8 Fetal Alcohol Spectrum Disorder: Embryogenesis Under …
199
the bloodstream and spreads very quickly in the body reaching all organs and the
fetus. Severely intoxicated individuals can reach ethanol blood concentrations up to
86 mmol/L (0.5% vol/vol, 4 g/L). Above this concentration, the individual might
lose consciousness, and in some cases, die (Schuckit 1998). Alcohol produced by
the microbiome or as a by-product of normal metabolism has also been proposed
as a contributing factor for FASD (Leung et al. 2016), but the contribution provided
by these sources is negligible in comparison with the levels reached by ingestion of
alcoholic beverages.
Ethanol is metabolized in the liver to reduce its harmful effects and to clear it from
the body (Edenberg and Foroud 2013). In the adult, the enzymatic clearance process
involves two sequential oxidation reactions. First, ethanol is oxidized to acetaldehyde primarily by alcohol dehydrogenases of the middle-chain family (ADH) (Crabb
et al. 2004; Cederbaum 2012; Edenberg and McClintick 2018; Zhong and Lemasters 2018). Then acetaldehyde is oxidized to acetic acid mainly by liver aldehyde
dehydrogenase 2 (ALDH2) (Deitrich et al. 2007; Cederbaum 2012; Koppaka et al.
2012; Edenberg and McClintick 2018). Both reactions involve NAD
+ as a co-factor,
which undergoes parallel reduction into NADH. Cytochrome P450 2E1 (CYP2E1)
and catalase (in an H 2 O 2 -dependent reaction) can also oxidize ethanol to acetaldehyde (Goyal and Basak 2010; Nicholls 2012). CYP2E1 eliminates about 10% of the
ethanol as part of the microsomal ethanol oxidizing system (MEOS) (Lieber 1999,
2004). Under normal physiological conditions, the contribution of catalase to the
elimination of ethanol is believed to be marginal.
Acetaldehyde, the first product of ethanol oxidation, is a very reactive compound
and is probably responsible for many of the harmful effects of ethanol. Indeed,
acetaldehyde accumulation is responsible for the unpleasant sensation of dizziness,
headaches, nausea, and other physical discomforts attributed to alcohol consumption
(hangover). Acetaldehyde also causes damage to basic cellular functions through
the formation of adducts with DNA, RNA, proteins and multiple cellular components (Tuma et al. 1991; Hoffmann et al. 1993; Harcombe et al. 1995; Balbo and
Brooks 2015). Importantly, in the blood of alcohol intoxicated individuals, the level
of acetaldehyde can reach about 20 μmol/L (Tsukamoto et al. 1989; Brecher et al.
1997).
In pregnant women, ethanol and its clearance metabolites, primarily acetaldehyde,
can readily cross the placenta and reach the fetus (Heller and Burd 2014). The
initial concentration of ethanol in the fetal blood is similar to the concentration
in the maternal blood (Heller and Burd 2014). In this scenario, both mother and
fetus have to clear ethanol and its metabolites. The efficiency of the maternal liver
in ethanol clearance is largely dependent upon the enzyme alleles encoded in her
genome (Edenberg and McClintick 2018). The fetus, on the other hand, is very
inefficient in ethanol/acetaldehyde clearance. Compared to maternal activity, the
efficiency of fetal oxidation of ethanol or acetaldehyde is only about 4% (Heller
and Burd 2014), and, additionally, the amniotic fluid accumulates ethanol clearance
metabolites (Guerri and Sanchis 1985). This inefficiency of clearance means the fetus
is exposed for relatively longer periods of time to ethanol and its teratogenic effects
while continuing with the process of embryonic development.
199
the bloodstream and spreads very quickly in the body reaching all organs and the
fetus. Severely intoxicated individuals can reach ethanol blood concentrations up to
86 mmol/L (0.5% vol/vol, 4 g/L). Above this concentration, the individual might
lose consciousness, and in some cases, die (Schuckit 1998). Alcohol produced by
the microbiome or as a by-product of normal metabolism has also been proposed
as a contributing factor for FASD (Leung et al. 2016), but the contribution provided
by these sources is negligible in comparison with the levels reached by ingestion of
alcoholic beverages.
Ethanol is metabolized in the liver to reduce its harmful effects and to clear it from
the body (Edenberg and Foroud 2013). In the adult, the enzymatic clearance process
involves two sequential oxidation reactions. First, ethanol is oxidized to acetaldehyde primarily by alcohol dehydrogenases of the middle-chain family (ADH) (Crabb
et al. 2004; Cederbaum 2012; Edenberg and McClintick 2018; Zhong and Lemasters 2018). Then acetaldehyde is oxidized to acetic acid mainly by liver aldehyde
dehydrogenase 2 (ALDH2) (Deitrich et al. 2007; Cederbaum 2012; Koppaka et al.
2012; Edenberg and McClintick 2018). Both reactions involve NAD
+ as a co-factor,
which undergoes parallel reduction into NADH. Cytochrome P450 2E1 (CYP2E1)
and catalase (in an H 2 O 2 -dependent reaction) can also oxidize ethanol to acetaldehyde (Goyal and Basak 2010; Nicholls 2012). CYP2E1 eliminates about 10% of the
ethanol as part of the microsomal ethanol oxidizing system (MEOS) (Lieber 1999,
2004). Under normal physiological conditions, the contribution of catalase to the
elimination of ethanol is believed to be marginal.
Acetaldehyde, the first product of ethanol oxidation, is a very reactive compound
and is probably responsible for many of the harmful effects of ethanol. Indeed,
acetaldehyde accumulation is responsible for the unpleasant sensation of dizziness,
headaches, nausea, and other physical discomforts attributed to alcohol consumption
(hangover). Acetaldehyde also causes damage to basic cellular functions through
the formation of adducts with DNA, RNA, proteins and multiple cellular components (Tuma et al. 1991; Hoffmann et al. 1993; Harcombe et al. 1995; Balbo and
Brooks 2015). Importantly, in the blood of alcohol intoxicated individuals, the level
of acetaldehyde can reach about 20 μmol/L (Tsukamoto et al. 1989; Brecher et al.
1997).
In pregnant women, ethanol and its clearance metabolites, primarily acetaldehyde,
can readily cross the placenta and reach the fetus (Heller and Burd 2014). The
initial concentration of ethanol in the fetal blood is similar to the concentration
in the maternal blood (Heller and Burd 2014). In this scenario, both mother and
fetus have to clear ethanol and its metabolites. The efficiency of the maternal liver
in ethanol clearance is largely dependent upon the enzyme alleles encoded in her
genome (Edenberg and McClintick 2018). The fetus, on the other hand, is very
inefficient in ethanol/acetaldehyde clearance. Compared to maternal activity, the
efficiency of fetal oxidation of ethanol or acetaldehyde is only about 4% (Heller
and Burd 2014), and, additionally, the amniotic fluid accumulates ethanol clearance
metabolites (Guerri and Sanchis 1985). This inefficiency of clearance means the fetus
is exposed for relatively longer periods of time to ethanol and its teratogenic effects
while continuing with the process of embryonic development.