Ethanol-mediated fetal dysmorphology and its relationship to the ontogeny of maternal liver metallothionein

Peter Coyle, Sean Martin, Luke C. Carey, Brooke L. Summers, Allan M. Rofe

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Fetal zinc (Zn) deficiency arising from ethanol-induction of the Zn-binding protein metallothionein (MT) in the mother's liver has been proposed as a mechanism of teratogenicity. Here, we determine the ontogeny of MT and Zn homeostasis in rats and mice and then examine the effect of acute ethanol exposure in early embryonic development on this relationship. The protective effect of Zn against ethanol-mediated fetal dysmorphology is also examined. Methods: Study 1: Maternal liver MT and Zn homeostasis was determined in Sprague-Dawley rats and C57BL/6J mice throughout gestation. Study 2: Rats were administered ethanol (25% in saline, intraperitoneal 0.015 ml/g) or vehicle alone on gestational day (GD) 9. Maternal liver MT and Zn, and plasma Zn was determined over the ensuing 24 hours. Study 3: Pregnant rats were treated with ethanol and Zn (s.c. 2.5 μg Zn/g) on GD9 and fetal dysmorphology was assessed on GD 19. Results: Study 1: Maternal liver MT began to rise around GD 9 peaking on GD 15 before falling to nonpregnant levels around term. The pregnancy-related increase in MT was associated with a fall in plasma Zn which was significantly lower on GD 15 thereafter returning to nonpregnant levels by parturition. Study 2: Ethanol administered to pregnant rats on GD 9 resulted in a 10-fold induction of MT in the maternal liver and was associated with a 33% rise in liver Zn and a 30% fall in plasma Zn, 16 hours after treatment. Study 3: Ethanol treatment on GD 9 resulted in a significant increase in craniofacial malformations which were prevented by concurrent Zn treatment. Conclusions: The findings indicate that maternal liver MT levels are lowest in early gestation (before GD 10) making this a sensitive period where ethanol-induction of MT can affect fetal Zn homeostasis and cause fetal dysmorphology. The study further provides evidence of a protective role for Zn against ethanol-mediated teratogenicity.

Original languageEnglish
Pages (from-to)1051-1058
Number of pages8
JournalAlcoholism: Clinical and Experimental Research
Volume33
Issue number6
DOIs
Publication statusPublished - 1 Jun 2009
Externally publishedYes

Keywords

  • Ethanol
  • Fetal dysmorphology
  • Gestation
  • Metallothionein
  • Rats and mice
  • Zinc

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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