Ethanol inhibition of retinoic acid synthesis as a potential mechanism for fetal alcohol syndrome

Abstract

Retinoic acid (RA) is known to act as a signaling molecule during embryonic development, but little is known about the regulation of RA synthesis from retinol. The rate-limiting step in RA synthesis is the oxidation of retinol, a reaction that can be catalyzed by alcohol dehydrogenase (ADH). Ethanol is also a substrate for ADH, and high levels of ethanol inhibit ADH-catalyzed retinol oxidation. This has prompted us to hypothesize that ethanol-induced defects observed in fetal alcohol syndrome involve ethanol inhibition of ADH-catalyzed RA synthesis. Here, we have examined the effect of ethanol on RA levels in cultured mouse embryos by using a bioassay. Treatment with 100 mM ethanol, but no 10 mM, led to a significant decrease in RA detection in 7.5-day-old embryos. Using whole-mount in situ hybridization, we detected mRNA for class IV ADH, but not ethanol-active cytochrome P450 2E1, in 7.5- and 8.5-day-old embryos, indicating that an ADH-linked pathway exists at these stages for metabolizing retinol and ethanol. Thus, the observed ethanol-induced reduction in RA may be caused by ethanol inhibition of retinol oxidation catalyzed by class IV ADH. In our postulated mechanism for fetal alcohol syndrome, this enzyme may well play a crucial role.

Retinoid‐dependent mRNA expression and poly‐(A) contents in bovine oocytes meiotically arrested and/or matured in vitro

“…This process would need days or weeks of treatment to occur, which does not correspond to our experimental conditions. In fact, ethanol did reduce endogenous RA concentrations in cultured mouse embryos (Deltour et al, 1996). However, we previously demonstrated that 1% ethanol does not stimulate parthenogenetic activation .…”

Fetal alcohol exposure impairs hedgehog cholesterol modification and signaling

“…Direct measurements determined a range of alcohol concentration from 0.71-7.4 mM or 0.003-0.034 g dl À1 in fetal tissue under our experimental conditions. These alcohol concentrations are about 5.9-to 123-fold lower than blood alcohol levels that induce FASD in mice; 62 these concentrations are also 4.2-to 153-fold lower than the alcohol concentrations that induce cell apoptosis, 63 and retinoic acid deficiency 37 or that have antagonistic effects on growth factors. 36 Hence, relatively low concentrations of fetal tissue alcohol also can induce FASD-like defects.…”

“…32 The mechanisms proposed to underlie the spectrum of birth defects caused by fetal alcohol exposure include: apoptosis, 33 cell adhesion defects, 34 accumulation of free radicals, 35 dysregulation of growth factors, 36 and altered retinoic acid biosynthesis. 37 Some simple and essential questions have not been well explained by these hypotheses, for instance, how one or, at most, a few social drinks, cause fetal defects, why alcohol preferentially induces defects targeting some organs and tissues and not others, or why the pattern of defects seen in FASD is predictable and reproducible.…”

Mechanisms for persistent microphthalmia following ethanol exposure during retinal neurogenesis in zebrafish embryos

“…In the present study, an earlier ethanol exposure regime also resulted in photoreceptor differentiation abnormalities, suggesting that this retinal cell population is sensitive to ethanol from the time of cell birth (and possibly earlier) through the time of outer segment maturation. One mechanism proposed to mediate the teratogenic effects of ethanol is inhibition of synthesis of retinoic acid (RA) (DeJonge & Zachman, 1995;Deltour et al, 1996;Zachman & Grummer, 1998). This inhibition may take place either by ethanol competing with retinol for alcohol dehydrogenase, or by acetaldehyde, an ethanol metabolite, competing with retinaldehyde for aldehyde dehydrogenase (Han et al, 1998).…”

“…Several mechanisms have been put forth for its action. Morphogens like retinoic acid (RA) (Duester, 1991;Deltour et al, 1996;Zachman & Grummer, 1998) and sonic hedgehog (Ahlgren et al, 2002;Sulik, 2005) have been suggested as mediating the effects of ethanol. The purpose of this study was to characterize the effects of embryonic ethanol exposure on the neurogenesis of the zebrafish retina, and to evaluate the potential mechanisms through which ethanol exposure may result in microphthalmia.…”