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Ethanol-induced insulin resistance suppresses the expression of embryonic ornithine decarboxylase activity
L P Sandstrom1, P A Sandstrom, S N Pennington
1Department of Biochemistry, East Carolina University, School of Medicine, Greenville, NC 27834.
Insights
Ethanol exposure in utero disrupts embryonic growth by inhibiting ornithine decarboxylase (ODC) activity. Restoring putrescine levels can block this growth suppression, suggesting a key molecular mechanism.
Area of Science:
- Developmental Biology
- Biochemistry
- Toxicology
Background:
- In utero ethanol exposure is linked to fetal growth suppression and later life behavioral issues.
- Growth suppression is a common physical effect of ethanol exposure, associated with molecular changes.
Purpose of the Study:
- To investigate the biochemical consequences of ethanol-induced inhibition of ornithine decarboxylase (ODC) activity on embryonic development.
- To determine the role of ODC and polyamines in ethanol-induced growth suppression.
Main Methods:
- Studies were conducted using intact chick embryos and cultured embryonic tissues.
- Assessed the impact of ethanol on ornithine decarboxylase (ODC) activity and putrescine levels.
- Investigated the effect of exogenous putrescine and insulin on ethanol-exposed tissues.
Main Results:
- Embryonic ethanol exposure dose-dependently suppresses ornithine decarboxylase (ODC) activity, correlating with growth suppression.
- Exogenous putrescine administration blocked ethanol-induced growth suppression in chick embryos.
- Ethanol exposure inhibited insulin's ability to induce ODC activity in cultured embryonic tissue, indicating tissue resistance to insulin.
Conclusions:
- Ethanol-induced suppression of ODC activity and subsequent reduction in polyamine synthesis contribute to embryonic growth retardation.
- Ethanol exposure creates resistance to insulin's growth-promoting effects by disrupting ODC induction pathways.
- These findings highlight a critical molecular mechanism underlying fetal alcohol spectrum disorder (FASD).
Abstract:
In utero exposure to ethanol is associated with significant increases in fetal morbidity and mortality as well as with behavioral and learning problems that appear later in life. Growth suppression of the developing child is the most frequent physical effect of ethanol exposure and is correlated with specific molecular changes within the developing organism. The present report suggests that embryonic ethanol exposure suppresses the normal developmental increase in ornithine decarboxylase (ODC) activity. The loss of ODC activity during the early stages of development is dose-dependent and is correlated with the degree of growth suppression. Because ODC is the rate-limiting step for the synthesis of the polyamines and thus appears to be a focal enzyme for the regulation of growth, we have investigated the biochemical consequences of an ethanol-induced inhibition of ODC activity. Using intact chick embryos as well as cultured embryonic tissue, these studies indicate that ethanol-induced changes in tissue putrescine content result in growth suppression because a single dose of exogenous putrescine blocked the growth suppression. In cultured tissue, ethanol exposure inhibited the ability of a known trophic factor (insulin) to induce ODC activity. The loss of insulin-inducible decarboxylase activity as a result of ethanol exposure was specific to ODC, but ethanol per se had no effect on ODC activity in vitro. The data suggest that exposure to ethanol results in a resistance of the embryonic tissue to the action of insulin and thereby disrupts the molecular path by which this mitogenic compound induces the expression of ODC enzymatic activity.