The fetal alcohol syndrome in mice: an animal model

CBA and C3H female mice were maintained on liquid diets--Metrecal plus ethanol--containing 15-35% ethanol-derived calories. These diets, which resulted in alcohol blood levels of 73-398 mg/100 ml blood in nonpregnant females, were the sole sustenance for the females for at least 30 days before and throughout gestation. Females were killed on day 18 of gestation and offspring examined for skeletal and soft tissue anomalies. Prenatal death and maldevelopment increased with the level of alcohol intake. Deficient occiput ossification, neural anomalies, and low fetal weight occurred with low ethanol diets, and cardiac and eye-lid dysmorphology with higher ethanol diets. This pattern of malformations, which exhibited both a dose-response effect and strain differences in susceptibility, indicated that chronic maternal alcoholism is embryolethal and teratogenic in mice.     

Polymicrogyria in fetal alcohol syndrome

BACKGROUND: Intrauterine exposure to alcohol may result in a distinct pattern of craniofacial abnormalities and central nervous system dysfunction, designated fetal alcohol syndrome (FAS). The spectrum of malformations of the brain associated with maternal alcohol abuse during pregnancy is much broader than the relatively uniform clinical phenotype of FAS. Among these malformations the most striking abnormalities involve the impairment of neuronal cell migration. However, polymicrogyria (PMG) has so far been reported only once in a human autopsy study of a child with FAS. CASE: A 16‐year‐old girl with confirmed maternal alcohol consumption during pregnancy and full phenotype of FAS presented after two generalized epileptic seizures for neurologic assessment. Cranial magnetic resonance imaging revealed bilateral PMG in the superior frontal gyrus with asymmetric distribution. History, clinical features, and genetic investigations provided no evidence for any of the known genetic or acquired causes of PMG. Therefore, we propose that prenatal alcohol exposure is the cause of PMG in this patient rather than a mere coincidence. CONCLUSION: Our observation represents only the second patient of PMG in FAS and confirms the phenotypic variability of cerebral malformations associated with maternal alcohol abuse during pregnancy. In patients with clinical features of FAS and neurologic deficits or seizures neuroimaging is recommended. Furthermore, FAS should be considered as a differential diagnosis for PMG. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

A periodic dosing model of fetal alcohol syndrome in the pig-tailed macaque (Macaca nemestrina)

A nonhuman primate on a periodic ethanol dosing schedule should provide a model of fetal alcohol syndrome (FAS) most relevant to the majority of pregnant women who are “social drinkers” and can exercise reasonable control over their ethanol intake. In this pilot study, four pregnant pig-tailed macaques (Macaca nemestrina) received ethanol once a week from 40 days' gestation. Doses were 2.5 gm/kg for three moderate-dose animals (MDAs) and 4.1 gm/kg for one high-dose animal (HDA). Peak blood ethanol levels reached a mean of 240–256 mg/dl for the MDAs and averaged 379 mg/dl for the HDA. Peak acetaldehyde did not vary with dose. One MDA aborted after the first dose. The other three pregnancies were compared with eight to ten control pregnancies, and the infants' development over the first six months was compared with that of the control offspring. Nutritional status of the pregnant females was normal. The fetal heart rate response to maternal restraint was absent in the HDA. Gestational duration and simian Apgar scores were normal. All three infants were abnormally large, and two were also abnormally heavy, with body weight appropriate to skeletal size. Skeletal maturation, judged by ossification and tooth eruption, was not accelerated. The high-dose infant (HDI) was scaphocephalic, with an underdeveloped cranial base and midface, and its brain was small and dysplastic; its reflex, motor, and cognitive development were retarded. One moderate-dose infant (MDI) had some brain abnormalities; it was hyperkinetic and showed developmental retardation on several behavioral measures. The other MDI was normal. We conclude that the periodic model offers an effective means of investigating FAS in M. nemestrina. Furthermore, when nutrition is maintained, intermittent intake of ethanol by the pregnant primate does not necessarily reatard fetal growth.     

Genetic polymorphisms: impact on the risk of fetal alcohol spectrum disorders

Clinical reports on monozygotic and dizygotic twins provided the initial evidence for the involvement of genetic factors in risk vulnerability for fetal alcohol spectrum disorders (FASD) including fetal alcohol syndrome (FAS). Research with selectively bred and inbred rodents, genetic crosses of these lines and strains, and embryo culture studies have further clarified the role of both maternal and fetal genetics in the development of FASD. Research to identify specific polymorphisms contributing to FASD is still at an early stage. To date, polymorphisms of only one of the genes for the alcohol dehydrogenase enzyme family, the ADH1B, have been demonstrated to contribute to FASD vulnerability. In comparison with ADH1B*1, both maternal and fetal ADH1B*2 have been shown to reduce risk for FAS in a mixed ancestry South African population. ADH1B*3 appears to afford protection for FASD outcomes in African-American populations. Other candidate genes should be examined with respect to FASD risk, including those for the enzymes of serotonin metabolism, in particular the serotonin transporter. By its very nature, alcohol teratogenesis is the expression of the interaction of genes with environment. The study of genetic factors in FASD falls within the new field of ecogenetics. Understanding of the array of genetic factors in FASD will be enhanced by future genetic investigations, including case-control, family association, and linkage studies.     

Screening for fetal alcohol syndrome in primary schools: a feasibility study

BACKGROUND: This project was undertaken as a feasibility study to determine the possibility of screening for fetal alcohol syndrome (FAS) in early school-age children for epidemiological and interventional purposes. METHODS: All elementary schools in two counties in Washington State were asked to screen first graders for possible FAS. A child was screen positive if found to be growth deficient, to have certain specific facial abnormalities, or have a known history of substantial alcohol exposure in gestation. All screen-positive children were invited to "special diagnostic clinics" for final diagnosis and treatment planning. RESULTS: In County A, virtually all students were screened. In County B only about 25% of children were screened. This difference was related to the number of schools that agreed to participate in the project and the methods employed by each county to obtain parental permission. In each county, only about one-half of the screen-positive children were seen in the special clinics for diagnostic considerations. Only one of the seven children found to have FAS had been diagnosed previously. The minimal prevalence of FAS in County A was 3.1 in 1,000 students. The minimal prevalence of FAS in County B could not be calculated. The most efficient component in the screening process leading to a diagnosis of FAS was finding the specific facial features of the disorder. The diagnosis of FAS was generally helpful in improving educational planning. CONCLUSIONS: This study demonstrated that population-based FAS screening within a school system may be possible, but participation is dependent on local trust and understanding of the project before its inception within the schools and the community at large.     

Vasoactive intestinal peptide mRNA and immunoreactivity are decreased in fetal alcohol syndrome model

Vasoactive intestinal peptide (VIP) regulates growth in the early post-implantation embryo. Previous work has demonstrated that peptide agonists (SALLRSIPA and NAPVSIPQ) from downstream mediators that are regulated by VIP were able to prevent the alcohol-induced fetal death, growth restriction and microcephaly associated with fetal alcohol syndrome. Here we evaluated the role of VIP in this mouse model of fetal alcohol syndrome, to determine if fetal or maternal levels of VIP are altered. In addition, we evaluated whether peptide treatment would alter the effects of alcohol on VIP levels. Treatment groups included control, alcohol, and alcohol+peptides. VIP levels were measured with enzyme immunoassay [EIA] (Peninsula Laboratories, Belmont, CA). Quantitation of VIP expression was measured with rt-PCR using mimic cDNA primers. Embryo/decidual VIP levels were similar in control and alcohol-treated groups 6 h after treatment. However, in the embryo/deciduas at 12 and 24 h, VIP levels were below the EIA's detection limit in the alcohol-treated groups, and significantly lower than the control or peptide-pretreated groups (p<0.05). Maternal cortex VIP levels were undetectable and significantly lower in the alcohol-treated group than control or peptide+alcohol group at 6 and 12 h (p<0.001). VIP mRNA expression was quantitated in the embryo and deciduas, with a significant decline noted at 6 h to 58% of control levels (p=0.02). Pretreatment with the peptides attenuated the alcohol-induced decrease in VIP mRNA. These studies demonstrate that treatment with alcohol can decrease the expression and immunoreactivity of VIP in both maternal and fetal tissues. This alcohol-induced loss of a recognized regulator of embryonic growth and differentiation may contribute to the sequelae of toxicity observed in fetal alcohol syndrome.     

Abortion is incommensurable with fetal alcohol syndrome

A recent article argued for the immorality of abortion regardless of personhood status by comparing the impairment caused by fetal alcohol syndrome to the impairment caused by abortion. I argue that two of the premises in this argument fail and that, as such, one cannot reasonably attribute moral harms to abortion on the basis of the moral harms caused by fetal alcohol syndrome. The impairment argument relies on an inconsistent instantiation, which undermines the claim that personhood is irrelevant, and it does not fulfill its own ceteris paribus clause, which demands that no additional benefit be gained from abortion that would not be gained from causing fetal alcohol syndrome.     

Impaired development of mitochondria plays a role in the central nervous system defects of fetal alcohol syndrome

BACKGROUND: Alcohol consumption during pregnancy can induce a wide spectrum of adverse effects in offspring. Microcephaly and mental retardation are two major defects of central nervous system (CNS). Most mechanism studies of alcohol-related CNS defects have been focused on the morphologically abnormal tissues, and more attention has been paid to nuclear alteration as opposed to organelle development. METHODS: A mouse model of fetal alcohol syndrome (FAS) was used to investigate the effect of alcohol on fetal cerebral mitochondria development. Pregnant mice were given different doses of ethanol intragastrically from GD6 to GD15. Fetal cerebral mitochondria were isolated and analyzed on GD18. RESULTS: Excessive cell apoptosis was found in the cerebra of prenatal alcohol exposure fetuses. Proliferation and differentiation of fetal cerebral mitochondria were inhibited by alcohol. Affected mitochondrial volume constriction and adenosine triphosphate (ATP) accumulation, reduced activities of respiratory chain complex I and IV and ATP synthase were detected in the cerebral tissue without obvious malformed appearance. CONCLUSIONS: Impaired mitochondria development plays a role in the CNS defects induced by prenatal alcohol exposure.     

Craniofacial and oral manifestations of fetal alcohol syndrome

Six representative patients with fetal alcohol syndrome (FAS) were studied for craniofacial and oral anomalies, dental development, and long-term bodily growth patterns. The craniofacial features observed were reduction of total head size, increased head-body ratio, the existence of upper and middle craniofacial asymmetry and telecanthus in some instances, and the features of a long face syndrome with a large gonial angle. Dental development was mildly to moderately delayed, and enamel anomalies were present. Analysis of growth patterns demonstrated compensatory growth in stature, weight, or head circumference and a delayed bone age in some instances. It is suggested that the semiquantitative score system for fetal alcohol syndrome study may fail to diagnose individual cases and that craniofacial features are more important in diagnosis than seems to have been appreciated in the past.     

The Klippel-Feil anomalad as part of the fetal alcohol syndrome

A brother and sister and described with malformations and handicaps consistent with both the Klippel-Feil Anomalad and the Fetal Alcohol Syndrome. The mother was known to be a chronic alcholic throughout both pregnancies. It is suggested that these anomalies are not purely fortuitous but rather that maternal alcoholism may cause errors in cervical vertebrae segmentation.