THE DEVELOPMENTAL TOXICITY OF

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THE DEVELOPMENTAL TOXICITY OF TETRATHIOMOLYBDATE
(TTM, NSC-714598) AND PROTECTIVE EFFECTS OF
COPPER IN RATS
Presented by A. V. Lyubimov, MD, PhD Toxicology
Research Laboratory University of Illinois at
Chicago
Teratology Society Meeting, 2002
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Central Hypothesis
Embryotoxicity of Ammonium Tetrathiomolybdate is
associated with copper depletion in mother and
fetus
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Summary

• Maternal Effects
• No maternal clinical signs of toxicity, or
  effects on body weights, food consumption or
  hematology parameters were seen.
• Serum ceruloplasmin levels were significantly
  decreased in copper supplemented and
  non-supplemented 20 mg/kg/day dose groups, which
  recovered rapidly after cessation of TTM
  treatment.
• Developmental Effects
• In the 20 mg/kg/day dose group (non-supplemented),
  the number of litters with at least one
  resorption was significantly higher (56 litters
  with resorptions) compared with the control group
  (26 litters with resorptions).
• Fetal liver copper levels was a representative
  biomarker of TTM embryotoxicity.

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Conclusions
Dietary copper supplementation provided a
protective effect on TTM toxicity for both
pregnant rats (ceruloplasmin levels) and fetuses
(liver copper levels, embryotoxicity). The
maternal and fetal No Observed Effect Level
(NOEL) was 6 mg/kg/day (36 mg/ m2/ day).
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Contributors
A. V. Lyubimov, B. S. Levine University of
Illinois at Chicago, Illinois M. D.
Mercieca Pathology Associates, Frederick,
Maryland J. E. Tomaszewski, A. C. Smith
National Cancer Institute, Bethesda, Maryland