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Computational modeling of a putative fetal alcohol syndrome mechanism
D Whitmire1, J P Bowen, J Y Shim
1Department of Biological and Agricultural Engineering, Enzyme Engineering Laboratory, Driftmier Engineering Center, Athens, Georgia, USA.
Insights
Fetal alcohol syndrome (FAS) is caused by alcohol consumption during pregnancy. Ethanol competes with retinol for alcohol dehydrogenase, disrupting retinoic acid signaling crucial for fetal development.
Area of Science:
- Biochemistry
- Developmental Biology
- Toxicology
Background:
- Fetal alcohol syndrome (FAS) is a spectrum of birth defects linked to prenatal alcohol exposure.
- FAS disproportionately affects minority populations, including African-American and Native American communities.
- Existing research highlights the significant medical, social, and economic burden of FAS.
Purpose of the Study:
- To investigate the proposed mechanism of FAS involving the competition between ethanol and retinol for alcohol dehydrogenase (ADH).
- To elucidate how this competition disrupts retinoic acid (RA) homeostasis and impacts fetal development.
- To provide a molecular and physiological basis for the FAS hypothesis.
Main Methods:
- Utilized molecular modeling to study the structures of retinol-ADH and ethanol-ADH interactions.
- Employed physiological pharmacokinetic modeling to assess the impact of ethanol on RA homeostasis.
- Reviewed existing literature and the proposed FAS mechanism by Duester and Pullarkat (1991).
Main Results:
- Preliminary molecular modeling data support the hypothesis of competition between ethanol and retinol for ADH.
- Physiological modeling indicates that ethanol binding to ADH deregulates RA homeostasis.
- The findings align with the proposed mechanism where disrupted RA signaling leads to FAS.
Conclusions:
- The competition between ethanol and retinol for ADH is a plausible mechanism underlying FAS.
- Disruption of retinoic acid homeostasis by ethanol is critical for abnormal fetal development.
- Further research and validation of this hypothesis are warranted.
Abstract:
Fetal alcohol syndrome (FAS) refers to a pattern of birth defects occurring in a subpopulation of children born to women who consume alcohol during pregnancy. The significant medical, social, and economic impact of FAS is increasing. Particularly hard-hit are African-American and native-American women and children. Over the past two decades, basic and clinical research produced voluminous data on ethanol effects on developing organisms. In 1991, Duester and Pullarkat proposed that competition of ethanol with retinol at the alcohol dehydrogenase (ADH) binding site formed the basis of the FAS mechanism. This competition adversely affects the developing fetus caused by deregulation of retinoic acid (RA) homeostasis essential for proper fetal tissue development. Stated concisely, the FAS hypothesis is: 1. Class I ADH catalyzes the rate-limiting step in oxidation of retinol (ROH) to RA, and ethanol (ETOH) to acetic acid, thus establishing competition for ADH between ROH and ETOH. 2. RA is required as a signal molecule for cell differentiation critical for normal fetal morphogenesis. 3. ADH binds ingested ETOH, thus deregulating RA homeostasis leading to improper RA signal transduction. Preliminary results from molecular modeling studies of ROH-ADH and ETOH-ADH structures, and physiologic pharmacokinetic modeling confirm the hypothesis with remarkable fidelity.