Fetal Alcohol Syndrome and Fatty Acid Ethyl Esters

Abstract

ABSTRACT. Fetal alcohol syndrome is the leading known cause of mental retardation. The syndrome, defined as growth retardation, midface hypoplasia, and neurologic dysfunction, represents only part of the spectrum of fetal alcohol effects. The biochemical mechanism of teratogenesis is unknown. In adults, metabolites of ethanol, FAEE, are known to accumulate in major organs. The formation of FAEE is catalyzed by a family of enzymes, FAEE synthases. Our hypothesis is that accumulation of FAEE in the embryo results in fetal alcohol syndrome. We have developed assays for FAEE and FAEE synthase activity using mg of tissue. Using these assays, we have shown the following: Human placenta, mouse placenta, heart, and liver are active in catalyzing the formation of FAEE. One h after maternal ethanol administration on gestational d 14, mouse placenta and fetuses accumulated significant quantities of FAEE. The fatty acid incorporated into FAEE was tissue dependent. Tissues from pregnant animals given ethanol on gestational d 7 showed persistence of FAEE on gestational d 14. We conclude that: 1 ) human and mouse placentas have significant FAEE synthase activity, 2) mouse heart, liver, placenta, and fetal tissues accumulate significant amounts of FAEE after maternal ethanol exposure, 3) there is tissue specificity for the fatty acid incorporated into FAEE, and 4) FAEE may persist for 7 d in placentas. These results provide a basis for further research into the role of FAEE in the development of fetal alcohol syndrome. (Pediatr Res 31: 492-495, 1992)

Placental Handling of Fatty Acid Ethyl Esters: Perfusion and Subcellular Studies

“…When perfused at an initial concentration of 20 M, linoleic EE was cleared the fastest by the mother, and stearic EE was the species eliminated most slowly from the maternal circulation and also most highly retained by the perfused placenta. This is in agreement with a previous report that showed preferential accumulation of stearic EE by the mouse placenta after maternal ethanol administration (Bearer et al, 1992). This selective retention of individual species and the large unrecoverable fraction of FAEE from the perfusion system suggest differential rates of metabolism (i.e., degradation) of individual FAEE species by placental enzymes.…”

“…Understanding the origin of meconium FAEE is of critical importance in the development of FAEE as biological markers of fetal exposure to ethanol in utero. It has been reported previously that certain FAEE accumulate in various tissues and organs following maternal ethanol administration in mice (Bearer et al, 1992).…”

Stimulation of synaptosomal free radical production by fatty acids: Relation to esterification and to degree of unsaturation

“…The formation of fatty acid ethyl esters after ethanol consumption occurs predominantly in the pancreas and liver, but also within the brain [3]. These esters have been proposed to produce neurological damage perhaps by causing both membrane disordering and disruption of mitochondrial function [4], and their accumulation may be a factor in the pathogenesis of fetal alcohol syndrome [5].…”

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

“…Conversely, the enzymes involved in the non-oxidative metabolism of ethanol are present early in gestation (Bearer et al 1992(Bearer et al , 1995Stanley et al 2005;Krekels et al 2012). Consequently, the non-oxidative pathways of ethanol metabolism may play a compensatory role in early gestation, in the context of alcohol exposure (Zelner and Koren 2013).…”

“…Fatty acid ethyl esters (FAEE) are non-oxidative metabolites formed via the breakdown of ethanol. These metabolites have been established as biomarkers of chronic excessive alcohol use in adults (Auwarter et al 2001;Pragst et al 2001) and in-utero exposure to alcohol (Bearer et al 1992(Bearer et al , 1999Hungund and Gokhale 1994;Klein et al 1999;Caprara et al 2005). FAEE have also been established as mediators of toxicity, because they have been demonstrated to reduce cell proliferation, uncouple oxidative phosphorylation, increase the fragility of lysosomes, decrease protein synthesis, increase the formation of lipid droplets, and incorporate into organic bilayers leading to their disordering Best and Laposata 2003).…”