Maternal ethanol exposure is associated with decreased plasma zinc and increased fetal abnormalities in normal but not metallothionein-null mice.
BACKGROUND
Ethanol profoundly affects fetal development, and this is proposed to be due primarily to a transient fetal zinc (Zn) deficiency that arises from the binding of Zn by metallothionein (MT) in the maternal liver. Zn homeostasis and fetal outcome were investigated in normal (MT+/+) and metallothionein-null (MT-/-) mice in response to ethanol exposure.


RESULTS
Mice were treated with saline or ethanol (0.015 m/g intraperitoneally at 0 and 4 hr) on day 8 of gestation (Gd8), and the degree of fetal dysmorphology was assessed on Gd18. The incidence of external abnormalities was significantly increased in offspring from MT+/+ dams exposed to ethanol, where 27.4% of fetuses were affected. MT-/- ethanol-, MT+/+ saline-, and MT-/- saline-treated dams had fetuses in which the frequencies of abnormalities were 2.2, 6.4, and 6.9%, respectively. To investigate Zn homeostasis, nonpregnant mice were killed at intervals over 16 hr after ethanol injection. Liver MT concentrations in MT+/+ mice were increased 20-fold by 16 hr, with a significant elevation evident by 4 hr, whereas liver Zn levels were also significantly increased by 2 hr and maintained for 16 hr. In parallel with these changes, plasma Zn concentrations in MT+/+ mice decreased by 65%, with minimum levels of 4.5+/-0.3 micromol/liter at 8 hr. Conversely, MT-/- mice exhibited increased plasma Zn concentrations, with peak values of 20.8+/-0.3 observed at 4 hr.


CONCLUSIONS
These findings link the teratogenic effect of ethanol to the induction of maternal MT and the limitation of fetal Zn supply from the plasma.
Carey
L C
LC
Division of Clinical Biochemistry, Institute of Medical and Veterinary Science, Adelaide, Australia.
Coyle
P
P
Philcox
J C
JC
Rofe
A M
AM
D000818:Animals; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000097:blood; D000431:Ethanol / Q000009:adverse effects* / Q000097:blood; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D015032:Zinc / Q000097:blood*
D002492:Central Nervous System Depressants; D000431:Ethanol; D008668:Metallothionein; D015032:Zinc