethal dose (10.0 mg/kg). RACE identified a novel splice variant of mitochondrial deoxyguanosine kinase, dGK-3, as the likely candidate for 2CdA bioactivation in the embryo.

Conclusions

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–disease continuum. Teratology 64:154–169, 2001. Published 2001 Wiley-Liss, Inc.

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