enzymes that metabolize DPH) could result in an accumulation of the DPH teratogen. The frequencies of CYP2C9 and CYP2C19 poor metabolizing polymorphisms range between 10% and 25% of individuals in different populations—very similar to the percent of women taking DHP who have children with the fetal hydantoin syndrome.

  • Aldehyde dehydrogenase 2, alcohol dehydrogenase 2, and the susceptibility to fetal alcohol syndrome: In the metabolism of ethyl alcohol, alcohol dehydrogenase (ADH) catalyzes the conversion of alcohol to acetaldyhyde, and acetylaldehyde dehydrogenase (ALDH) oxidizes the conversion of this product to acetic acid. Alcohol and acetaldehyde, but not acetic acid, are thought to have the potential for deleterious effects. Humans possess at least seven ADH genes and 13 ALDH genes. Crabb (1990) pointed out that the single base mutation in ALDH2 (the mitochondrial as opposed to the cytosolic ALDH), which is responsible for acute alcohol-flushing reaction and alcohol intolerance mostly in Asians, is the best-characterized genetic factor influencing alcohol drinking behavior (lower activity correlating with intolerance). He raised the possibility that polymorphisms in the several alcohol dehydrogenase genes might be related to risk of fetal alcohol syndrome (FAS). A genetic influence in fetal alcohol syndrome is suggested by twin studies: Streissguth and Dehaene (1993) established that the rate of concordance for the diagnosis of fetal alcohol syndrome was 5 out of 5 for monozygotic and 7 out of 11 for dizygotic twins. In two dizygotic pairs, one twin had FAS, and the other had fetal alcohol effects (FAE). In two other dizygotic pairs, one twin had no evident abnormality, and the other had FAE. Intelligence Quotient scores were most similar within pairs of monozygotic twins and least similar within pairs of dizygotic twins discordant for diagnosis. Johnson et al. (1996) documented the central nervous system (CNS) anomalies of FAS by magnetic resonance imaging. CNS and craniofacial abnormalities were predominantly symmetric and central or midline. The authors stated that the association emphasized the concept of the midline as a special developmental field. The CNS is vulnerable to adverse factors during embryogenesis and fetal growth and development.

As those four examples indicate, further investigation of gene-environment interactions using the tools of molecular epidemiology is likely to yield important new information on multifactorial causes of developmental defects. Two of the above-cited examples concern polymorphisms of genes encoding enzymes involved in the metabolism of an agent, namely, phenytoin or alcohol, and two of the examples concern polymorphisms of genes encoding protein intermediates of signal transduction pathways and genetic regulatory circuits (TGFα or MSX1), which are components of developmental processes.

The examination of gene-environment interactions is particularly advanced for disease conditions related to the DMEs, and this area of study is called ecogenetics or pharmacogenetics. There are phase I and phase II metabolizing



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement