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2017 ; 12
(4
): e0176440
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Ethanol itself is a holoprosencephaly-inducing teratogen
#MMPMID28441416
Hong M
; Krauss RS
PLoS One
2017[]; 12
(4
): e0176440
PMID28441416
show ga
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.
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