US EPA

3809804 

Journal Article 

Ethanol itself is a holoprosencephaly-inducing teratogen 

Hong, M; Krauss, RS 

2017 

1 

PLoS ONE
EISSN: 1932-6203 

12 

4 

e0176440 

English 

28441416 

10.1371/journal.pone.0176440 

WOS:000400308800056 

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85018845590&doi=10.1371%2fjournal.pone.0176440&partnerID=40&md5=dc53cda562b7b8a3198028962dfe083e
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Ethanol is a teratogen, inducing a variety of structural defects in developing humans and animals that are exposed in utero. Mechanisms of ethanol teratogenicity in specific defects are not well understood. Oxidative metabolism of ethanol by alcohol dehydrogenase or cytochrome P450 2E1 has been implicated in some of ethanol's teratogenic effects, either via production of acetaldehyde or competitive inhibition of retinoic acid synthesis. Generalized oxidative stress in response to ethanol may also play a role in its teratogenicity. Among the developmental defects that ethanol has been implicated in is holoprosencephaly, a failure to define the midline of the forebrain and midface that is associated with a deficiency in Sonic hedgehog pathway function. Etiologically, holoprosencephaly is thought to arise from a complex combination of genetic and environmental factors. We have developed a gene-environment interaction model of holoprosencephaly in mice, in which mutation of the Sonic hedgehog coreceptor, Cdon, synergizes with transient in utero exposure to ethanol. This system was used to address whether oxidative metabolism is required for ethanol's teratogenic activity in holoprosencephaly. We report here that t-butyl alcohol, which is neither a substrate nor an inhibitor of alcohol dehydrogenases or Cyp2E1, is a potent inducer of holoprosencephaly in Cdon mutant mice. Additionally, antioxidant treatment did not prevent ethanol- or t-butyl alcohol-induced HPE in these mice. These findings are consistent with the conclusion that ethanol itself, rather than a consequence of its metabolism, is a holoprosencephaly-inducing teratogen. 

Sciences: Comprehensive Works; Embryos; Antioxidants; Ethanol; Enzyme metabolism; Alcohols; Oxidative stress; Acetaldehyde; Phenotypes; Intrauterine exposure; Birth defects; Forebrain; Etiology; Teratogenicity; Free radicals; Mutation; Biology; Metabolism; Kinases; Defects; Dehydrogenases; Morphogenesis; Laboratory animals; Fetuses; Alcohol dehydrogenase; Medicine; Retinoic acid; Cytochrome P450; Exposure; Holoprosencephaly; Alcohol; Oxidative metabolism; t-Butyl alcohol; Environmental factors; Hedgehog protein; Pathogenesis; Butanol