Experimental Biology and Medicine 230:366-375 (2005)
© 2005 Society for Experimental Biology and Medicine
SYMPOSIA
Genesis of Alcohol-Induced Craniofacial Dysmorphism
Kathleen K. Sulik1
Department of Cell and Developmental Biology and Bowles Center for Alcohol Studies, The University of North Carolina, Chapel Hill, North Carolina 27599
1
To whom requests for reprints should be addressed at
Department of Cell and Developmental Biology and Bowles Center for Alcohol Studies, The University of North Carolina, CB 7090, Chapel Hill, NC 27599. E-mail: mouse{at}camed.unc.edu
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Abstract
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The initial diagnosis of fetal alcohol syndrome (FAS) in the United States was made because of the facial features common to the first cohort of patients. This article reviews the development of an FAS mouse model whose craniofacial features are remarkably similar to those of affected humans. The model is based on short-term maternal treatment with a high dosage of ethanol at stages of pregnancy that are equivalent to Weeks 3 and 4 of human gestation. At these early stages of development, alcohol’s insult to the developing face is concurrent with that to the brain, eyes, and inner ear. That facial and central nervous system defects consistent with FAS can be induced by more "realistic" alcohol dosages as illustrated with data from an oral alcohol intake mouse model in which maternal blood alcohol levels do not exceed 200 mg/dl. The ethanol-induced pathogenesis involves apoptosis that occurs within 12 hrs of alcohol exposure in selected cell populations of Day 7, 8, and 9 mouse embryos. Experimental evidence from other species also shows that apoptosis underlies ethanol-induced malformations. With knowledge of sensitive and resistant cell populations at specific developmental stages, studies designed to identify the basis for these differing cellular responses and, therefore, to determine the primary mechanisms of ethanol’s teratogenesis are possible. For example, microarray comparisons of sensitive and resistant embryonic cell populations have been made, as have in situ studies of gene expression patterns in the populations of interest. Studies that illustrate agents that are effective in diminishing or exacerbating ethanol’s teratogenesis have also been helpful in determining mechanisms. Among these agents are antioxidants, sonic hedgehog protein, retinoids, and the peptides SAL and NAP.
Key Words: craniofacial dysmorphism • fetal alcohol syndrome • oral alcohol intake mouse model • ethanol-induced malformation
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Introduction
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The craniofacial features in individuals severely affected by maternal alcohol abuse were key to the recognition in the 20th century that alcohol is a human teratogen (1–4). As reported by Clarren and Smith (5) in 1978, data compiled on 245 individuals affected with fetal alcohol syndrome (FAS) showed that more than 80% had microcephaly, short palpebral fissures, a hypoplastic philtrum, thin upper vermilion border, and, in infancy, retrognathism. The microcephaly and short palpebral fissures were recognized by these authors to reflect deficient brain and eye size. They also noted that short palpebral fissures are one of the most important physical findings in making the FAS diagnosis. In more than 50% of the patients, the maxilla appeared hypoplastic and the nose was short and upturned, giving "the real or apparent impression that the distance from the alae nasae to the upper lip is long." Cleft lip and cleft palate were occasionally observed. Diagnosis of full-blown FAS remains dependent on the presence of the "typical" facies (Fig. 1a
). Indeed, one of the four key features in a new and increasingly used diagnostic method, the 4-Digit Diagnostic Code, is the facial phenotype (6).
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Figure 1. A child with FAS (a) shares the typical craniofacial features, including microcephaly, short palpebral fissures, a small nose, and long (from nose to mouth) upper lip with a deficient philtrum, with a mouse fetus whose mother was treated with alcohol on her seventh day of pregnancy (b). Illustrated for comparison is a normal mouse fetus of the same developmental stage (c). Modified from Sulik et al. (11).
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It is clear that individuals with the FAS facial phenotype comprise only a portion of the population adversely affected by prenatal maternal alcohol use. As with other teratogenic agents, the amount and frequency of alcohol consumed by the pregnant mother, as well as the stage(s) of pregnancy during which an unborn child is exposed to alcohol, are critical in determining the pattern of abnormal development. Research with a number of animal species has well illustrated this principle.
As early as 1910, Stockard (7) used a fish model to demonstrate the sensitivity of the developing forebrain, eyes, and face to alcohol’s teratogenic effects. Exposure to a 3% solution of alcohol initiated during the four to eight cell stages of development and lasting no more than 36 hrs resulted in very high percentages of fish embryos with microphthalmia or cyclopia and forebrain deficiencies that fall within the spectrum known as holoprosencephaly. More recently, using this same model system, Blader and Strahle (8) showed that alcohol exposure for only 3 hrs beginning at early gastrula stages was sufficient to yield these defects of the brain and face. Studies conducted in several other species, including nonhuman primates (9), provide additional support for very early stages of embryogenesis as being critical for induction of alcohol-induced craniofacial alterations, alterations that are consistent with those in human FAS.
Of course, extrapolation of experimental results from animal models to humans relies on interspecies similarities with respect to morphogenesis and responses to teratogenic insults. Indeed, the recent explosion of knowledge in the field of developmental biology has revealed remarkable interspecies similarities at molecular and cellular levels and at higher levels of embryonic and fetal development. Recognition of these similarities and application of new technological developments are, in turn, fostering the design of experiments that promise to further our understanding of ethanol’s teratogenesis at the mechanistic level.
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Dysmorphogenesis in a Mouse Model for the FAS Face and Brain
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Webster et al. (10) showed, in 1980, that gestational stage-dependent abnormalities of the face and brain could be induced by alcohol in the offspring of C57BL/6J mice. Maternal treatment on Day 7 of pregnancy was reported to result in exencephaly, mandibular hypoplasia, cyclopia, and cleft lip; Day 8 exposures yielded maxillary hypoplasia associated with median cleft lip and cleft palate, as well as occasional mandibular hypoplasia. In those animals with maxillary hypoplasia, abnormalities of the eyes (anophthalmia or microphthalmia) and brain were observed. The alcohol exposure regimen developed by Webster et al. (10), and later applied by others to studies of the embryogenesis of these defects, entails maternal intraperitoneal treatment with two doses of alcohol given during a 4-hr interval on a single day of pregnancy. This treatment results in blood alcohol concentrations (BACs) that peak at approximately 400 mg/dl within 30 mins following the first dose and at 500 mg/dl following the second dose. In this model, BACs remain above 100 mg/dl for approximately 10 hrs.
Sulik et al. (11), in 1981, related the craniofacial malformations induced in mice at stages of embryogenesis that correspond to those occurring in Week 3 of human development to virtually all of those in individuals with full-blown FAS. As illustrated in Figure 1
, comparison of affected versus normal mouse fetuses shows microcephaly, microphthalmia with accompanying short palpebral fissures, and a long upper lip with a deficient philtrum. The degree of severity of the alcohol-induced facial defects in the mice is widely variable. Histologic and scanning electron microscopic analyses illustrated that the defects entail a selected deficiency in the facial tissue between and including the medial nasal prominences. The facial deficiency is directly related to that involving the median forebrain (12, 13). This is readily evident morphologically within 24 hrs of alcohol treatment (14, 15) through embryonic (Fig. 2) and fetal stages, as well as in adult animals (Fig. 3). Forebrain deficiencies observed included hypoplasia or aplasia of the corpus callosum and septal nuclei, hypoplasia of the basal ganglia, and deficiency in the hippocampus and the anterior cingulate cortex (13, 16). Ocular abnormalities, which occur spontaneously in approximately 10% of C57BL/6J mice, are found in nearly half of the offspring of alcohol-exposed dams. Associated with reduced globe size are corneal opacity, anterior segment dysgenesis, microphakia, and persistent hyperplastic primary vitreous (17, 18). In 1982, Sulik and Johnston (12) noted that these defects of the face, brain, and eyes are consistent with the holoprosencephaly spectrum of malformation and suggested that the typical craniofacies of FAS, indeed, are representative of the mild end of this spectrum (Fig. 4). This conclusion is also supported by the work of Webster et al. (19).
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Figure 2. The face and forebrain of a normal gestational Day 11 mouse embryo (a and b) compared with those of three embryos (c and d; e and f; g and h) affected to differing degrees by maternal ethanol treatment on Day 7 of pregnancy illustrate concurrent loss of the "midline" tissues. In particular, note the abnormally close proximity of the nostrils, with absence of portions of the medial nasal prominences (m), as well as similar abnormal proximity of the ganglionic eminences (g) and absence of the septal region (s). Modified from Sulik et al. (13)
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Figure 3. Comparison of the face and frontal section through the brain of a normal (a and c) and abnormal (b and d) C57BL/6J mouse whose mother was treated with alcohol on her seventh day of pregnancy illustrates the same features as pointed out for embryonic stages (see Fig. 2). Loss of the septal region of the brain (s) and a long upper lip (arrows) are particularly evident in the affected animal.
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Figure 4. The facial features of mouse fetuses acutely exposed to alcohol on their seventh day of gestation and showing varying degrees of affect (a, c, and e) can be compared with those of an individual with FAS (b) and those whose defects are recognized as falling within the holoprosencephaly spectrum (d and f). Modified from Sulik et al. (28).
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Alcohol treatment on Day 8 of pregnancy in mice yields craniofacial features that differ from those on Day 7 (Fig. 5). As reported in 1986 by Sulik et al. (20), the abnormalities of the face and accompanying malformations in other organ systems that are caused by short-term alcohol exposure at presomite to early somite stages correspond to those in DiGeorge syndrome. The craniofacial features of this syndrome include micrognathia, a short philtrum, midline clefts in the nose, cleft palate, hypertelorism, and ocular and central nervous system (CNS) abnormalities. Additionally, in mice at this time, (lateral or typical) cleft lip is among the resulting end points (15). The short philtrum and oral clefting is a result, at least in part, of deficiency in the maxillary prominences. In addition to facial defects and CNS abnormalities that involve the forebrain, Day 8 exposure affects the developing inner ear, as well as the hindbrain and its derivatives (21–23).
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Figure 5. Normal fetal (a) and neonatal (d) mouse facies compared with those resulting from gestational Day 7 (b and e) versus Day 8 (c and f) correspond to those of normal (g), "typical" FAS (h), and DiGeorge syndrome facial phenotypes (i), respectively. Modified from Sulik et al. (20).
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Recently, an alcohol exposure regimen that involves maternal oral intake on Days 7 and 8 of pregnancy has been adopted for further analyses of ethanol’s facial and CNS teratogenesis (24). For this work, the alcohol deprivation effect is used to obtain high maternal ethanol intake during this critical developmental period. With peak BACs approaching 200 mg/dl, high incidences of ocular abnormalities are induced in the fetuses. The presence of ocular defects serves as an indicator for those individuals whose CNS is affected and facilitates identification of individuals to be examined in further detail for CNS end points. In addition to being a reasonable model for human exposures, this is a promising system for in vivo investigations of agents or factors that may prevent or exacerbate ethanol’s teratogenesis.
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Pathogenesis and Teratogenic Mechanisms
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In developing organisms, a readily observable condition that results from ethanol exposure is excessive cell death. As early as 1968, Sandor (25) observed ethanol-induced cell death in chick embryos, and in the early 1980s, Bannigan and Burke (26) and Bannigan and Cottell (27) made a similar observation in mouse embryos. Subsequently, use of the vital dyes, Nile blue sulfate, acridine orange, and Lysotracker red has allowed whole-embryo analyses of the extent and pattern of ethanol-induced cell death (21, 22, 28, 29). Correlation of cell death patterns observable within 8–12 hrs following initial ethanol exposure to the dysmorphologic features that follow is striking and strongly supports the premise that cell death is an important component of the pathogenesis underlying ethanol-induced major malformations.
With respect to the typical facial features of FAS and the CNS abnormalities that develop concurrently, cellular loss at the rostral boundary of the preclosure forebrain and of the corresponding cell population that makes up the immediately postclosure telencephalic midline appears to be key (Fig. 6) (22). This population of cells is now termed the anterior neural ridge (ANR) and is known to act during gastrulation and early postgastrulation stages as an organizer for the prosencephalon (30, 31). Extensive fate mapping studies have illustrated the cellular derivatives of the ANR (Fig. 7) (32, 33). Of particular note with respect to FAS is that the epithelium that lines the nasal cavities (i.e., that associated with the medial nasal prominences of the developing face), as well as the commissural plate of the telencephalon form from this progenitor population, a population that is particularly vulnerable to ethanol-induced cell death. As in the mouse model, absence or deficiencies in the corpus callosum occur in humans severely affected by maternal alcohol consumption (34). In the presence of the typical FAS face, it is expected that this results from early loss of the commissural plate.
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Figure 6. Within 8–12 hrs of maternal ethanol treatment, embryos illustrate excessive cell death in the ANR (arrows in d, e, and f) as evidenced by vital staining with Nile blue sulfate (d and e) and Lysotracker red (c and f). This is apparent in embryos at presomite (a and d), early somite (b and e) and neural tube closure (c and f) stages of development. Embryos in (a) and (b) are shown in scanning electron micrographs, whereas that in (c) is a serially reconstructed confocal image of which the image in (f) is a part. Asterisk, developing eye. Modified from Kotch and Sulik (15) and Dunty et al. (22).
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Figure 7. Scanning electron micrographs of a human, gestational Day 21, 4 somite pair embryo (a and b); a human, 25-day, 19–somite pair embryo cut midsagittally (c); and a gestational Day 11 mouse embryo cut midsagittally (d) illustrate the position of the ANR (arrows) and its derivatives. Shown in (b) is a dorsal view of the right half of the anterior neural plate, with the ANR outlined and the position of the progenitors of the anterior commissure (ac), pallial commissure (pc), septum pellucidum (s), and fibria hippocampi (f) indicated. Additionally, the location of telencephalic progenitors for the striatum (st) and pallium (p), as well as the diencephalic progenitors of the optic chiasm (oc), optic stalk (os), and retina (r), are indicated. The dashed line in (b) indicates the approximate division between the telencephalon and diencephalon. White arrow, optic stalk; open arrow, interventricular foramen; d, diencephalon; m, midbrain; h, hindbrain.
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In addition to the ANR, other cell populations of the embryonic face and brain are sensitive to ethanol-induced cell death. These populations include the neural crest, epibranchial placodes, and subpopulations of the otic placodes or vesicles (21, 22, 28, 29). The developmental stage dependency of the cellular vulnerability, coupled with the variable drinking patterns of those individuals who give birth to affected children, to a large extent is expected to account for the wide spectrum of observable defects that comprise FAS disorders.
Knowledge of sensitive developmental stages and cell populations has allowed the design of experiments to elucidate the cellular mechanism(s) of ethanol’s teratogenesis. For example, the sensitivity of neural crest cells has made them a valuable population for in vitro studies; studies in which the ability to diminish ethanol-induced cell death has pointed to free radical damage as an important player (35, 36) and to the peptides SAL and NAP as potential therapeutic agents (37, 38). Also, recognizing differing cellular vulnerabilities has made it possible to design microarray analyses to begin to sort out genetic differences in cells that may confer resistance or sensitivity to ethanol-induced cell death.
No doubt, understanding how alcohol perturbs normal gene expression patterns and signaling cascades is critical to our further understanding of ethanol’s teratogenic mechanism(s). Current data suggest that ethanol exposure causes rapid changes in intracellular calcium (39), an effect that is expected to alter numerous signaling cascades and result in dysmorphogenesis. Among the gene cascades that may be key players for ethanol-induced craniofacial abnormalities are those involving sonic hedgehog (40), a gene whose expression is required at early developmental stages for normal forebrain development; Fgf-8, which is expressed in organizing centers of the brain, including the ANR (41); Pax6, which is critical for normal development of the forebrain and eyes (42–44); and the genes that code for bone morphogenetic proteins that are involved in cell death (apoptosis) signaling and dorsal telencephalic patterning (45–48).
The sensitivity of the embryo at early stages of development to the teratogenic effects of ethanol provides both advantages and disadvantages for scientific investigation. Advantages include the relative simplicity of the early embryo and the tremendous increase in our knowledge regarding normal embryogenesis that can be applied to elucidating the mechanism(s) of insult. A disadvantage is the small amount of tissue that comprises each embryo, making experiments technically demanding and, in some cases, unfeasible.
In conclusion, studies conducted with animal models strongly support the premise that the facial dysmorphism characteristic of FAS results from an insult that concurrently affects the developing forebrain and eyes. The dysmorphism ranges widely in terms of severity, with the most subtle defects being hard to distinguish from normal. For those individuals who are affected by early gestational alcohol exposure and in whom the facial appearance is unremarkable, it is expected that even a relatively minor loss of forebrain progenitors may have important consequences to subsequent CNS function. In this light, much more work needs to be performed to define the full range of effects on the brain that result from alcohol exposure at times equivalent to the third and fourth weeks of human pregnancy.
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Top
Abstract
Introduction
