Rev. Neurosci. 2014; 25(5): 631–639
Ioannis Bakoyiannis*, Eleana Gkioka, Vasileios Pergialiotis, Ioanna Mastroleon, Anastasia Prodromidou, Georgios D. Vlachos and Despina Perrea
Fetal alcohol spectrum disorders and cognitive functions of young children Abstract: Fetal alcohol spectrum disorder (FASD) is one of the main causes of mental retardation worldwide. Nearly 1% of children in North America are affected from antenatal exposure to ethanol. Its economic burden in industrialized countries is increasing. It is estimated that, in the United States, 4.0 billion dollars are annually expended in the treatment and rehabilitation of these patients. As a pathologic entity, they present with a broad symptomatology. Fetal alcohol syndrome (FAS) is the most readily recognized clinical manifestation of these disorders. Various factors seem to contribute in the pathogenesis of FASD-related cognitive disorders. During the last 20 years, several potential pretranslational and posttranslational factors have been extensively studied in various experimental animal models. Research has specifically focused on several neurotransmitters, insulin resistance, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, abnormal glycosylation of several proteins, oxidative stress, nutritional antioxidants, and various epigenetic factors. The purpose of the present review is to summarize the clinical manifestations of this disorder during childhood and adolescence and to summarize the possible pathophysiologic and epigenetic pathways that have been implicated in the pathophysiology of FASD. Keywords: alcohol; cognitive; FASD. DOI 10.1515/revneuro-2014-0029 Received April 14, 2014; accepted May 29, 2014; previously published online June 28, 2014
*Corresponding author: Ioannis Bakoyiannis, Laboratory of Experimental Surgery and Surgical Research ‘N.S. Christeas’, National and Kapodistrian University of Athens Medical School, Agiou Thoma 15B, GR-11527 Athens, Greece, e-mail: [email protected] Eleana Gkioka, Vasileios Pergialiotis, Ioanna Mastroleon, Anastasia Prodromidou, Georgios D. Vlachos and Despina Perrea: Laboratory of Experimental Surgery and Surgical Research ‘N.S. Christeas’, National and Kapodistrian University of Athens Medical School, Agiou Thoma 15B, GR-11527 Athens, Greece
Introduction Fetal alcohol spectrum disorders (FASD) are considered as the leading nonhereditary cause of mental retardation in Western civilization, with fetal alcohol syndrome (FAS) being their main representative. FAS has a reported prevalence that ranges between 1 and 7 per 1000 live-born infants in the United States (May et al., 2009). These disorders were first identified by Sullivan back in 1899 (Niccols, 2007). However, they were not investigated until the late 1970s. The main causative factor of the syndrome is prenatal-antenatal ethanol exposure, which is considered to be teratogenic. Ethanol crosses the placenta and affects organogenesis and embryonic development (Niccols, 2007). FASD patients may present with a variety of signs and symptoms. Both developmental abnormalities as well as neurological and functional manifestations have been described in the international literature. Interestingly, however, the majority of antenatally exposed children does not develop FASD. According to an early study, only heavily drinking mothers have the possibility to bear a child with mental retardation with an incidence that varies between 1% and 50% (Burd and Martsolf, 1989). A recent meta-analysis, however, suggested that pregnant women should completely abstain from alcohol consumption, as it seems that even mild binge drinking might hinder child cognition (Flak et al., 2014). The same researchers conclude in this context that there seems to be a lack of compelling evidence regarding the actual cutoff value of alcohol consumption that could prove to be harmless to the fetus. Besides its clinical implications, FASD poses also a significant economic burden for countries. In Canada, it is estimated that the treatment of children who are affected by FASD costs 5.3 billion dollars per year (Stade et al., 2009). In the United States, the annual cost estimates were augmented from 75 million dollars in 1984 to 4 billion dollars in 1998 (Lupton et al., 2004). The same researchers also observed that every day six to 22 of born fetuses suffer from FAS, rendering the disease an epidemic for this country. The purpose of the present review is to summarize the clinical manifestations of these disorders during childhood
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
632 I. Bakoyiannis et al.: FASD and cognitive disorders and to present the pathophysiologic and genetic pathways that lead to the occurrence of these symptoms.
patients with FASD might present visual/spatial disabilities such as impairment of spatial recognition and spanning.
Clinical manifestations
Cognitive manifestations Language skills
Structural manifestations Recent studies have proposed that the brain of people with FASD develops morphologic abnormalities (Clarren and Smith, 1978; Lebel et al., 2008). According to Lebel et al. (2008), the brain volume of patients suffering from FASD is decreased compared to that of healthy controls. Recent studies also revealed that certain regions of the parietal lobe and the ventral frontal lobe are denser in gray matter and are poorly developed, an effect that seems to be exaggerated in the left hemisphere of the brain (Sowell et al., 2001a,b, 2002). In a recent report, Sowell et al. (2008) observed that the cerebral cortex of children and adolescents suffering from FASD was thicker compared to that of normally developing controls. The thicker parts were those of the temporal lobe, the inferior parietal lobe, and the right frontal lobe. Contradictive results were, however, reported by Zhou et al. (2011), which observed a reduction of cortical mass in all four brain lobes (frontal, parietal, temporal, and occipital) among patients suffering from FASD. Previous studies have suggested that cortical thinning might be the result of inhibition of synaptogenesis, which finally provokes programmed cell death (Lovinger et al., 1989; Ikonomidou et al., 2000). This apoptotic neurodegeneration could explain the reduced cortical mass and the clinical manifestations accompanying FASD. The findings of these later studies were also reproduced in experimental animal studies, where a decrease on the absolute number of neurons of the somatosensory cortex has been observed after antenatal exposure to ethanol (Miller, 2007; Aronne et al., 2008).
Neurological manifestations Patients suffering from FASD may present with a variety of neurological symptoms. In a recent retrospective study, researchers observed that the prevalence of epilepsy and seizures among FASD patients reached 5.9% and 11.8%, respectively (Bell et al., 2010). Motor disabilities have also been observed, including abnormal gait and clumsiness, and seem to arise from impairment of both the central nervous system (CNS) and the peripheral nervous system (Marcus, 1987). Mattson et al. (2010) also suggested that
Studies engaging with the ethanol-induced language problems are limited in the international literature. However, all of them state that children with FASD are having both receptive and expressive language deficits (McGee et al., 2009). Coggins et al. (2007) observed that these deficits altered the social communication of these children at the age of 12. Previously, Becker et al. (1990) proposed that children with FASD have impaired grammar and vocabulary skills, which, consequently, hinder language comprehension. Such problems are frequent among cases with mental disorders and indicate a delay in FASD children’s brain development. They also seem to persist even among teenagers, impairing ‘higher-level language skills’ such as narration (Thorne et al., 2007). According to McGee et al. (2009), the incidence of FASD is dependent to the prenatal levels of ethanol. In this context, May et al. (2013) assumed that the varying symptomatology of FASD might be affected by the quantity, frequency, and timing of alcohol consumption, which differ among parous women.
Social behavior The language deficits presented among children suffering from FASD often contribute to their social rejection (Redmond and Rice, 1998). It is well recognized that language skills are of vital importance during the development of interpersonal relationships. Peer acceptance, which is obtained through the processes of speaking, listening, and comprehending, is essential in order to develop a normal behavior, while peer denial leads to further behavioral abnormalities in adult life (Wadman et al., 2008). Therefore, it is important to handle patients with FASD taking in mind their social inabilities, even among cases with legal implications (Fast and Conry, 2009).
Memory function Learning and memory functions are also affected by ethanol. Several studies have addressed the pathophysio logic process that underlies this clinical observation,
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 633
concentrating in the hippocampus and especially to its potential dysfunction (Squire, 1992; Hamilton et al., 2002). The Morris water task (MWT) has been used in order to assess learning and memory functions, as it is a representative index in rodents, which is also used in humans (virtual MWT or VMWT) (Sutherland et al., 1997). Children antenatally exposed to alcohol seem to have deficits in spatial and working memory (Berman and Hannigan, 2000; Green et al., 2009). Patients with FASD have difficulties in absorbing or recalling information, which is not always correlated to lower IQ scores, and function of attention is influenced, though (Burden et al., 2005; O’Hare et al., 2009). This is accompanied by altered glutamatergic transmission and long-term potentiation (LTP) of hippocampal neuronal synapses. These alterations in the hippocampal physiology are mainly depicted either as a decrease of the spinal density of pyramidal hippocampal dendrites or as an alteration of their pattern (Berman and Hannigan, 2000). Hippocampal impairments are associated with difficulties in the VMWT based on the results of neuroimaging techniques (Goodrich-Hunsaker et al., 2010). These findings were also confirmed by Hamilton et al. (2002), which observed that children suffering from FASD need more time to find the hidden platform of the VMWT, because they take longer pathways, compared to controls.
IQ McGee et al. (2009) also proposed that language impairments are linked to intellectual problems in children with FASD, implying that lower IQ might be related to difficulties in cognitive functions. Other researchers have also suggested that certain deficits, which are observed among children with prenatal exposure to alcohol, such as verbal learning and impairments on behavioral phenotype, correlate with the low IQs observed in this population (Vaurio et al., 2011). This specific point complicates the explanation of neurodevelopmental deficits and renders imperative the substratification of patients according to this significant parameter. Nevertheless, although certain children with FASD suffer from lower IQ, there is a possibility of recovering as they grow.
FASD and attention-deficit hyperactivity disorder (ADHD) Hyperexcitability is one of the clinical symptoms of people suffering from FASD (Kim et al., 2010). Previous studies implied that hyperactive behavior might be
related to ADHD (Hanson et al., 1976; Fryer et al., 2007). Moreover, prenatal alcohol exposure may evoke inattentive and impulsive behavior, which is also correlated to ADHD (Kim et al., 2013). This potential interplay of FASD and ADHD has also been investigated in clinical and experimental studies, which concluded that the functions of methyl-CpG-binding protein 2 (MeCP2) and dopamine transporter (DAT) were similarly altered in both FASD and ADHD (Jucaite et al., 2005; Spencer et al., 2007; Diaz de Leon-Guerrero et al., 2011; Kim et al., 2013).
Pathophysiologic and epigenetic pathways that contribute to FASD Effects on neurotransmitters Prenatal exposure to ethanol seems to affect various neurotransmitters (Detering et al., 1980; Kelly et al., 1986; Light et al., 1989; Druse et al., 1990; Tajuddin and Druse, 1999). Previous studies showed that alcohol may reduce both the size and the spontaneous activity of dopaminergic neurons (Detering et al., 1980; Cooper and Rudeen, 1988; Druse et al., 1990; Shetty et al., 1993). Antenatal ethanol exposure also affects dopamine-1 receptors, which are decreased in certain brain areas such as the striatum (Gillespie et al., 1997; Shen et al., 1999). Experimental animal studies suggested that ethanol exposure during the early antenatal period reduces dopaminergic function during adulthood, whereas late ethanol exposure results in an exactly opposite effect (increment of dopaminergic function) (Schneider et al., 2005). Antenatal ethanol exposure affects the interrelation of the dopaminergic system with the hypothalamic-pituitary-adrenal (HPA) axis. This effect is sex dependent (Uban et al., 2013). Specifically, males are characterized by low testosterone levels, which may reduce their capacity to control the HPA axis responsiveness to stimuli, something that is not reported among females (Uban et al., 2013). Besides dopamine, prenatal alcohol exposure has been also implicated in a reduction of serotoninergic neurons (Sari and Zhou, 2004; Zhou et al., 2005). This observation could partly explain the neuropsychiatric deficits of FASD. Tajuddin and Druse (1993) reported in their experimental animal study that antenatal treatment with buspirone (a 5-HT1A agonist) reversed this reduction, an observation that might be of vital importance for future clinical practice. Further experimental studies on rats prenatally exposed to ethanol showed that the serotoninergic
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
634 I. Bakoyiannis et al.: FASD and cognitive disorders system is also influenced by the HPA axis through an alternative way (Rathbun and Druse, 1985). These observations may partly explain the anxious or depression-like behavior of patients with FASD (Hellemans et al., 2010). Glutamatergic neurotransmission has been previously linked to the maturation of developing neuronal networks and seems to be also affected by fetal ethanol exposure (Puglia and Valenzuela, 2010). A recent experimental study proposed that antenatal ethanol exposure disrupts the normal balance between glutamatergic and GABAergic neuronal differentiation of neural progenitor cells, an effect that could partly explain the hyperactive behavior of FASD patients (Kim et al., 2010). The pathophysiologic alterations that underlie this imbalance include an overexpression of mRNA levels of Pax6, Ngn2, and NeuroD (which are essential for glutamatergic differentiation) and a consequent reduction of the expression of the Mash1 gene (which is essential for GABAergic differentiation) (Powell et al., 2003; Aronne et al., 2008; Kim et al., 2010). Acetylcholine (ACh) is another important neurotransmitter that seems to be affected by prenatal ethanol exposure (Swanson et al., 1995). The role of ACh in cognitive functions, including learning and memory functions, has been already described (Gold, 2003). It seems that alcohol inhibits neuritogenesis induced by astrocytal muscarinic receptors, while at the same time ACh supplementation seems to reverse these effects (Ryan et al., 2008; Guizzetti et al., 2010). In this context, Ryan et al. (2008) proposed that further clinical studies could potentially clarify whether early neonatal choline supplementation could improve some of the cognitive deficits associated with FASD. In a mechanistic approach of the potential proteomic pathways that finally contribute to FASD, VanDemark et al. (2009) reproduced the findings of Ryan et al. (2008) by observing that antenatal alcohol exposure seems to also inhibit carbachol-induced hippocampal pyramidal neurite outgrowth through an impairment of the protein kinase C and ERK1/2 phosphorylation pathways.
Effects on HPA axis Early experimental studies suggested that antenatal alcohol exposure seems to dysregulate the HPA in a manner that renders it hyperresponsive to repeated stress (Weinberg et al., 1996). While male rats seem to be more susceptible to prolonged or intense restraint stress, female rats are more prone to acute restraint stress (Hellemans et al., 2010). Both sexes, however, increase their ACTH and CORT levels in response to these stimuli. The number of
clinical studies that investigate the influence of antenatal ethanol exposure on the dysregulation of the HPA axis is limited. According to Haley et al. (2006), it seems that cortisol levels seem to be more mutable among males, whereas heart rate may be more vulnerable among females.
Impact on insulin-insulin resistance The CNS is characterized by an intense interaction between cellular integrity and insulin/insulin-like growth factor (IGF) signaling. Specifically, researchers observed that insulin promotes neuronal growth, synaptogenesis, and protein synthesis, especially during cytoskeletal formation (de la Monte and Wands, 2010). Similarly, IGF-1 and IGF-2 are known to be essential for neuronal survival and plasticity (de la Monte and Wands, 2005). Insulin and IGF-1 interact with the cytoskeletal protein τ. The phosphorylation of τ may be correlated to Alzheimer’s disease (AD) (Koppel et al., 2014; Sasaoka et al., 2014; Yang et al., 2014). Insulin and IGF also regulate the expression of choline acetyltransferase (ChAT), an enzyme that catalyzes ACh (Soscia et al., 2006; de la Monte and Wands, 2010). ACh deficiency has been found in alcohol-exposed animals and may be responsible for cognitive and motor impairments characterizing FASD patients (de la Monte and Wands, 2010). It is well established that alcohol can lead to developmental impairments by causing changes in many growth factors such as inhibiting the nerve growth factor and the IGF-1 in neural progenitor cells (Luo and Miller, 1997, 1998). It seems that ethanol can inhibit both insulin and IGF-1 signaling through insulin receptor substrate-1 (IRS-1) in the developing brain (de la Monte et al., 1999). This suppression is correlated to impairments on phosphatidylinositol 3-kinase pathway, which is essential for cell survival through Akt/protein kinase B (PKB) activation (Dudek et al., 1997; de la Monte et al., 1999; de la Monte and Wands, 2002). Ethanol-induced neuronal apoptosis has been also proposed through the activation of proapoptotic factors, such as Bax, Bad, GSK-3β, and caspases, suppression of survival signaling of Bcl-2, or through intracellular Ca2+ augmentation (Gordon et al., 1986; Dudek et al., 1997; de la Monte et al., 1999, 2000; Ikonomidou et al., 2000; Ge et al., 2004; Takadera and Ohyashiki, 2004). Simultaneously, chronic or in utero alcohol exposure may affect mitochondrial physiology as a harmful toxic factor (de la Monte et al., 2001; Ramachandran et al., 2001; de la Monte and Wands, 2002; Chu et al., 2007). However, the pathophysiologic pathways that ultimately result to insulin and/or IGF resistance reveal that
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 635
the alterations of these two molecules might contribute to locomotor or cognitive deficiencies that characterize the FASD phenotype (de la Monte and Wands, 2010).
Oxidative stress, nutritional antioxidants, and dietary habits Antenatal ethanol exposure induces oxidative stress in various organs (Amini et al., 1996; Ramadoss and Magness, 2011; Patten et al., 2013). The fetal brain is affected by this type of stress even when the consumption of alcohol is relatively low (Chu et al., 2007; Dong et al., 2010). The main reason for this observation lies in the relatively low expression of antioxidants in this tissue (Floyd and Carney, 1992). Another possible explanation might be the fact that the amount of antioxidants augments with advancing age, therefore rendering fetuses more susceptible to oxidatives (Bergamini et al., 2004). Several antioxidants are described as potential antagonists of oxidative stress, including vitamin E, folic acid, and flavonoids. Previous researchers implicated that the consumption of these products seems to improve the clinical manifestations of FASD (Brocardo et al., 2011). Previous studies have also proposed that, besides antioxidants, healthy dietetic habits might also improve the cognitive disorders provoked by ethanol (Idrus et al., 2013). In this context, it is believed that the children’s nutrition might influence brain development (Nyaradi et al., 2013). Fuglestad et al. (2013) observed that although children with FASD tended to have similar caloric uptakes compared to those of normal children, the quality of their diet was quite different. A decrease in the uptake of vitamin D, calcium, and saturated fats has been also suggested and seems to be related to a simultaneous reduction of dairy intake (Fuglestad et al., 2013). Patten et al. (2013) observed in an experimental study that ω-3 supplementation from birth until adulthood significantly decreased the oxidative stress in the prefrontal cortex and the hippocampus of mice that were prenatally exposed to ethanol. In this context, they proposed that ω-3 supplementation could successfully reverse some of the deficits associated with FASD.
Epigenetics and FASD The protective molecular mechanisms against alcohol exposure have not been yet identified. Various potential epigenetic factors have been implicated in the occurrence of FASD. DNA methylation, histone alterations, and interference of microRNAs with the epigenome have been
extensively studied during the last years (Ungerer et al., 2013). In experimental animal studies, researchers have observed a significant decrease of DNA methylase among fetuses antenatally exposed to alcohol (Haycock and Ramsay, 2009). In this context, Stouder et al. (2011) cultured germ cells and observed a reduction of DNA methylation in five genetic loci (H19 adjusting locus). Chen et al. (2013) also noted that prenatal ethanol exposure leads to growth deficits due to its action on the hippocampal dentate gyrus. Certain brain regions seem to be more sensitive to alcohol exposure than others. According to Downing et al. (2011), fetuses that were exposed to ethanol prenatally showed a decrease in the methylation of Igf2 locus, which encodes the IGF-2. In a recent study, researchers observed that a number of genes implicated in several neurodevelopmental disorders such as Bcl2, Ache, Lcat, Cul4b, Dkc1, Ebp, Sstr3, and Nsdh1 (cognitive deficits), Bcl2 (anxiety), Nsdh1 (ADHD), and Bcl2, Otx2, and Sstr3 (mood disorders) are severely affected by antenatal alcohol exposure (Kleiber et al., 2012). Certain genes seem to gain higher transcription levels such as the chemokine receptor 3 (Cxcr3), the aurora kinase C (aurkc), the G protein-coupled receptor 15 (grpr15), the neuron navigator 1 (Nav1), and microRNAs (Mir1956, Mir196a-1, Mir196a-2, Mir204, Mir222, Mir449a, and Mir9-3), whereas other genes develop an expression deficit, such as Mrpl18, Mrpl42, and Mrps17, which encode mitochondrial ribosomal proteins, and the Dgkz, which encodes diacylglycerol kinase ζ (Kleiber et al., 2012). A recent experimental study suggested that the acetylation of histones H3 and H4 is overexpressed in the amygdala, a brain region interfering in emotion response (Ungerer et al., 2013). These modifications on the histones alter the encoding of neuropeptide Y, which contributes to cell signaling (Pandey et al., 2008). Similar changes in histone acetylation level may also occur in the cerebellum, affecting the CREB binding protein (CBP), which is an acetyltransferase of histones (Ungerer et al., 2013). This ultimately results in lysine acetylation deficits of H3 and H4, which might explain motor problems of FASD patients. Taken together, these observations suggest that epigenetics of FASD development are labyrinthine and there are several epigenetic pathways that contribute to the final development of the syndrome.
Glycosylation and FASD Glycosylation, a posttranslational modification, may occur in proteins of patients with FASD (e.g., blood transferrin and thyroglobulin). Ethanol alters isoprenoid
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
636 I. Bakoyiannis et al.: FASD and cognitive disorders metabolism and contributes to a congenital disorder of glycosylation (CDG) (Binkhorst et al., 2012). This influence may disrupt cholesterol, dolichol, and retinol synthesis, which contribute in the pathophysiology of FASD (Binkhorst et al., 2012). In a cellular basis, the cholesterol deficiency evoked by ethanol is correlated to Sonic hedgehog (Shh) signaling reduction, which is an essential molecule for neurodevelopment, cell survival, and proliferation of the CNS cells (Guizzetti and Costa, 2007; Li et al., 2007). Cholesterol-Shh signaling is disrupted in animals prenatally exposed to ethanol and is also correlated with the FASD phenotype (Li et al., 2007; Binkhorst et al., 2012). Retinol deficiency leads to decreased levels of retinoic acid (RA), an eminent morphogenic factor for basal cellular functions (Binkhorst et al., 2012). Ethanol inhibits RA biosynthesis by blocking the enzymatic transformation of retinol into RA (Kot-Leibovich and Fainsod, 2009; Binkhorst et al., 2012). This effect has been linked to certain neurodevelopmental abnormalities of FASD patients.
Implications for future research Despite the extensive experimental research in the field of FASD, the clinical studies that engage with the therapeutic options of these disorders are very limited. It seems that, besides primary prevention of FAS through the adoption of social policies that target this specific population of women, we also have secondary preventive alternatives. Nutritional antioxidants, choline, and retinol supplementation might prove to be future adequate treatment strategies. It is imperative, however, to corroborate their clinical potency and/or adverse effects through clinical trials before these substances become available in current clinical practice.
Conclusion FASDs represent a spectrum of deteriorations from normal brain development that seems to occur through complex genetic and physiologic pathways. This partly explains the broad clinical symptomatology that may vary from small language deficits to significant mental retardation. Future studies might investigate further the mechanisms of its development in an effort to establish treatments that may be alternatives to the essential primary prevention of alcoholism. Conflict of interest statement Disclosure: The authors report no conflict of interest. Funding: None to disclose for all authors.
References Amini, S.A., Dunstan, R.H., Dunkley, P.R., and Murdoch, R.N. (1996). Oxidative stress and the fetotoxicity of alcohol consumption during pregnancy. Free Radic. Biol. Med. 21, 357–365. Aronne, M.P., Evrard, S.G., Mirochnic, S., and Brusco, A. (2008). Prenatal ethanol exposure reduces the expression of the transcriptional factor Pax6 in the developing rat brain. Ann. NY Acad. Sci. 1139, 478–498. Becker, M., Warr-Leeper, G.A., and Leeper, H.A., Jr. (1990). Fetal alcohol syndrome: a description of oral motor, articulatory, short-term memory, grammatical, and semantic abilities. J. Commun. Disord. 23, 97–124. Bell, S.H., Stade, B., Reynolds, J.N., Rasmussen, C., Andrew, G., Hwang, P.A., and Carlen, P.L. (2010). The remarkably high prevalence of epilepsy and seizure history in fetal alcohol spectrum disorders. Alcohol Clin. Exp. Res. 34, 1084–1089. Bergamini, C.M., Gambetti, S., Dondi, A., and Cervellati, C. (2004). Oxygen, reactive oxygen species and tissue damage. Curr. Pharm. Des. 10, 1611–1626. Berman, R.F. and Hannigan, J.H. (2000). Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology, and neuroanatomy. Hippocampus 10, 94–110. Binkhorst, M., Wortmann, S.B., Funke, S., Kozicz, T., Wevers, R.A., and Morava, E. (2012). Glycosylation defects underlying fetal alcohol spectrum disorder: a novel pathogenetic model. ‘When the wine goes in, strange things come out’ – S.T. Coleridge, The Piccolomini. J. Inherit. Metab. Dis. 35, 399–405. Brocardo, P.S., Gil-Mohapel, J., and Christie, B.R. (2011). The role of oxidative stress in fetal alcohol spectrum disorders. Brain Res. Rev. 67, 209–225. Burd, L. and Martsolf, J.T. (1989). Fetal alcohol syndrome: diagnosis and syndromal variability. Physiol. Behav. 46, 39–43. Burden, M.J., Jacobson, S.W., and Jacobson, J.L. (2005). Relation of prenatal alcohol exposure to cognitive processing speed and efficiency in childhood. Alcohol Clin. Exp. Res. 29, 1473–1483. Chen, Y., Ozturk, N.C., and Zhou, F.C. (2013). DNA methylation program in developing hippocampus and its alteration by alcohol. PLoS One 8, e60503. Chu, J., Tong, M., and de la Monte, S.M. (2007). Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons. Acta Neuropathol. 113, 659–673. Clarren, S.K. and Smith, D.W. (1978). The fetal alcohol syndrome. Lamp 35, 4–7. Coggins, T.E., Timler, G.R., and Olswang, L.B. (2007). A state of double jeopardy: impact of prenatal alcohol exposure and adverse environments on the social communicative abilities of school-age children with fetal alcohol spectrum disorder. Lang. Speech Hear. Serv. Sch. 38, 117–127. Cooper, J.D. and Rudeen, P.K. (1988). Alterations in regional catecholamine content and turnover in the male rat brain in response to in utero ethanol exposure. Alcohol Clin. Exp. Res. 12, 282–285. de la Monte, S.M. and Wands, J.R. (2002). Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons. Cell Mol. Life Sci. 59, 882–893. de la Monte, S.M. and Wands, J.R. (2005). Review of insulin and insulin-like growth factor expression, signaling, and
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 637 alfunction in the central nervous system: relevance to m Alzheimer’s disease. J. Alzheimers Dis. 7, 45–61. de la Monte, S.M. and Wands, J.R. (2010). Role of central nervous system insulin resistance in fetal alcohol spectrum disorders. J. Popul. Ther. Clin. Pharmacol. 17, e390–e404. de la Monte, S.M., Ganju, N., Tanaka, S., Banerjee, K., Karl, P.J., Brown, N.V., and Wands, J.R. (1999). Differential effects of ethanol on insulin-signaling through the insulin receptor substrate-1. Alcohol Clin. Exp. Res. 23, 770–777. de la Monte, S.M., Ganju, N., Banerjee, K., Brown, N.V., Luong, T., and Wands, J.R. (2000). Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol3-kinase. Alcohol Clin. Exp. Res. 24, 716–726. de la Monte, S.M., Neely, T.R., Cannon, J., and Wands, J.R. (2001). Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons. Cell Mol. Life Sci. 58, 1950–1960. Detering, N., Collins, R., Hawkins, R.L., Ozand, P.T., and Karahasan, A.M. (1980). The effects of ethanol on developing catecholamine neurons. Adv. Exp. Med. Biol. 132, 721–727. Diaz de Leon-Guerrero, S., Pedraza-Alva, G., and Perez-Martinez, L. (2011). In sickness and in health: the role of methyl-CpG binding protein 2 in the central nervous system. Eur. J. Neurosci. 33, 1563–1574. Dong, J., Sulik, K.K., and Chen, S.Y. (2010). The role of NOX enzymes in ethanol-induced oxidative stress and apoptosis in mouse embryos. Toxicol. Lett. 193, 94–100. Downing, C., Johnson, T.E., Larson, C., Leakey, T.I., Siegfried, R.N., Rafferty, T.M., and Cooney, C.A. (2011). Subtle decreases in DNA methylation and gene expression at the mouse Igf2 locus following prenatal alcohol exposure: effects of a methyl-supplemented diet. Alcohol 45, 65–71. Druse, M.J., Tajuddin, N., Kuo, A., and Connerty, M. (1990). Effects of in utero ethanol exposure on the developing dopaminergic system in rats. J. Neurosci. Res. 27, 233–240. Dudek, H., Datta, S.R., Franke, T.F., Birnbaum, M.J., Yao, R., Cooper, G.M., Segal, R.A., Kaplan, D.R., and Greenberg, M.E. (1997). Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275, 661–665. Fast, D.K. and Conry, J. (2009). Fetal alcohol spectrum disorders and the criminal justice system. Dev. Disabil. Res. Rev. 15, 250–257. Flak, A.L., Su, S., Bertrand, J., Denny, C.H., Kesmodel, U.S., and Cogswell, M.E. (2014). The association of mild, moderate, and binge prenatal alcohol exposure and child neuropsychological outcomes: a meta-analysis. Alcohol Clin. Exp. Res. 38, 214–226. Floyd, R.A. and Carney, J.M. (1992). Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann. Neurol. 32, S22–S27. Fryer, S.L., McGee, C.L., Matt, G.E., Riley, E.P., and Mattson, S.N. (2007). Evaluation of psychopathological conditions in children with heavy prenatal alcohol exposure. Pediatrics 119, e733–e741. Fuglestad, A.J., Fink, B.A., Eckerle, J.K., Boys, C.J., Hoecker, H.L., Kroupina, M.G., Zeisel, S.H., Georgieff, M.K., and Wozniak, J.R. (2013). Inadequate intake of nutrients essential for neurodevelopment in children with fetal alcohol spectrum disorders (FASD). Neurotoxicol. Teratol. 39, 128–132. Ge, Y., Belcher, S.M., Pierce, D.R., and Light, K.E. (2004). Altered expression of Bcl2, Bad and Bax mRNA occurs in the rat cerebellum within hours after ethanol exposure on postnatal
day 4 but not on postnatal day 9. Brain Res. Mol. Brain Res. 129, 124–134. Gillespie, R.A., Eriksen, J., Hao, H.L., and Druse, M.J. (1997). Effects of maternal ethanol consumption and buspirone treatment on dopamine and norepinephrine reuptake sites and D1 receptors in offspring. Alcohol Clin. Exp. Res. 21, 452–459. Gold, P.E. (2003). Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol. Learn. Mem. 80, 194–210. Goodrich-Hunsaker, N.J., Livingstone, S.A., Skelton, R.W., and Hopkins, R.O. (2010). Spatial deficits in a virtual water maze in amnesic participants with hippocampal damage. Hippocampus 20, 481–491. Gordon, A.S., Collier, K., and Diamond, I. (1986). Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol. Proc. Natl. Acad. Sci. USA 83, 2105–2108. Green, C.R., Mihic, A.M., Nikkel, S.M., Stade, B.C., Rasmussen, C., Munoz, D.P., and Reynolds, J.N. (2009). Executive function deficits in children with fetal alcohol spectrum disorders (FASD) measured using the Cambridge Neuropsychological Tests Automated Battery (CANTAB). J. Child Psychol. Psychiatry. 50, 688–697. Guizzetti, M. and Costa, L.G. (2007). Cholesterol homeostasis in the developing brain: a possible new target for ethanol. Hum. Exp. Toxicol. 26, 355–360. Guizzetti, M., Moore, N.H., Giordano, G., VanDemark, K.L., and Costa, L.G. (2010). Ethanol inhibits neuritogenesis induced by astrocyte muscarinic receptors. Glia 58, 1395–1406. Haley, D.W., Handmaker, N.S., and Lowe, J. (2006). Infant stress reactivity and prenatal alcohol exposure. Alcohol Clin. Exp. Res. 30, 2055–2064. Hamilton, D.A., Driscoll, I., and Sutherland, R.J. (2002). Human place learning in a virtual Morris water task: some important constraints on the flexibility of place navigation. Behav. Brain Res. 129, 159–170. Hanson, J.W., Jones, K.L., and Smith, D.W. (1976). Fetal alcohol syndrome. Experience with 41 patients. J. Am. Med. Assoc. 235, 1458–1460. Haycock, P.C. and Ramsay, M. (2009). Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol. Reprod. 81, 618–627. Hellemans, K.G., Sliwowska, J.H., Verma, P., and Weinberg, J. (2010). Prenatal alcohol exposure: fetal programming and later life vulnerability to stress, depression and anxiety disorders. Neurosci. Biobehav. Rev. 34, 791–807. Idrus, N.M., Happer, J.P., and Thomas, J.D. (2013). Cholecalciferol attenuates perseverative behavior associated with developmental alcohol exposure in rats in a dose-dependent manner. J. Steroid Biochem. Mol. Biol. 136, 146–149. Ikonomidou, C., Bittigau, P., Ishimaru, M.J., Wozniak, D.F., Koch, C., Genz, K., Price, M.T., Stefovska, V., Horster, F., Tenkova, T., et al. (2000). Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287, 1056–1060. Jucaite, A., Fernell, E., Halldin, C., Forssberg, H., and Farde, L. (2005). Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol. Psychiatr. 57, 229–238.
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
638 I. Bakoyiannis et al.: FASD and cognitive disorders Kelly, G.M., Druse, M.J., Tonetti, D.A., and Oden, B.G. (1986). Maternal ethanol consumption: binding of L-glutamate to synaptic membranes from whole brain, cortices, and cerebella of offspring. Exp. Neurol. 91, 219–228. Kim, K.C., Go, H.S., Bak, H.R., Choi, C.S., Choi, I., Kim, P., Han, S.H., Han, S.M., Shin, C.Y., and Ko, K.H. (2010). Prenatal exposure of ethanol induces increased glutamatergic neuronal differentiation of neural progenitor cells. J. Biomed. Sci. 17, 85. Kim, P., Park, J.H., Choi, C.S., Choi, I., Joo, S.H., Kim, M.K., Kim, S.Y., Kim, K.C., Park, S.H., Kwon, K.J., et al. (2013). Effects of ethanol exposure during early pregnancy in hyperactive, inattentive and impulsive behaviors and MeCP2 expression in rodent offspring. Neurochem. Res. 38, 620–631. Kleiber, M.L., Laufer, B.I., Wright, E., Diehl, E.J., and Singh, S.M. (2012). Long-term alterations to the brain transcriptome in a maternal voluntary consumption model of fetal alcohol spectrum disorders. Brain Res. 1458, 18–33. Koppel, J., Acker, C., Davies, P., Lopez, O.L., Jimenez, H., Azose, M., Greenwald, B.S., Murray, P.S., Kirkwood, C.M., Kofler, J., et al. (2014). Psychotic Alzheimer’s disease is associated with gender-specific tau phosphorylation abnormalities. Neurobiol. Aging S0197-4580, 00237-1. Kot-Leibovich, H. and Fainsod, A. (2009). Ethanol induces embryonic malformations by competing for retinaldehyde dehydrogenase activity during vertebrate gastrulation. Dis. Model Mech. 2, 295–305. Lebel, C., Rasmussen, C., Wyper, K., Walker, L., Andrew, G., Yager, J., and Beaulieu, C. (2008). Brain diffusion abnormalities in children with fetal alcohol spectrum disorder. Alcohol Clin. Exp. Res. 32, 1732–1740. Li, Y.X., Yang, H.T., Zdanowicz, M., Sicklick, J.K., Qi, Y., Camp, T.J., and Diehl, A.M. (2007). Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling. Lab. Invest. 87, 231–240. Light, K.E., Serbus, D.C., and Santiago, M. (1989). Exposure of rats to ethanol from postnatal days 4 to 8: alterations of cholinergic neurochemistry in the cerebral cortex and corpus striatum at day 20. Alcohol Clin. Exp. Res. 13, 29–35. Lovinger, D.M., White, G., and Weight, F.F. (1989). Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243, 1721–1724. Luo, J. and Miller, M.W. (1997). Differential sensitivity of human neuroblastoma cell lines to ethanol: correlations with their proliferative responses to mitogenic growth factors and expression of growth factor receptors. Alcohol Clin. Exp. Res. 21, 1186–1194. Luo, J. and Miller, M.W. (1998). Growth factor-mediated neural proliferation: target of ethanol toxicity. Brain Res. Brain Res. Rev. 27, 157–167. Lupton, C., Burd, L., and Harwood, R. (2004). Cost of fetal alcohol spectrum disorders. Am. J. Med. Genet. C Semin. Med. Genet. 15, 42–50. Marcus, J.C. (1987). Neurological findings in the fetal alcohol syndrome. Neuropediatrics 18, 158–160. Mattson, S.N., Roesch, S.C., Fagerlund, A., Autti-Ramo, I., Jones, K.L., May, P.A., Adnams, C.M., Konovalova, V., and Riley, E.P. (2010). Toward a neurobehavioral profile of fetal alcohol spectrum disorders. Alcohol Clin. Exp. Res. 34, 1640–1650. May, P.A., Gossage, J.P., Kalberg, W.O., Robinson, L.K., Buckley, D., Manning, M., and Hoyme, H.E. (2009). Prevalence and epidemiologic characteristics of FASD from various research
methods with an emphasis on recent in-school studies. Dev. Disabil. Res. Rev. 15, 176–192. May, P.A., Blankenship, J., Marais, A.S., Gossage, J.P., Kalberg, W.O., Joubert, B., Cloete, M., Barnard, R., De Vries, M., Hasken, J., et al. (2013). Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): quantity, frequency, and timing of drinking. Drug Alcohol Depend. 133, 502–512. McGee, C.L., Bjorkquist, O.A., Riley, E.P., and Mattson, S.N. (2009). Impaired language performance in young children with heavy prenatal alcohol exposure. Neurotoxicol. Teratol. 31, 71–75. Miller, M.W. (2007). Exposure to ethanol during gastrulation alters somatosensory-motor cortices and the underlying white matter in the macaque. Cereb. Cortex 17, 2961–2971. Niccols, A. (2007). Fetal alcohol syndrome and the developing socio-emotional brain. Brain Cognit. 65, 135–142. Nyaradi, A., Li, J., Hickling, S., Foster, J., and Oddy, W.H. (2013). The role of nutrition in children’s neurocognitive development, from pregnancy through childhood. Front. Hum. Neurosci. 26, 97. O’Hare, E.D., Lu, L.H., Houston, S.M., Bookheimer, S.Y., Mattson, S.N., O’Connor, M.J., and Sowell, E.R. (2009). Altered frontalparietal functioning during verbal working memory in children and adolescents with heavy prenatal alcohol exposure. Hum. Brain Mapp. 30, 3200–3208. Pandey, S.C., Ugale, R., Zhang, H., Tang, L., and Prakash, A. (2008). Brain chromatin remodeling: a novel mechanism of alcoholism. J. Neurosci. 28, 3729–3737. Patten, A.R., Brocardo, P.S., and Christie, B.R. (2013). Omega-3 supplementation can restore glutathione levels and prevent oxidative damage caused by prenatal ethanol exposure. J. Nutr. Biochem. 24, 760–769. Powell, E.M., Campbell, D.B., Stanwood, G.D., Davis, C., Noebels, J.L., and Levitt, P. (2003). Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. J. Neurosci. 23, 622–631. Puglia, M.P. and Valenzuela, C.F. (2010). Ethanol acutely inhibits ionotropic glutamate receptor-mediated responses and longterm potentiation in the developing CA1 hippocampus. Alcohol Clin. Exp. Res. 34, 594–606. Ramachandran, V., Perez, A., Chen, J., Senthil, D., Schenker, S., and Henderson, G.I. (2001). In utero ethanol exposure causes mitochondrial dysfunction, which can result in apoptotic cell death in fetal brain: a potential role for 4-hydroxynonenal. Alcohol Clin. Exp. Res. 25, 862–871. Ramadoss, J. and Magness, R.R. (2011). 2-D DIGE uterine endothelial proteomic profile for maternal chronic binge-like alcohol exposure. J. Proteomics 74, 2986–2994. Rathbun, W. and Druse, M.J. (1985). Dopamine, serotonin, and acid metabolites in brain regions from the developing offspring of ethanol-treated rats. J. Neurochem. 44, 57–62. Redmond, S.M. and Rice, M.L. (1998). The socioemotional behaviors of children with SLI: social adaptation or social deviance? J. Speech Lang. Hear. Res. 41, 688–700. Ryan, S.H., Williams, J.K., and Thomas, J.D. (2008). Choline supplementation attenuates learning deficits associated with neonatal alcohol exposure in the rat: effects of varying the timing of choline administration. Brain Res. 27, 91–100. Sari, Y. and Zhou, F.C. (2004). Prenatal alcohol exposure causes long-term serotonin neuron deficit in mice. Alcohol Clin. Exp. Res. 28, 941–948.
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 639 Sasaoka, T., Wada, T., and Tsuneki, H. (2014). [Insulin resistance and cognitive function]. Nihon Rinsho 72, 633–640. Schneider, M.L., Moore, C.F., Barnhart, T.E., Larson, J.A., DeJesus, O.T., Mukherjee, J., Nickles, R.J., Converse, A.K., Roberts, A.D., and Kraemer, G.W. (2005). Moderate-level prenatal alcohol exposure alters striatal dopamine system function in rhesus monkeys. Alcohol Clin. Exp. Res. 29, 1685–1697. Shen, R.Y., Hannigan, J.H., and Kapatos, G. (1999). Prenatal ethanol reduces the activity of adult midbrain dopamine neurons. Alcohol Clin. Exp. Res. 23, 1801–1807. Shetty, A.K., Burrows, R.C., and Phillips, D.E. (1993). Alterations in neuronal development in the substantia nigra pars compacta following in utero ethanol exposure: immunohistochemical and Golgi studies. Neuroscience 52, 311–322. Soscia, S.J., Tong, M., Xu, X.J., Cohen, A.C., Chu, J., Wands, J.R., and de la Monte, S.M. (2006). Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain. Cell Mol. Life Sci. 63, 2039–2056. Sowell, E.R., Mattson, S.N., Thompson, P.M., Jernigan, T.L., Riley, E.P., and Toga, A.W. (2001a). Mapping callosal morphology and cognitive correlates: effects of heavy prenatal alcohol exposure. Neurology 57, 235–244. Sowell, E.R., Thompson, P.M., Mattson, S.N., Tessner, K.D., Jernigan, T.L., Riley, E.P., and Toga, A.W. (2001b). Voxel-based morphometric analyses of the brain in children and adolescents prenatally exposed to alcohol. Neuroreport 12, 515–523. Sowell, E.R., Thompson, P.M., Peterson, B.S., Mattson, S.N., Welcome, S.E., Henkenius, A.L., Riley, E.P., Jernigan, T.L., and Toga, A.W. (2002). Mapping cortical gray matter asymmetry patterns in adolescents with heavy prenatal alcohol exposure. Neuroimage 17, 1807–1819. Sowell, E.R., Mattson, S.N., Kan, E., Thompson, P.M., Riley, E.P., and Toga, A.W. (2008). Abnormal cortical thickness and brain-behavior correlation patterns in individuals with heavy prenatal alcohol exposure. Cereb. Cortex 18, 136–144. Spencer, T.J., Biederman, J., Madras, B.K., Dougherty, D.D., Bonab, A.A., Livni, E., Meltzer, P.C., Martin, J., Rauch, S., and Fischman, A.J. (2007). Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane. Biol. Psychiatry 62, 1059–1061. Squire, L.R. (1992). Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231. Stade, B., Ali, A., Bennett, D., Campbell, D., Johnston, M., Lens, C., Tran, S., and Koren, G. (2009). The burden of prenatal exposure to alcohol: revised measurement of cost. Can. J. Clin. Pharmacol. 16, e91–e102. Stouder, C., Somm, E., and Paoloni-Giacobino, A. (2011). Prenatal exposure to ethanol: a specific effect on the H19 gene in sperm. Reprod. Toxicol. 31, 507–512. Sutherland, R.J., McDonald, R.J., and Savage, D.D. (1997). Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring. Hippocampus 7, 232–238. Swanson, D.J., King, M.A., Walker, D.W., and Heaton, M.B. (1995). Chronic prenatal ethanol exposure alters the normal ontogeny
of choline acetyltransferase activity in the rat septohippocampal system. Alcohol Clin. Exp. Res. 19, 1252–1260. Tajuddin, N.F. and Druse, M.J. (1993). Treatment of pregnant alcoholconsuming rats with buspirone: effects on serotonin and 5-hydroxyindoleacetic acid content in offspring. Alcohol Clin. Exp. Res. 17, 110–114. Tajuddin, N.F. and Druse, M.J. (1999). In utero ethanol exposure decreased the density of serotonin neurons. Maternal ipsapirone treatment exerted a protective effect. Brain Res. Dev. Brain Res. 117, 91–97. Takadera, T. and Ohyashiki, T. (2004). Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons. Eur. J. Pharmacol. 499, 239–245. Thorne, J.C., Coggins, T.E., Carmichael Olson, H., and Astley, S.J. (2007). Exploring the utility of narrative analysis in diagnostic decision making: picture-bound reference, elaboration, and fetal alcohol spectrum disorders. J. Speech Lang. Hear. Res. 50, 459–474. Uban, K.A., Comeau, W.L., Ellis, L.A., Galea, L.A., and Weinberg, J. (2013). Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress. Psychoneuroendocrinology 38, 1953–1966. Ungerer, M., Knezovich, J., and Ramsay, M. (2013). In utero alcohol exposure, epigenetic changes, and their consequences. Alcohol Res. 35, 37–46. VanDemark, K.L., Guizzetti, M., Giordano, G., and Costa, L.G. (2009). Ethanol inhibits muscarinic receptor-induced axonal growth in rat hippocampal neurons. Alcohol Clin. Exp. Res. 33, 1945–1955. Vaurio, L., Riley, E.P., and Mattson, S.N. (2011). Neuropsychological comparison of children with heavy prenatal alcohol exposure and an IQ-matched comparison group. J. Int. Neuropsychol. Soc. 17, 463–473. Wadman, R., Durkin, K., and Conti-Ramsden, G. (2008). Selfesteem, shyness, and sociability in adolescents with specific language impairment (SLI). J. Speech Lang. Hear. Res. 51, 938–952. Weinberg, J., Taylor, A.N., and Gianoulakis, C. (1996). Fetal ethanol exposure: hypothalamic-pituitary-adrenal and beta-endorphin responses to repeated stress. Alcohol Clin. Exp. Res. 20, 122–131. Yang, M., Lu, J., Miao, J., Rizak, J., Yang, J., Zhai, R., Zhou, J., Qu, J., Wang, J., Ma, Y., et al. (2014). Alzheimer’s disease and methanol toxicity (part 1): chronic methanol feeding led to memory impairments and tau hyperphosphorylation in mice. J. Alzheimers Dis. doi:10.3233/jad-131529 [E-pub ahead of print]. Zhou, F.C., Sari, Y., and Powrozek, T.A. (2005). Fetal alcohol exposure reduces serotonin innervation and compromises development of the forebrain along the serotonergic pathway. Alcohol Clin. Exp. Res. 29, 141–149. Zhou, D., Lebel, C., Lepage, C., Rasmussen, C., Evans, A., Wyper, K., Pei, J., Andrew, G., Massey, A., Massey, D., et al. (2011). Developmental cortical thinning in fetal alcohol spectrum disorders. Neuroimage 58, 16–25.
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
Ioannis Bakoyiannis*, Eleana Gkioka, Vasileios Pergialiotis, Ioanna Mastroleon, Anastasia Prodromidou, Georgios D. Vlachos and Despina Perrea
Fetal alcohol spectrum disorders and cognitive functions of young children Abstract: Fetal alcohol spectrum disorder (FASD) is one of the main causes of mental retardation worldwide. Nearly 1% of children in North America are affected from antenatal exposure to ethanol. Its economic burden in industrialized countries is increasing. It is estimated that, in the United States, 4.0 billion dollars are annually expended in the treatment and rehabilitation of these patients. As a pathologic entity, they present with a broad symptomatology. Fetal alcohol syndrome (FAS) is the most readily recognized clinical manifestation of these disorders. Various factors seem to contribute in the pathogenesis of FASD-related cognitive disorders. During the last 20 years, several potential pretranslational and posttranslational factors have been extensively studied in various experimental animal models. Research has specifically focused on several neurotransmitters, insulin resistance, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, abnormal glycosylation of several proteins, oxidative stress, nutritional antioxidants, and various epigenetic factors. The purpose of the present review is to summarize the clinical manifestations of this disorder during childhood and adolescence and to summarize the possible pathophysiologic and epigenetic pathways that have been implicated in the pathophysiology of FASD. Keywords: alcohol; cognitive; FASD. DOI 10.1515/revneuro-2014-0029 Received April 14, 2014; accepted May 29, 2014; previously published online June 28, 2014
*Corresponding author: Ioannis Bakoyiannis, Laboratory of Experimental Surgery and Surgical Research ‘N.S. Christeas’, National and Kapodistrian University of Athens Medical School, Agiou Thoma 15B, GR-11527 Athens, Greece, e-mail: [email protected] Eleana Gkioka, Vasileios Pergialiotis, Ioanna Mastroleon, Anastasia Prodromidou, Georgios D. Vlachos and Despina Perrea: Laboratory of Experimental Surgery and Surgical Research ‘N.S. Christeas’, National and Kapodistrian University of Athens Medical School, Agiou Thoma 15B, GR-11527 Athens, Greece
Introduction Fetal alcohol spectrum disorders (FASD) are considered as the leading nonhereditary cause of mental retardation in Western civilization, with fetal alcohol syndrome (FAS) being their main representative. FAS has a reported prevalence that ranges between 1 and 7 per 1000 live-born infants in the United States (May et al., 2009). These disorders were first identified by Sullivan back in 1899 (Niccols, 2007). However, they were not investigated until the late 1970s. The main causative factor of the syndrome is prenatal-antenatal ethanol exposure, which is considered to be teratogenic. Ethanol crosses the placenta and affects organogenesis and embryonic development (Niccols, 2007). FASD patients may present with a variety of signs and symptoms. Both developmental abnormalities as well as neurological and functional manifestations have been described in the international literature. Interestingly, however, the majority of antenatally exposed children does not develop FASD. According to an early study, only heavily drinking mothers have the possibility to bear a child with mental retardation with an incidence that varies between 1% and 50% (Burd and Martsolf, 1989). A recent meta-analysis, however, suggested that pregnant women should completely abstain from alcohol consumption, as it seems that even mild binge drinking might hinder child cognition (Flak et al., 2014). The same researchers conclude in this context that there seems to be a lack of compelling evidence regarding the actual cutoff value of alcohol consumption that could prove to be harmless to the fetus. Besides its clinical implications, FASD poses also a significant economic burden for countries. In Canada, it is estimated that the treatment of children who are affected by FASD costs 5.3 billion dollars per year (Stade et al., 2009). In the United States, the annual cost estimates were augmented from 75 million dollars in 1984 to 4 billion dollars in 1998 (Lupton et al., 2004). The same researchers also observed that every day six to 22 of born fetuses suffer from FAS, rendering the disease an epidemic for this country. The purpose of the present review is to summarize the clinical manifestations of these disorders during childhood
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
632 I. Bakoyiannis et al.: FASD and cognitive disorders and to present the pathophysiologic and genetic pathways that lead to the occurrence of these symptoms.
patients with FASD might present visual/spatial disabilities such as impairment of spatial recognition and spanning.
Clinical manifestations
Cognitive manifestations Language skills
Structural manifestations Recent studies have proposed that the brain of people with FASD develops morphologic abnormalities (Clarren and Smith, 1978; Lebel et al., 2008). According to Lebel et al. (2008), the brain volume of patients suffering from FASD is decreased compared to that of healthy controls. Recent studies also revealed that certain regions of the parietal lobe and the ventral frontal lobe are denser in gray matter and are poorly developed, an effect that seems to be exaggerated in the left hemisphere of the brain (Sowell et al., 2001a,b, 2002). In a recent report, Sowell et al. (2008) observed that the cerebral cortex of children and adolescents suffering from FASD was thicker compared to that of normally developing controls. The thicker parts were those of the temporal lobe, the inferior parietal lobe, and the right frontal lobe. Contradictive results were, however, reported by Zhou et al. (2011), which observed a reduction of cortical mass in all four brain lobes (frontal, parietal, temporal, and occipital) among patients suffering from FASD. Previous studies have suggested that cortical thinning might be the result of inhibition of synaptogenesis, which finally provokes programmed cell death (Lovinger et al., 1989; Ikonomidou et al., 2000). This apoptotic neurodegeneration could explain the reduced cortical mass and the clinical manifestations accompanying FASD. The findings of these later studies were also reproduced in experimental animal studies, where a decrease on the absolute number of neurons of the somatosensory cortex has been observed after antenatal exposure to ethanol (Miller, 2007; Aronne et al., 2008).
Neurological manifestations Patients suffering from FASD may present with a variety of neurological symptoms. In a recent retrospective study, researchers observed that the prevalence of epilepsy and seizures among FASD patients reached 5.9% and 11.8%, respectively (Bell et al., 2010). Motor disabilities have also been observed, including abnormal gait and clumsiness, and seem to arise from impairment of both the central nervous system (CNS) and the peripheral nervous system (Marcus, 1987). Mattson et al. (2010) also suggested that
Studies engaging with the ethanol-induced language problems are limited in the international literature. However, all of them state that children with FASD are having both receptive and expressive language deficits (McGee et al., 2009). Coggins et al. (2007) observed that these deficits altered the social communication of these children at the age of 12. Previously, Becker et al. (1990) proposed that children with FASD have impaired grammar and vocabulary skills, which, consequently, hinder language comprehension. Such problems are frequent among cases with mental disorders and indicate a delay in FASD children’s brain development. They also seem to persist even among teenagers, impairing ‘higher-level language skills’ such as narration (Thorne et al., 2007). According to McGee et al. (2009), the incidence of FASD is dependent to the prenatal levels of ethanol. In this context, May et al. (2013) assumed that the varying symptomatology of FASD might be affected by the quantity, frequency, and timing of alcohol consumption, which differ among parous women.
Social behavior The language deficits presented among children suffering from FASD often contribute to their social rejection (Redmond and Rice, 1998). It is well recognized that language skills are of vital importance during the development of interpersonal relationships. Peer acceptance, which is obtained through the processes of speaking, listening, and comprehending, is essential in order to develop a normal behavior, while peer denial leads to further behavioral abnormalities in adult life (Wadman et al., 2008). Therefore, it is important to handle patients with FASD taking in mind their social inabilities, even among cases with legal implications (Fast and Conry, 2009).
Memory function Learning and memory functions are also affected by ethanol. Several studies have addressed the pathophysio logic process that underlies this clinical observation,
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 633
concentrating in the hippocampus and especially to its potential dysfunction (Squire, 1992; Hamilton et al., 2002). The Morris water task (MWT) has been used in order to assess learning and memory functions, as it is a representative index in rodents, which is also used in humans (virtual MWT or VMWT) (Sutherland et al., 1997). Children antenatally exposed to alcohol seem to have deficits in spatial and working memory (Berman and Hannigan, 2000; Green et al., 2009). Patients with FASD have difficulties in absorbing or recalling information, which is not always correlated to lower IQ scores, and function of attention is influenced, though (Burden et al., 2005; O’Hare et al., 2009). This is accompanied by altered glutamatergic transmission and long-term potentiation (LTP) of hippocampal neuronal synapses. These alterations in the hippocampal physiology are mainly depicted either as a decrease of the spinal density of pyramidal hippocampal dendrites or as an alteration of their pattern (Berman and Hannigan, 2000). Hippocampal impairments are associated with difficulties in the VMWT based on the results of neuroimaging techniques (Goodrich-Hunsaker et al., 2010). These findings were also confirmed by Hamilton et al. (2002), which observed that children suffering from FASD need more time to find the hidden platform of the VMWT, because they take longer pathways, compared to controls.
IQ McGee et al. (2009) also proposed that language impairments are linked to intellectual problems in children with FASD, implying that lower IQ might be related to difficulties in cognitive functions. Other researchers have also suggested that certain deficits, which are observed among children with prenatal exposure to alcohol, such as verbal learning and impairments on behavioral phenotype, correlate with the low IQs observed in this population (Vaurio et al., 2011). This specific point complicates the explanation of neurodevelopmental deficits and renders imperative the substratification of patients according to this significant parameter. Nevertheless, although certain children with FASD suffer from lower IQ, there is a possibility of recovering as they grow.
FASD and attention-deficit hyperactivity disorder (ADHD) Hyperexcitability is one of the clinical symptoms of people suffering from FASD (Kim et al., 2010). Previous studies implied that hyperactive behavior might be
related to ADHD (Hanson et al., 1976; Fryer et al., 2007). Moreover, prenatal alcohol exposure may evoke inattentive and impulsive behavior, which is also correlated to ADHD (Kim et al., 2013). This potential interplay of FASD and ADHD has also been investigated in clinical and experimental studies, which concluded that the functions of methyl-CpG-binding protein 2 (MeCP2) and dopamine transporter (DAT) were similarly altered in both FASD and ADHD (Jucaite et al., 2005; Spencer et al., 2007; Diaz de Leon-Guerrero et al., 2011; Kim et al., 2013).
Pathophysiologic and epigenetic pathways that contribute to FASD Effects on neurotransmitters Prenatal exposure to ethanol seems to affect various neurotransmitters (Detering et al., 1980; Kelly et al., 1986; Light et al., 1989; Druse et al., 1990; Tajuddin and Druse, 1999). Previous studies showed that alcohol may reduce both the size and the spontaneous activity of dopaminergic neurons (Detering et al., 1980; Cooper and Rudeen, 1988; Druse et al., 1990; Shetty et al., 1993). Antenatal ethanol exposure also affects dopamine-1 receptors, which are decreased in certain brain areas such as the striatum (Gillespie et al., 1997; Shen et al., 1999). Experimental animal studies suggested that ethanol exposure during the early antenatal period reduces dopaminergic function during adulthood, whereas late ethanol exposure results in an exactly opposite effect (increment of dopaminergic function) (Schneider et al., 2005). Antenatal ethanol exposure affects the interrelation of the dopaminergic system with the hypothalamic-pituitary-adrenal (HPA) axis. This effect is sex dependent (Uban et al., 2013). Specifically, males are characterized by low testosterone levels, which may reduce their capacity to control the HPA axis responsiveness to stimuli, something that is not reported among females (Uban et al., 2013). Besides dopamine, prenatal alcohol exposure has been also implicated in a reduction of serotoninergic neurons (Sari and Zhou, 2004; Zhou et al., 2005). This observation could partly explain the neuropsychiatric deficits of FASD. Tajuddin and Druse (1993) reported in their experimental animal study that antenatal treatment with buspirone (a 5-HT1A agonist) reversed this reduction, an observation that might be of vital importance for future clinical practice. Further experimental studies on rats prenatally exposed to ethanol showed that the serotoninergic
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
634 I. Bakoyiannis et al.: FASD and cognitive disorders system is also influenced by the HPA axis through an alternative way (Rathbun and Druse, 1985). These observations may partly explain the anxious or depression-like behavior of patients with FASD (Hellemans et al., 2010). Glutamatergic neurotransmission has been previously linked to the maturation of developing neuronal networks and seems to be also affected by fetal ethanol exposure (Puglia and Valenzuela, 2010). A recent experimental study proposed that antenatal ethanol exposure disrupts the normal balance between glutamatergic and GABAergic neuronal differentiation of neural progenitor cells, an effect that could partly explain the hyperactive behavior of FASD patients (Kim et al., 2010). The pathophysiologic alterations that underlie this imbalance include an overexpression of mRNA levels of Pax6, Ngn2, and NeuroD (which are essential for glutamatergic differentiation) and a consequent reduction of the expression of the Mash1 gene (which is essential for GABAergic differentiation) (Powell et al., 2003; Aronne et al., 2008; Kim et al., 2010). Acetylcholine (ACh) is another important neurotransmitter that seems to be affected by prenatal ethanol exposure (Swanson et al., 1995). The role of ACh in cognitive functions, including learning and memory functions, has been already described (Gold, 2003). It seems that alcohol inhibits neuritogenesis induced by astrocytal muscarinic receptors, while at the same time ACh supplementation seems to reverse these effects (Ryan et al., 2008; Guizzetti et al., 2010). In this context, Ryan et al. (2008) proposed that further clinical studies could potentially clarify whether early neonatal choline supplementation could improve some of the cognitive deficits associated with FASD. In a mechanistic approach of the potential proteomic pathways that finally contribute to FASD, VanDemark et al. (2009) reproduced the findings of Ryan et al. (2008) by observing that antenatal alcohol exposure seems to also inhibit carbachol-induced hippocampal pyramidal neurite outgrowth through an impairment of the protein kinase C and ERK1/2 phosphorylation pathways.
Effects on HPA axis Early experimental studies suggested that antenatal alcohol exposure seems to dysregulate the HPA in a manner that renders it hyperresponsive to repeated stress (Weinberg et al., 1996). While male rats seem to be more susceptible to prolonged or intense restraint stress, female rats are more prone to acute restraint stress (Hellemans et al., 2010). Both sexes, however, increase their ACTH and CORT levels in response to these stimuli. The number of
clinical studies that investigate the influence of antenatal ethanol exposure on the dysregulation of the HPA axis is limited. According to Haley et al. (2006), it seems that cortisol levels seem to be more mutable among males, whereas heart rate may be more vulnerable among females.
Impact on insulin-insulin resistance The CNS is characterized by an intense interaction between cellular integrity and insulin/insulin-like growth factor (IGF) signaling. Specifically, researchers observed that insulin promotes neuronal growth, synaptogenesis, and protein synthesis, especially during cytoskeletal formation (de la Monte and Wands, 2010). Similarly, IGF-1 and IGF-2 are known to be essential for neuronal survival and plasticity (de la Monte and Wands, 2005). Insulin and IGF-1 interact with the cytoskeletal protein τ. The phosphorylation of τ may be correlated to Alzheimer’s disease (AD) (Koppel et al., 2014; Sasaoka et al., 2014; Yang et al., 2014). Insulin and IGF also regulate the expression of choline acetyltransferase (ChAT), an enzyme that catalyzes ACh (Soscia et al., 2006; de la Monte and Wands, 2010). ACh deficiency has been found in alcohol-exposed animals and may be responsible for cognitive and motor impairments characterizing FASD patients (de la Monte and Wands, 2010). It is well established that alcohol can lead to developmental impairments by causing changes in many growth factors such as inhibiting the nerve growth factor and the IGF-1 in neural progenitor cells (Luo and Miller, 1997, 1998). It seems that ethanol can inhibit both insulin and IGF-1 signaling through insulin receptor substrate-1 (IRS-1) in the developing brain (de la Monte et al., 1999). This suppression is correlated to impairments on phosphatidylinositol 3-kinase pathway, which is essential for cell survival through Akt/protein kinase B (PKB) activation (Dudek et al., 1997; de la Monte et al., 1999; de la Monte and Wands, 2002). Ethanol-induced neuronal apoptosis has been also proposed through the activation of proapoptotic factors, such as Bax, Bad, GSK-3β, and caspases, suppression of survival signaling of Bcl-2, or through intracellular Ca2+ augmentation (Gordon et al., 1986; Dudek et al., 1997; de la Monte et al., 1999, 2000; Ikonomidou et al., 2000; Ge et al., 2004; Takadera and Ohyashiki, 2004). Simultaneously, chronic or in utero alcohol exposure may affect mitochondrial physiology as a harmful toxic factor (de la Monte et al., 2001; Ramachandran et al., 2001; de la Monte and Wands, 2002; Chu et al., 2007). However, the pathophysiologic pathways that ultimately result to insulin and/or IGF resistance reveal that
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 635
the alterations of these two molecules might contribute to locomotor or cognitive deficiencies that characterize the FASD phenotype (de la Monte and Wands, 2010).
Oxidative stress, nutritional antioxidants, and dietary habits Antenatal ethanol exposure induces oxidative stress in various organs (Amini et al., 1996; Ramadoss and Magness, 2011; Patten et al., 2013). The fetal brain is affected by this type of stress even when the consumption of alcohol is relatively low (Chu et al., 2007; Dong et al., 2010). The main reason for this observation lies in the relatively low expression of antioxidants in this tissue (Floyd and Carney, 1992). Another possible explanation might be the fact that the amount of antioxidants augments with advancing age, therefore rendering fetuses more susceptible to oxidatives (Bergamini et al., 2004). Several antioxidants are described as potential antagonists of oxidative stress, including vitamin E, folic acid, and flavonoids. Previous researchers implicated that the consumption of these products seems to improve the clinical manifestations of FASD (Brocardo et al., 2011). Previous studies have also proposed that, besides antioxidants, healthy dietetic habits might also improve the cognitive disorders provoked by ethanol (Idrus et al., 2013). In this context, it is believed that the children’s nutrition might influence brain development (Nyaradi et al., 2013). Fuglestad et al. (2013) observed that although children with FASD tended to have similar caloric uptakes compared to those of normal children, the quality of their diet was quite different. A decrease in the uptake of vitamin D, calcium, and saturated fats has been also suggested and seems to be related to a simultaneous reduction of dairy intake (Fuglestad et al., 2013). Patten et al. (2013) observed in an experimental study that ω-3 supplementation from birth until adulthood significantly decreased the oxidative stress in the prefrontal cortex and the hippocampus of mice that were prenatally exposed to ethanol. In this context, they proposed that ω-3 supplementation could successfully reverse some of the deficits associated with FASD.
Epigenetics and FASD The protective molecular mechanisms against alcohol exposure have not been yet identified. Various potential epigenetic factors have been implicated in the occurrence of FASD. DNA methylation, histone alterations, and interference of microRNAs with the epigenome have been
extensively studied during the last years (Ungerer et al., 2013). In experimental animal studies, researchers have observed a significant decrease of DNA methylase among fetuses antenatally exposed to alcohol (Haycock and Ramsay, 2009). In this context, Stouder et al. (2011) cultured germ cells and observed a reduction of DNA methylation in five genetic loci (H19 adjusting locus). Chen et al. (2013) also noted that prenatal ethanol exposure leads to growth deficits due to its action on the hippocampal dentate gyrus. Certain brain regions seem to be more sensitive to alcohol exposure than others. According to Downing et al. (2011), fetuses that were exposed to ethanol prenatally showed a decrease in the methylation of Igf2 locus, which encodes the IGF-2. In a recent study, researchers observed that a number of genes implicated in several neurodevelopmental disorders such as Bcl2, Ache, Lcat, Cul4b, Dkc1, Ebp, Sstr3, and Nsdh1 (cognitive deficits), Bcl2 (anxiety), Nsdh1 (ADHD), and Bcl2, Otx2, and Sstr3 (mood disorders) are severely affected by antenatal alcohol exposure (Kleiber et al., 2012). Certain genes seem to gain higher transcription levels such as the chemokine receptor 3 (Cxcr3), the aurora kinase C (aurkc), the G protein-coupled receptor 15 (grpr15), the neuron navigator 1 (Nav1), and microRNAs (Mir1956, Mir196a-1, Mir196a-2, Mir204, Mir222, Mir449a, and Mir9-3), whereas other genes develop an expression deficit, such as Mrpl18, Mrpl42, and Mrps17, which encode mitochondrial ribosomal proteins, and the Dgkz, which encodes diacylglycerol kinase ζ (Kleiber et al., 2012). A recent experimental study suggested that the acetylation of histones H3 and H4 is overexpressed in the amygdala, a brain region interfering in emotion response (Ungerer et al., 2013). These modifications on the histones alter the encoding of neuropeptide Y, which contributes to cell signaling (Pandey et al., 2008). Similar changes in histone acetylation level may also occur in the cerebellum, affecting the CREB binding protein (CBP), which is an acetyltransferase of histones (Ungerer et al., 2013). This ultimately results in lysine acetylation deficits of H3 and H4, which might explain motor problems of FASD patients. Taken together, these observations suggest that epigenetics of FASD development are labyrinthine and there are several epigenetic pathways that contribute to the final development of the syndrome.
Glycosylation and FASD Glycosylation, a posttranslational modification, may occur in proteins of patients with FASD (e.g., blood transferrin and thyroglobulin). Ethanol alters isoprenoid
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
636 I. Bakoyiannis et al.: FASD and cognitive disorders metabolism and contributes to a congenital disorder of glycosylation (CDG) (Binkhorst et al., 2012). This influence may disrupt cholesterol, dolichol, and retinol synthesis, which contribute in the pathophysiology of FASD (Binkhorst et al., 2012). In a cellular basis, the cholesterol deficiency evoked by ethanol is correlated to Sonic hedgehog (Shh) signaling reduction, which is an essential molecule for neurodevelopment, cell survival, and proliferation of the CNS cells (Guizzetti and Costa, 2007; Li et al., 2007). Cholesterol-Shh signaling is disrupted in animals prenatally exposed to ethanol and is also correlated with the FASD phenotype (Li et al., 2007; Binkhorst et al., 2012). Retinol deficiency leads to decreased levels of retinoic acid (RA), an eminent morphogenic factor for basal cellular functions (Binkhorst et al., 2012). Ethanol inhibits RA biosynthesis by blocking the enzymatic transformation of retinol into RA (Kot-Leibovich and Fainsod, 2009; Binkhorst et al., 2012). This effect has been linked to certain neurodevelopmental abnormalities of FASD patients.
Implications for future research Despite the extensive experimental research in the field of FASD, the clinical studies that engage with the therapeutic options of these disorders are very limited. It seems that, besides primary prevention of FAS through the adoption of social policies that target this specific population of women, we also have secondary preventive alternatives. Nutritional antioxidants, choline, and retinol supplementation might prove to be future adequate treatment strategies. It is imperative, however, to corroborate their clinical potency and/or adverse effects through clinical trials before these substances become available in current clinical practice.
Conclusion FASDs represent a spectrum of deteriorations from normal brain development that seems to occur through complex genetic and physiologic pathways. This partly explains the broad clinical symptomatology that may vary from small language deficits to significant mental retardation. Future studies might investigate further the mechanisms of its development in an effort to establish treatments that may be alternatives to the essential primary prevention of alcoholism. Conflict of interest statement Disclosure: The authors report no conflict of interest. Funding: None to disclose for all authors.
References Amini, S.A., Dunstan, R.H., Dunkley, P.R., and Murdoch, R.N. (1996). Oxidative stress and the fetotoxicity of alcohol consumption during pregnancy. Free Radic. Biol. Med. 21, 357–365. Aronne, M.P., Evrard, S.G., Mirochnic, S., and Brusco, A. (2008). Prenatal ethanol exposure reduces the expression of the transcriptional factor Pax6 in the developing rat brain. Ann. NY Acad. Sci. 1139, 478–498. Becker, M., Warr-Leeper, G.A., and Leeper, H.A., Jr. (1990). Fetal alcohol syndrome: a description of oral motor, articulatory, short-term memory, grammatical, and semantic abilities. J. Commun. Disord. 23, 97–124. Bell, S.H., Stade, B., Reynolds, J.N., Rasmussen, C., Andrew, G., Hwang, P.A., and Carlen, P.L. (2010). The remarkably high prevalence of epilepsy and seizure history in fetal alcohol spectrum disorders. Alcohol Clin. Exp. Res. 34, 1084–1089. Bergamini, C.M., Gambetti, S., Dondi, A., and Cervellati, C. (2004). Oxygen, reactive oxygen species and tissue damage. Curr. Pharm. Des. 10, 1611–1626. Berman, R.F. and Hannigan, J.H. (2000). Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology, and neuroanatomy. Hippocampus 10, 94–110. Binkhorst, M., Wortmann, S.B., Funke, S., Kozicz, T., Wevers, R.A., and Morava, E. (2012). Glycosylation defects underlying fetal alcohol spectrum disorder: a novel pathogenetic model. ‘When the wine goes in, strange things come out’ – S.T. Coleridge, The Piccolomini. J. Inherit. Metab. Dis. 35, 399–405. Brocardo, P.S., Gil-Mohapel, J., and Christie, B.R. (2011). The role of oxidative stress in fetal alcohol spectrum disorders. Brain Res. Rev. 67, 209–225. Burd, L. and Martsolf, J.T. (1989). Fetal alcohol syndrome: diagnosis and syndromal variability. Physiol. Behav. 46, 39–43. Burden, M.J., Jacobson, S.W., and Jacobson, J.L. (2005). Relation of prenatal alcohol exposure to cognitive processing speed and efficiency in childhood. Alcohol Clin. Exp. Res. 29, 1473–1483. Chen, Y., Ozturk, N.C., and Zhou, F.C. (2013). DNA methylation program in developing hippocampus and its alteration by alcohol. PLoS One 8, e60503. Chu, J., Tong, M., and de la Monte, S.M. (2007). Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons. Acta Neuropathol. 113, 659–673. Clarren, S.K. and Smith, D.W. (1978). The fetal alcohol syndrome. Lamp 35, 4–7. Coggins, T.E., Timler, G.R., and Olswang, L.B. (2007). A state of double jeopardy: impact of prenatal alcohol exposure and adverse environments on the social communicative abilities of school-age children with fetal alcohol spectrum disorder. Lang. Speech Hear. Serv. Sch. 38, 117–127. Cooper, J.D. and Rudeen, P.K. (1988). Alterations in regional catecholamine content and turnover in the male rat brain in response to in utero ethanol exposure. Alcohol Clin. Exp. Res. 12, 282–285. de la Monte, S.M. and Wands, J.R. (2002). Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons. Cell Mol. Life Sci. 59, 882–893. de la Monte, S.M. and Wands, J.R. (2005). Review of insulin and insulin-like growth factor expression, signaling, and
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 637 alfunction in the central nervous system: relevance to m Alzheimer’s disease. J. Alzheimers Dis. 7, 45–61. de la Monte, S.M. and Wands, J.R. (2010). Role of central nervous system insulin resistance in fetal alcohol spectrum disorders. J. Popul. Ther. Clin. Pharmacol. 17, e390–e404. de la Monte, S.M., Ganju, N., Tanaka, S., Banerjee, K., Karl, P.J., Brown, N.V., and Wands, J.R. (1999). Differential effects of ethanol on insulin-signaling through the insulin receptor substrate-1. Alcohol Clin. Exp. Res. 23, 770–777. de la Monte, S.M., Ganju, N., Banerjee, K., Brown, N.V., Luong, T., and Wands, J.R. (2000). Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol3-kinase. Alcohol Clin. Exp. Res. 24, 716–726. de la Monte, S.M., Neely, T.R., Cannon, J., and Wands, J.R. (2001). Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons. Cell Mol. Life Sci. 58, 1950–1960. Detering, N., Collins, R., Hawkins, R.L., Ozand, P.T., and Karahasan, A.M. (1980). The effects of ethanol on developing catecholamine neurons. Adv. Exp. Med. Biol. 132, 721–727. Diaz de Leon-Guerrero, S., Pedraza-Alva, G., and Perez-Martinez, L. (2011). In sickness and in health: the role of methyl-CpG binding protein 2 in the central nervous system. Eur. J. Neurosci. 33, 1563–1574. Dong, J., Sulik, K.K., and Chen, S.Y. (2010). The role of NOX enzymes in ethanol-induced oxidative stress and apoptosis in mouse embryos. Toxicol. Lett. 193, 94–100. Downing, C., Johnson, T.E., Larson, C., Leakey, T.I., Siegfried, R.N., Rafferty, T.M., and Cooney, C.A. (2011). Subtle decreases in DNA methylation and gene expression at the mouse Igf2 locus following prenatal alcohol exposure: effects of a methyl-supplemented diet. Alcohol 45, 65–71. Druse, M.J., Tajuddin, N., Kuo, A., and Connerty, M. (1990). Effects of in utero ethanol exposure on the developing dopaminergic system in rats. J. Neurosci. Res. 27, 233–240. Dudek, H., Datta, S.R., Franke, T.F., Birnbaum, M.J., Yao, R., Cooper, G.M., Segal, R.A., Kaplan, D.R., and Greenberg, M.E. (1997). Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275, 661–665. Fast, D.K. and Conry, J. (2009). Fetal alcohol spectrum disorders and the criminal justice system. Dev. Disabil. Res. Rev. 15, 250–257. Flak, A.L., Su, S., Bertrand, J., Denny, C.H., Kesmodel, U.S., and Cogswell, M.E. (2014). The association of mild, moderate, and binge prenatal alcohol exposure and child neuropsychological outcomes: a meta-analysis. Alcohol Clin. Exp. Res. 38, 214–226. Floyd, R.A. and Carney, J.M. (1992). Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann. Neurol. 32, S22–S27. Fryer, S.L., McGee, C.L., Matt, G.E., Riley, E.P., and Mattson, S.N. (2007). Evaluation of psychopathological conditions in children with heavy prenatal alcohol exposure. Pediatrics 119, e733–e741. Fuglestad, A.J., Fink, B.A., Eckerle, J.K., Boys, C.J., Hoecker, H.L., Kroupina, M.G., Zeisel, S.H., Georgieff, M.K., and Wozniak, J.R. (2013). Inadequate intake of nutrients essential for neurodevelopment in children with fetal alcohol spectrum disorders (FASD). Neurotoxicol. Teratol. 39, 128–132. Ge, Y., Belcher, S.M., Pierce, D.R., and Light, K.E. (2004). Altered expression of Bcl2, Bad and Bax mRNA occurs in the rat cerebellum within hours after ethanol exposure on postnatal
day 4 but not on postnatal day 9. Brain Res. Mol. Brain Res. 129, 124–134. Gillespie, R.A., Eriksen, J., Hao, H.L., and Druse, M.J. (1997). Effects of maternal ethanol consumption and buspirone treatment on dopamine and norepinephrine reuptake sites and D1 receptors in offspring. Alcohol Clin. Exp. Res. 21, 452–459. Gold, P.E. (2003). Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol. Learn. Mem. 80, 194–210. Goodrich-Hunsaker, N.J., Livingstone, S.A., Skelton, R.W., and Hopkins, R.O. (2010). Spatial deficits in a virtual water maze in amnesic participants with hippocampal damage. Hippocampus 20, 481–491. Gordon, A.S., Collier, K., and Diamond, I. (1986). Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol. Proc. Natl. Acad. Sci. USA 83, 2105–2108. Green, C.R., Mihic, A.M., Nikkel, S.M., Stade, B.C., Rasmussen, C., Munoz, D.P., and Reynolds, J.N. (2009). Executive function deficits in children with fetal alcohol spectrum disorders (FASD) measured using the Cambridge Neuropsychological Tests Automated Battery (CANTAB). J. Child Psychol. Psychiatry. 50, 688–697. Guizzetti, M. and Costa, L.G. (2007). Cholesterol homeostasis in the developing brain: a possible new target for ethanol. Hum. Exp. Toxicol. 26, 355–360. Guizzetti, M., Moore, N.H., Giordano, G., VanDemark, K.L., and Costa, L.G. (2010). Ethanol inhibits neuritogenesis induced by astrocyte muscarinic receptors. Glia 58, 1395–1406. Haley, D.W., Handmaker, N.S., and Lowe, J. (2006). Infant stress reactivity and prenatal alcohol exposure. Alcohol Clin. Exp. Res. 30, 2055–2064. Hamilton, D.A., Driscoll, I., and Sutherland, R.J. (2002). Human place learning in a virtual Morris water task: some important constraints on the flexibility of place navigation. Behav. Brain Res. 129, 159–170. Hanson, J.W., Jones, K.L., and Smith, D.W. (1976). Fetal alcohol syndrome. Experience with 41 patients. J. Am. Med. Assoc. 235, 1458–1460. Haycock, P.C. and Ramsay, M. (2009). Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol. Reprod. 81, 618–627. Hellemans, K.G., Sliwowska, J.H., Verma, P., and Weinberg, J. (2010). Prenatal alcohol exposure: fetal programming and later life vulnerability to stress, depression and anxiety disorders. Neurosci. Biobehav. Rev. 34, 791–807. Idrus, N.M., Happer, J.P., and Thomas, J.D. (2013). Cholecalciferol attenuates perseverative behavior associated with developmental alcohol exposure in rats in a dose-dependent manner. J. Steroid Biochem. Mol. Biol. 136, 146–149. Ikonomidou, C., Bittigau, P., Ishimaru, M.J., Wozniak, D.F., Koch, C., Genz, K., Price, M.T., Stefovska, V., Horster, F., Tenkova, T., et al. (2000). Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287, 1056–1060. Jucaite, A., Fernell, E., Halldin, C., Forssberg, H., and Farde, L. (2005). Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol. Psychiatr. 57, 229–238.
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
638 I. Bakoyiannis et al.: FASD and cognitive disorders Kelly, G.M., Druse, M.J., Tonetti, D.A., and Oden, B.G. (1986). Maternal ethanol consumption: binding of L-glutamate to synaptic membranes from whole brain, cortices, and cerebella of offspring. Exp. Neurol. 91, 219–228. Kim, K.C., Go, H.S., Bak, H.R., Choi, C.S., Choi, I., Kim, P., Han, S.H., Han, S.M., Shin, C.Y., and Ko, K.H. (2010). Prenatal exposure of ethanol induces increased glutamatergic neuronal differentiation of neural progenitor cells. J. Biomed. Sci. 17, 85. Kim, P., Park, J.H., Choi, C.S., Choi, I., Joo, S.H., Kim, M.K., Kim, S.Y., Kim, K.C., Park, S.H., Kwon, K.J., et al. (2013). Effects of ethanol exposure during early pregnancy in hyperactive, inattentive and impulsive behaviors and MeCP2 expression in rodent offspring. Neurochem. Res. 38, 620–631. Kleiber, M.L., Laufer, B.I., Wright, E., Diehl, E.J., and Singh, S.M. (2012). Long-term alterations to the brain transcriptome in a maternal voluntary consumption model of fetal alcohol spectrum disorders. Brain Res. 1458, 18–33. Koppel, J., Acker, C., Davies, P., Lopez, O.L., Jimenez, H., Azose, M., Greenwald, B.S., Murray, P.S., Kirkwood, C.M., Kofler, J., et al. (2014). Psychotic Alzheimer’s disease is associated with gender-specific tau phosphorylation abnormalities. Neurobiol. Aging S0197-4580, 00237-1. Kot-Leibovich, H. and Fainsod, A. (2009). Ethanol induces embryonic malformations by competing for retinaldehyde dehydrogenase activity during vertebrate gastrulation. Dis. Model Mech. 2, 295–305. Lebel, C., Rasmussen, C., Wyper, K., Walker, L., Andrew, G., Yager, J., and Beaulieu, C. (2008). Brain diffusion abnormalities in children with fetal alcohol spectrum disorder. Alcohol Clin. Exp. Res. 32, 1732–1740. Li, Y.X., Yang, H.T., Zdanowicz, M., Sicklick, J.K., Qi, Y., Camp, T.J., and Diehl, A.M. (2007). Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling. Lab. Invest. 87, 231–240. Light, K.E., Serbus, D.C., and Santiago, M. (1989). Exposure of rats to ethanol from postnatal days 4 to 8: alterations of cholinergic neurochemistry in the cerebral cortex and corpus striatum at day 20. Alcohol Clin. Exp. Res. 13, 29–35. Lovinger, D.M., White, G., and Weight, F.F. (1989). Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243, 1721–1724. Luo, J. and Miller, M.W. (1997). Differential sensitivity of human neuroblastoma cell lines to ethanol: correlations with their proliferative responses to mitogenic growth factors and expression of growth factor receptors. Alcohol Clin. Exp. Res. 21, 1186–1194. Luo, J. and Miller, M.W. (1998). Growth factor-mediated neural proliferation: target of ethanol toxicity. Brain Res. Brain Res. Rev. 27, 157–167. Lupton, C., Burd, L., and Harwood, R. (2004). Cost of fetal alcohol spectrum disorders. Am. J. Med. Genet. C Semin. Med. Genet. 15, 42–50. Marcus, J.C. (1987). Neurological findings in the fetal alcohol syndrome. Neuropediatrics 18, 158–160. Mattson, S.N., Roesch, S.C., Fagerlund, A., Autti-Ramo, I., Jones, K.L., May, P.A., Adnams, C.M., Konovalova, V., and Riley, E.P. (2010). Toward a neurobehavioral profile of fetal alcohol spectrum disorders. Alcohol Clin. Exp. Res. 34, 1640–1650. May, P.A., Gossage, J.P., Kalberg, W.O., Robinson, L.K., Buckley, D., Manning, M., and Hoyme, H.E. (2009). Prevalence and epidemiologic characteristics of FASD from various research
methods with an emphasis on recent in-school studies. Dev. Disabil. Res. Rev. 15, 176–192. May, P.A., Blankenship, J., Marais, A.S., Gossage, J.P., Kalberg, W.O., Joubert, B., Cloete, M., Barnard, R., De Vries, M., Hasken, J., et al. (2013). Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): quantity, frequency, and timing of drinking. Drug Alcohol Depend. 133, 502–512. McGee, C.L., Bjorkquist, O.A., Riley, E.P., and Mattson, S.N. (2009). Impaired language performance in young children with heavy prenatal alcohol exposure. Neurotoxicol. Teratol. 31, 71–75. Miller, M.W. (2007). Exposure to ethanol during gastrulation alters somatosensory-motor cortices and the underlying white matter in the macaque. Cereb. Cortex 17, 2961–2971. Niccols, A. (2007). Fetal alcohol syndrome and the developing socio-emotional brain. Brain Cognit. 65, 135–142. Nyaradi, A., Li, J., Hickling, S., Foster, J., and Oddy, W.H. (2013). The role of nutrition in children’s neurocognitive development, from pregnancy through childhood. Front. Hum. Neurosci. 26, 97. O’Hare, E.D., Lu, L.H., Houston, S.M., Bookheimer, S.Y., Mattson, S.N., O’Connor, M.J., and Sowell, E.R. (2009). Altered frontalparietal functioning during verbal working memory in children and adolescents with heavy prenatal alcohol exposure. Hum. Brain Mapp. 30, 3200–3208. Pandey, S.C., Ugale, R., Zhang, H., Tang, L., and Prakash, A. (2008). Brain chromatin remodeling: a novel mechanism of alcoholism. J. Neurosci. 28, 3729–3737. Patten, A.R., Brocardo, P.S., and Christie, B.R. (2013). Omega-3 supplementation can restore glutathione levels and prevent oxidative damage caused by prenatal ethanol exposure. J. Nutr. Biochem. 24, 760–769. Powell, E.M., Campbell, D.B., Stanwood, G.D., Davis, C., Noebels, J.L., and Levitt, P. (2003). Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. J. Neurosci. 23, 622–631. Puglia, M.P. and Valenzuela, C.F. (2010). Ethanol acutely inhibits ionotropic glutamate receptor-mediated responses and longterm potentiation in the developing CA1 hippocampus. Alcohol Clin. Exp. Res. 34, 594–606. Ramachandran, V., Perez, A., Chen, J., Senthil, D., Schenker, S., and Henderson, G.I. (2001). In utero ethanol exposure causes mitochondrial dysfunction, which can result in apoptotic cell death in fetal brain: a potential role for 4-hydroxynonenal. Alcohol Clin. Exp. Res. 25, 862–871. Ramadoss, J. and Magness, R.R. (2011). 2-D DIGE uterine endothelial proteomic profile for maternal chronic binge-like alcohol exposure. J. Proteomics 74, 2986–2994. Rathbun, W. and Druse, M.J. (1985). Dopamine, serotonin, and acid metabolites in brain regions from the developing offspring of ethanol-treated rats. J. Neurochem. 44, 57–62. Redmond, S.M. and Rice, M.L. (1998). The socioemotional behaviors of children with SLI: social adaptation or social deviance? J. Speech Lang. Hear. Res. 41, 688–700. Ryan, S.H., Williams, J.K., and Thomas, J.D. (2008). Choline supplementation attenuates learning deficits associated with neonatal alcohol exposure in the rat: effects of varying the timing of choline administration. Brain Res. 27, 91–100. Sari, Y. and Zhou, F.C. (2004). Prenatal alcohol exposure causes long-term serotonin neuron deficit in mice. Alcohol Clin. Exp. Res. 28, 941–948.
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
I. Bakoyiannis et al.: FASD and cognitive disorders 639 Sasaoka, T., Wada, T., and Tsuneki, H. (2014). [Insulin resistance and cognitive function]. Nihon Rinsho 72, 633–640. Schneider, M.L., Moore, C.F., Barnhart, T.E., Larson, J.A., DeJesus, O.T., Mukherjee, J., Nickles, R.J., Converse, A.K., Roberts, A.D., and Kraemer, G.W. (2005). Moderate-level prenatal alcohol exposure alters striatal dopamine system function in rhesus monkeys. Alcohol Clin. Exp. Res. 29, 1685–1697. Shen, R.Y., Hannigan, J.H., and Kapatos, G. (1999). Prenatal ethanol reduces the activity of adult midbrain dopamine neurons. Alcohol Clin. Exp. Res. 23, 1801–1807. Shetty, A.K., Burrows, R.C., and Phillips, D.E. (1993). Alterations in neuronal development in the substantia nigra pars compacta following in utero ethanol exposure: immunohistochemical and Golgi studies. Neuroscience 52, 311–322. Soscia, S.J., Tong, M., Xu, X.J., Cohen, A.C., Chu, J., Wands, J.R., and de la Monte, S.M. (2006). Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain. Cell Mol. Life Sci. 63, 2039–2056. Sowell, E.R., Mattson, S.N., Thompson, P.M., Jernigan, T.L., Riley, E.P., and Toga, A.W. (2001a). Mapping callosal morphology and cognitive correlates: effects of heavy prenatal alcohol exposure. Neurology 57, 235–244. Sowell, E.R., Thompson, P.M., Mattson, S.N., Tessner, K.D., Jernigan, T.L., Riley, E.P., and Toga, A.W. (2001b). Voxel-based morphometric analyses of the brain in children and adolescents prenatally exposed to alcohol. Neuroreport 12, 515–523. Sowell, E.R., Thompson, P.M., Peterson, B.S., Mattson, S.N., Welcome, S.E., Henkenius, A.L., Riley, E.P., Jernigan, T.L., and Toga, A.W. (2002). Mapping cortical gray matter asymmetry patterns in adolescents with heavy prenatal alcohol exposure. Neuroimage 17, 1807–1819. Sowell, E.R., Mattson, S.N., Kan, E., Thompson, P.M., Riley, E.P., and Toga, A.W. (2008). Abnormal cortical thickness and brain-behavior correlation patterns in individuals with heavy prenatal alcohol exposure. Cereb. Cortex 18, 136–144. Spencer, T.J., Biederman, J., Madras, B.K., Dougherty, D.D., Bonab, A.A., Livni, E., Meltzer, P.C., Martin, J., Rauch, S., and Fischman, A.J. (2007). Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane. Biol. Psychiatry 62, 1059–1061. Squire, L.R. (1992). Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231. Stade, B., Ali, A., Bennett, D., Campbell, D., Johnston, M., Lens, C., Tran, S., and Koren, G. (2009). The burden of prenatal exposure to alcohol: revised measurement of cost. Can. J. Clin. Pharmacol. 16, e91–e102. Stouder, C., Somm, E., and Paoloni-Giacobino, A. (2011). Prenatal exposure to ethanol: a specific effect on the H19 gene in sperm. Reprod. Toxicol. 31, 507–512. Sutherland, R.J., McDonald, R.J., and Savage, D.D. (1997). Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring. Hippocampus 7, 232–238. Swanson, D.J., King, M.A., Walker, D.W., and Heaton, M.B. (1995). Chronic prenatal ethanol exposure alters the normal ontogeny
of choline acetyltransferase activity in the rat septohippocampal system. Alcohol Clin. Exp. Res. 19, 1252–1260. Tajuddin, N.F. and Druse, M.J. (1993). Treatment of pregnant alcoholconsuming rats with buspirone: effects on serotonin and 5-hydroxyindoleacetic acid content in offspring. Alcohol Clin. Exp. Res. 17, 110–114. Tajuddin, N.F. and Druse, M.J. (1999). In utero ethanol exposure decreased the density of serotonin neurons. Maternal ipsapirone treatment exerted a protective effect. Brain Res. Dev. Brain Res. 117, 91–97. Takadera, T. and Ohyashiki, T. (2004). Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons. Eur. J. Pharmacol. 499, 239–245. Thorne, J.C., Coggins, T.E., Carmichael Olson, H., and Astley, S.J. (2007). Exploring the utility of narrative analysis in diagnostic decision making: picture-bound reference, elaboration, and fetal alcohol spectrum disorders. J. Speech Lang. Hear. Res. 50, 459–474. Uban, K.A., Comeau, W.L., Ellis, L.A., Galea, L.A., and Weinberg, J. (2013). Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress. Psychoneuroendocrinology 38, 1953–1966. Ungerer, M., Knezovich, J., and Ramsay, M. (2013). In utero alcohol exposure, epigenetic changes, and their consequences. Alcohol Res. 35, 37–46. VanDemark, K.L., Guizzetti, M., Giordano, G., and Costa, L.G. (2009). Ethanol inhibits muscarinic receptor-induced axonal growth in rat hippocampal neurons. Alcohol Clin. Exp. Res. 33, 1945–1955. Vaurio, L., Riley, E.P., and Mattson, S.N. (2011). Neuropsychological comparison of children with heavy prenatal alcohol exposure and an IQ-matched comparison group. J. Int. Neuropsychol. Soc. 17, 463–473. Wadman, R., Durkin, K., and Conti-Ramsden, G. (2008). Selfesteem, shyness, and sociability in adolescents with specific language impairment (SLI). J. Speech Lang. Hear. Res. 51, 938–952. Weinberg, J., Taylor, A.N., and Gianoulakis, C. (1996). Fetal ethanol exposure: hypothalamic-pituitary-adrenal and beta-endorphin responses to repeated stress. Alcohol Clin. Exp. Res. 20, 122–131. Yang, M., Lu, J., Miao, J., Rizak, J., Yang, J., Zhai, R., Zhou, J., Qu, J., Wang, J., Ma, Y., et al. (2014). Alzheimer’s disease and methanol toxicity (part 1): chronic methanol feeding led to memory impairments and tau hyperphosphorylation in mice. J. Alzheimers Dis. doi:10.3233/jad-131529 [E-pub ahead of print]. Zhou, F.C., Sari, Y., and Powrozek, T.A. (2005). Fetal alcohol exposure reduces serotonin innervation and compromises development of the forebrain along the serotonergic pathway. Alcohol Clin. Exp. Res. 29, 141–149. Zhou, D., Lebel, C., Lepage, C., Rasmussen, C., Evans, A., Wyper, K., Pei, J., Andrew, G., Massey, A., Massey, D., et al. (2011). Developmental cortical thinning in fetal alcohol spectrum disorders. Neuroimage 58, 16–25.
Brought to you by | Carleton University OCUL Authenticated Download Date | 6/27/15 4:43 AM
