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.     

The effects of alcohol on fetal development

Prenatal exposure to alcohol has profound effects on many aspects of fetal development. Although alterations of somatic growth and specific minor malformations of facial structure are most characteristic, the effects of alcohol on brain development are most significant in that they lead to substantial problems with neurobehavioral development. Since the initial recognition of the fetal alcohol syndrome (FAS), a number of important observations have been made from studies involving both humans and animals. Of particular importance, a number of maternal risk factors have been identified, which may well be of relevance relative to the development of strategies for prevention of the FAS as well as intervention for those who have been affected. These include maternal age >30 years, ethnic group, lower socioeconomic status, having had a previously affected child, maternal under-nutrition, and genetic background. The purpose of this review is to discuss these issues as well as to set forth a number of questions that have not adequately been addressed relative to alcohol's effect on fetal development. Of particular importance is the critical need to identify the full spectrum of structural defects associated with the prenatal effects of alcohol as well as to establish a neurobehavioral phenotype. Appreciation of both of these issues is necessary to understand the full impact of alcohol on fetal development.     

Developing ways of reducing allograft immunogenicity.

Heavy alcohol consumption by the mother during pregnancy has long been suspected of being a risk factor for abnormalities in the fetus or infant. Only during the last decade have these assumptions been supported by scientific studies. A clustering of fetal defects observed in some cases has been labelled the fetal alcohol syndrome. The syndrome involves prenatal and postnatal growth retardation, central nervous system involvement and craniofacial abnormalities, some of which are characteristic of the syndrome. Fetal alcohol syndrome is relatively rare, affecting from 1 in 300 to 1 in 2000 infants; approximately 450 cases have been reported since the syndrome was identified. Despite this rarity, however, heavy alcohol consumption is an important risk factor during pregnancy. A review of the current literature indicates that in animals alcohol in high doses is embryotoxic and teratogenic, the heavy drinking is not uncommon before and during pregnancy and that the fetal alcohol syndrome and other effects on the fetus associated with alcohol abuse appear with significant frequency among mothers who drink heavily. Heavy alcohol consumption is a perinatal risk factor that not only can be detected by the physician, but also can be reduced in concerned, cooperative patients. Thus, awareness of this problem gives health care personnel an opportunity to help in the prevention of abnormal outcomes of pregnancy.     

Retinoic acid signaling reduction recapitulates the effects of alcohol on embryo size

Intrauterine growth restriction (IUGR) is commonly observed in human pregnancies and can result in severe clinical outcomes. IUGR is observed in Fetal Alcohol Syndrome (FAS) fetuses as a result of alcohol (ethanol) exposure during pregnancy. To further understand FAS, the severe form of Fetal Alcohol Spectrum Disorder, we performed an extensive quantitative analysis of the effects of ethanol on embryo size utilizing our Xenopus model. Ethanol‐treated embryos exhibited size reduction along the anterior–posterior axis. This effect was evident primarily from the hindbrain caudally, while rostral regions appeared refractive to ethanol‐induced size changes, also known as asymmetric IUGR. Interestingly, some embryo batches in addition to shortening from the hindbrain caudally also exhibited an alcohol‐dependent reduction of the anterior head domain, known as symmetric IUGR. To study the connection between ethanol exposure and reduced retinoic acid levels we treated embryos with the retinaldehyde dehydrogenase inhibitors, DEAB and citral. Inhibition of retinoic acid biosynthesis recapitulated the growth defects induced by ethanol affecting mainly axial elongation from the hindbrain caudally. To study the competition between ethanol clearance and retinoic acid biosynthesis we demonstrated that, co‐exposure to alcohol reduces the teratogenic effects of treatment with retinol (vitamin A), the retinoic acid precursor. These results further support the role of retinoic acid in the regulation of axial elongation.     

Nesfatin-1 Ameliorate Learning and Memory Deficit via Inhibiting Apoptosis and Neuroinflammation Following Ethanol-Induced Neurotoxicity in Early Postnatal Rats

International Journal of Peptide Research and Therapeutics - Fetal exposure to alcohol can cause a wide range of long-lasting physiological and behavioral effects, collectively referred to as fetal...     

Ethanol-induced face-brain dysmorphology patterns are correlative and exposure-stage dependent

Prenatal ethanol exposure is the leading preventable cause of congenital mental disability. Whereas a diagnosis of fetal alcohol syndrome (FAS) requires identification of a specific pattern of craniofacial dysmorphology, most individuals with behavioral and neurological sequelae of heavy prenatal ethanol exposure do not exhibit these defining facial characteristics. Here, a novel integration of MRI and dense surface modeling-based shape analysis was applied to characterize concurrent face-brain phenotypes in C57Bl/6J fetuses exposed to ethanol on gestational day (GD)7 or GD8.5. The facial phenotype resulting from ethanol exposure depended upon stage of insult and was predictive of unique patterns of corresponding brain abnormalities. Ethanol exposure on GD7 produced a constellation of dysmorphic facial features characteristic of human FAS, including severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum. In contrast, ethanol exposure on GD8.5 caused mild midfacial hypoplasia and palpebral fissure shortening, a shortened upper lip, and a preserved philtrum. These distinct, stage-specific facial phenotypes were associated with unique volumetric and shape abnormalities of the septal region, pituitary, and olfactory bulbs. By demonstrating that early prenatal ethanol exposure can cause more than one temporally-specific pattern of defects, these findings illustrate the need for an expansion of current diagnostic criteria to better capture the full range of facial and brain dysmorphology in fetal alcohol spectrum disorders.     

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.     

Morphometric analysis of the craniofacial development of the CD-1 mouse fetus exposed to alcohol on gestational day eight

Fetal alcohol syndrome (FAS) describes a pattern of dysmorphogenesis observed in some offspring of women who consumed alcohol during pregnancy; partial expression of this pattern are fetal alcohol effects (FAE). The purpose of this investigation was to measure selected craniofacial parameters in the CD-1 mouse fetus following exposure to alcohol on gestational day (D) 8. CD-1 mice were mated for 1 hr; D0.0 designated by the presence of a vaginal plug. On D8, 0 hr, and D8, 4 hr, 33 dams were injected intraperitoneally (IP) with 25% (v/v) alcohol in physiological saline solution (0.015 ml/gm maternal body weight). Appropriate controls were maintained. The animals were sacrificed every 12 hr from D12.0 through D17.0. Implantation sites were examined and recorded as live, dead, or resorbed fetuses. All live fetuses were weighed, examined for gross defects, and fixed in Bouin's solution. Twenty-three bilateral parameters were recorded for linear dimensions defining face and cranium. The fetal weights were statistically lower in treated as compared to control fetuses only on D16.0 through D17.0. Statistical analysis of the morphometrics identified five distinct growth patterns in treated mice as compared to controls. The anomalies induced in the CD-1 mouse fetus following exposure to alcohol on D8.0 resembled FAE rather than FAS. Morphometric analysis of the craniofacial region may be an important clinical tool for the quantitative identification of alcohol-related effects in the offspring of women who consumed alcohol while pregnant.     

Teratogenic effects of alcohol and isotretinoin on craniofacial development: an analysis of animal models.

The teratogens alcohol and isotretinoin cause different patterns of facial dysmorphogenesis in the human. For isotretinoin the pattern is consistent with interference with the normal development of the cranial neural crest, particularly that destined for the second visceral arch. In vitro studies in the rat indicate that, at threshold levels of exposure to isotretinoin, the development of the second arch crest represents the most sensitive process of organogenic development. For alcohol, the facial abnormalities result from exposure very early in development, during the gastrulation process. There is no evidence that this is a peculiarly sensitive stage of development with respect to alcohol; animal studies indicate that other processes in the organogenic period are equally or more vulnerable. The emphasis given to the abnormal facial features in the fetal alcohol syndrome is considered a phenomenon associated with the exclusivity of syndromes.     

Construction of Vapor Chambers Used to Expose Mice to Alcohol During the Equivalent of all Three Trimesters of Human Development

Exposure to alcohol during development can result in a constellation of morphological and behavioral abnormalities that are collectively known as Fetal Alcohol Spectrum Disorders (FASDs). At the most severe end of the spectrum is Fetal Alcohol Syndrome (FAS), characterized by growth retardation, craniofacial dysmorphology, and neurobehavioral deficits. Studies with animal models, including rodents, have elucidated many molecular and cellular mechanisms involved in the pathophysiology of FASDs. Ethanol administration to pregnant rodents has been used to model human exposure during the first and second trimesters of pregnancy. Third trimester ethanol consumption in humans has been modeled using neonatal rodents. However, few rodent studies have characterized the effect of ethanol exposure during the equivalent to all three trimesters of human pregnancy, a pattern of exposure that is common in pregnant women. Here, we show how to build vapor chambers from readily obtainable materials that can each accommodate up to six standard mouse cages. We describe a vapor chamber paradigm that can be used to model exposure to ethanol, with minimal handling, during all three trimesters. Our studies demonstrate that pregnant dams developed significant metabolic tolerance to ethanol. However, neonatal mice did not develop metabolic tolerance and the number of fetuses, fetus weight, placenta weight, number of pups/litter, number of dead pups/litter, and pup weight were not significantly affected by ethanol exposure. An important advantage of this paradigm is its applicability to studies with genetically-modified mice. Additionally, this paradigm minimizes handling of animals, a major confound in fetal alcohol research.     

Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

Assessing Teratogenic Changes in a Zebrafish Model of Fetal Alcohol Exposure

Fetal alcohol syndrome (FAS) is a severe manifestation of embryonic exposure to ethanol. It presents with characteristic defects to the face and organs, including mental retardation due to disordered and damaged brain development. Fetal alcohol spectrum disorder (FASD) is a term used to cover a continuum of birth defects that occur due to maternal alcohol consumption, and occurs in approximately 4% of children born in the United States. With 50% of child-bearing age women reporting consumption of alcohol, and half of all pregnancies being unplanned, unintentional exposure is a continuing issue². In order to best understand the damage produced by ethanol, plus produce a model with which to test potential interventions, we developed a model of developmental ethanol exposure using the zebrafish embryo. Zebrafish are ideal for this kind of teratogen study^3-8. Each pair lays hundreds of eggs, which can then be collected without harming the adult fish. The zebrafish embryo is transparent and can be readily imaged with any number of stains. Analysis of these embryos after exposure to ethanol at different doses and times of duration and application shows that the gross developmental defects produced by ethanol are consistent with the human birth defect. Described here are the basic techniques used to study and manipulate the zebrafish FAS model.     

Health care burden and cost associated with fetal alcohol syndrome: based on official canadian data

Background

Fetal Alcohol Spectrum Disorder (FASD) is a group of disorders caused by prenatal alcohol exposure. From this group, Fetal Alcohol Syndrome (FAS) is the only disorder coded in the International Classification of Diseases, version 10 (ICD-10). This coding was used to gain an understanding on the health care utilization and the mortality rate for individuals diagnosed with FAS, as well as to estimate the associated health care costs in Canada for the most recent available fiscal year (2008–2009).

Methods

Health care utilization data associated with a diagnosis of FAS were directly obtained from the Canadian Institute for Health Information (CIHI). Mortality data associated with a diagnosis of FAS were obtained from Statistics Canada.

Results

The total direct health care cost of acute care, psychiatric care, day surgery, and emergency department services associated with FAS in Canada in 2008–2009, based on the official CIHI data, was about $6.7 million. The vast majority of the most responsible diagnoses, which account for the majority of a patient’s length of stay in hospital, fall within the ICD-10 category Mental and Behavioural Disorders (F00–F99). It was evident that the burden and cost of acute care hospitalizations due to FAS is increasing −1.6 times greater in 2008–2009, compared to 2002–2003. The mortality data due to FAS, obtained from Statistics Canada (2000–2008), may be underreported, and are likely invalid.

Discussion

The official data on the utilization of health care services by individuals diagnosed with FAS are likely to be underreported and therefore, the reported cost figures are most likely underestimated. The quantification of the health care costs associated with FAS is crucial for policy developers and decision makers alike, of the impact of prenatal alcohol exposure, with the ultimate goal of initiating preventive interventions to address FASD.     

Effects of hyperthermia on fetal breathing movements

High environmental temperature is known to impair fetal growth and development. We now report long lasting changes in fetal breathing activity following the exposure of pregnant ewes to an ambient temperature of 43 degrees C for 8 h. In 16 trials in 10 ewes (119-138 days gestation) heat exposure increased maternal and fetal core temperatures 1.5-2.0 degrees C, and the hyperventilation by the ewe produced a fall in fetal PaCO2 from 53.5 +/- 1.3 to 34.8 +/- 5.3 mmHg (P less than 0.05). Fetal breathing movements decreased in incidence during the hyperthermia but remained episodic (present during low-voltage electrocortical activity) with occasional brief episodes of breathing at high rates (greater than 4 breaths/s). However, 1-2 h after the end of heating, when maternal and fetal core temperature and PaCO2 had returned to normal, fetal breathing movements became continuous, and were augmented 30-100% in amplitude. Fetal breathing movements occurred during both low- and high-voltage electrocortical activity. The results show that a heat load similar to that experienced by sheep in sub-tropical regions in the summer months cause prolonged changes in the central regulation of fetal breathing.     

Effects of a single administration of prostaglandin F2alpha, or a combination of prostaglandin F2alpha and prostaglandin E2, or placebo on fertility variables in dairy cows 3–5 weeks post partum, a randomized, double-blind clinical trial

In female mammals, including humans, deviations from normal androgenic or estrogenic exposure during fetal development are detrimental to subsequent adult ovarian function. Androgen deficiency, without accompanying estrogen deficit, has little apparent impact on ovarian development. Fetal estrogen deficiency, on the other hand, results in impaired oocyte and follicle development, immature and abnormal adult ovaries, and excessive ovarian stimulation from endogenous gonadotropins ultimately generating hemorrhagic follicles. Complete estrogen deficiency lasting into adulthood results in partial ovarian masculinization. Fetal androgen excess, on the other hand, mediated either by direct androgen action or following androgen aromatization to estrogen, reprograms ovarian development and reproductive neuroendocrinology to mimic that found in women with polycystic ovary syndrome: enlarged, polyfollicular, hyperandrogenic, anovulatory ovaries with accompanying LH hypersecretion. Oocyte developmental competence is also compromised. Insulin is implicated in the mechanism of both anovulation and deficient oocyte development. Fetal estrogen excess induces somewhat similar disruption of adult ovarian function to fetal androgen excess. Understanding the quality of the fetal female sex steroid hormone environment is thus becoming increasingly important in improving our knowledge of mechanisms underlying a variety of female reproductive pathologies.     

In utero-initiated cancer: the role of reactive oxygen species

It is becoming more evident that not only can drugs and environmental chemicals interfere with normal fetal development by causing structural malformations, such as limb defects, but that xenobiotic exposure during development can also cause biochemical and functional abnormalities that may ultimately lead to cancer later on in life. Fetal toxicity may be partly mediated by the embryonic bioactivation of xenobiotics to free radical intermediates that can lead to oxidative stress and potentially lead, in some cases, to carcinogenesis. Using a number of examples, this review will focus on the role of reactive oxygen species (ROS) in the mechanisms pertaining to in utero initiated cancers.     

Prenatal alcohol exposure triggers ceramide-induced apoptosis in neural crest-derived tissues concurrent with defective cranial development

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy. The reason why specific embryonic tissues are sensitive toward ethanol is not understood. We found that in neural crest-derived cell (NCC) cultures from the first branchial arch of E10 mouse embryos, incubation with ethanol increases the number of apoptotic cells by fivefold. Apoptotic cells stain intensely for ceramide, suggesting that ceramide-induced apoptosis mediates ethanol damage to NCCs. Apoptosis is reduced by incubation with CDP-choline (citicoline), a precursor for the conversion of ceramide to sphingomyelin. Consistent with NCC cultures, ethanol intubation of pregnant mice results in ceramide elevation and increased apoptosis of NCCs in vivo. Ethanol also increases the protein level of prostate apoptosis response 4 (PAR-4), a sensitizer to ceramide-induced apoptosis. Prenatal ethanol exposure is concurrent with malformation of parietal bones in 20% of embryos at day E18. Meninges, a tissue complex derived from NCCs, is disrupted and generates reduced levels of TGF-β1, a growth factor critical for bone and brain development. Ethanol-induced apoptosis of NCCs leading to defects in the meninges may explain the simultaneous presence of cranial bone malformation and cognitive retardation in FAS. In addition, our data suggest that treatment with CDP-choline may alleviate the tissue damage caused by alcohol.