208
A. Fainsod et al.
Fig. 8.5 RA biochemistry and acetaldehyde competition in the early gastrula embryo. The maternal
contribution of RA precursors and ethanol clearance intermediates is shown
Acetaldehyde Competes with Retinaldehyde for RALDH
Activity
Although not explored in initial experiments, it was proposed that acetaldehyde
produced from ethanol oxidation might compete with retinaldehyde for the RALDH
activity in the embryo (Fig. 8.5) (Duester 1991; Pullarkat 1991). Over the years, this
latter possibility has gained more interest based on several experimental observations.
The use of pharmacological inhibitors of ADH and SDR enzymes, in combination with ethanol, has provided important new information. First, SDR inhibitors
have been shown to have additive effects with ethanol in modifying RA-dependent
gene expression. Second, ADH has been found to be essential for the conversion of
ethanol to its teratogenic intermediate, acetaldehyde (Shabtai et al. 2018), placing
acetaldehyde and retinaldehyde, the ethanol and retinol metabolites, respectively, at
the center of the competition. RALDH2 is the main ALDH activity during gastrula
and early neurula stages when the embryo is most sensitive to the alcohol exposure
(Yelin et al. 2005; Shabtai et al. 2018) (Fig. 8.4). These observations have raised the
possibility that, in the early embryo, RALDH2 might be an important target in the
ethanol/retinol competition. For that reason, a modified competition hypothesis was
proposed.
In vertebrate embryos, evidence has accumulated that gastrulation marks the onset
of RA signaling in the embryo. First, it has been shown that early Xenopus gastrula
embryos contain retinol, retinaldehyde and retinoic acid (Creech Kraft et al. 1994;
Kraft et al. 1994; Creech Kraft et al. 1995; Kraft et al. 1995). Second, among the
aldh1A genes, aldh1A2, which encodes the RALDH2 enzyme, is the first to be
transcribed during embryogenesis, close to the onset of gastrulation (Niederreither
et al. 1997; Swindell et al. 1999; Xi et al. 2015; Shabtai et al. 2018). It is widely
accepted that the initial expression of an RALDH enzyme, most probably RALDH2,
completes the RA biosynthesis pathway and initiates RA signaling (Ang and Duester
1999; Chen et al. 2001). In agreement, mutations in the aldh1A2 gene result in
developmental lethality during early post-gastrula stages, supporting the importance
A. Fainsod et al.
Fig. 8.5 RA biochemistry and acetaldehyde competition in the early gastrula embryo. The maternal
contribution of RA precursors and ethanol clearance intermediates is shown
Acetaldehyde Competes with Retinaldehyde for RALDH
Activity
Although not explored in initial experiments, it was proposed that acetaldehyde
produced from ethanol oxidation might compete with retinaldehyde for the RALDH
activity in the embryo (Fig. 8.5) (Duester 1991; Pullarkat 1991). Over the years, this
latter possibility has gained more interest based on several experimental observations.
The use of pharmacological inhibitors of ADH and SDR enzymes, in combination with ethanol, has provided important new information. First, SDR inhibitors
have been shown to have additive effects with ethanol in modifying RA-dependent
gene expression. Second, ADH has been found to be essential for the conversion of
ethanol to its teratogenic intermediate, acetaldehyde (Shabtai et al. 2018), placing
acetaldehyde and retinaldehyde, the ethanol and retinol metabolites, respectively, at
the center of the competition. RALDH2 is the main ALDH activity during gastrula
and early neurula stages when the embryo is most sensitive to the alcohol exposure
(Yelin et al. 2005; Shabtai et al. 2018) (Fig. 8.4). These observations have raised the
possibility that, in the early embryo, RALDH2 might be an important target in the
ethanol/retinol competition. For that reason, a modified competition hypothesis was
proposed.
In vertebrate embryos, evidence has accumulated that gastrulation marks the onset
of RA signaling in the embryo. First, it has been shown that early Xenopus gastrula
embryos contain retinol, retinaldehyde and retinoic acid (Creech Kraft et al. 1994;
Kraft et al. 1994; Creech Kraft et al. 1995; Kraft et al. 1995). Second, among the
aldh1A genes, aldh1A2, which encodes the RALDH2 enzyme, is the first to be
transcribed during embryogenesis, close to the onset of gastrulation (Niederreither
et al. 1997; Swindell et al. 1999; Xi et al. 2015; Shabtai et al. 2018). It is widely
accepted that the initial expression of an RALDH enzyme, most probably RALDH2,
completes the RA biosynthesis pathway and initiates RA signaling (Ang and Duester
1999; Chen et al. 2001). In agreement, mutations in the aldh1A2 gene result in
developmental lethality during early post-gastrula stages, supporting the importance