1989). Weinberg (1989) found that during the first week of life, alcohol-exposed pups exhibited a blunted response to several stressors. Although this reduced responsiveness was a transient phenomenon (the stress response normalized by the second week of life), the perturbation in basal and stress-related HPA activity early in life may have long-term consequences on the manner in which these animals respond to stress in adulthood. Indeed, although basal plasma corticosteroid levels are normal in adult rats exposed prenatally to alcohol, several studies have demonstrated that these animals exhibit a heightened stress response (elevated plasma corticosteroid levels) and retarded recovery from the stress response (e.g., Weinberg 1988). These animals were also less sensitive than control offspring to manipulations that typically dampen the stress response, thus suggesting that prenatal alcohol exposure results in a deficit in HPA response inhibition or recovery from stress. Because these deficits were primarily demonstrated in females, Weinberg (1988) suggested that females may be more vulnerable to this effect. The mechanism whereby alcohol exposure during fetal life heightens the HPA response to certain stressors later in adulthood is unclear at present. A growing body of literature... indicates that prenatal alcohol exposure compromises immunological function and consequently may lead to an increased vulnerability to infectious diseases and tumorigenesis. Effects on the Immune A growing body of literature, reviewed by Gottes- within the immune system) and FAS were suggested; four children with DiGeorge syndrome were born to alcoholic mothers in that study population (Ammann et al. 1982). Animal research has recently begun to explore how prenatal alcohol exposure influences the development and functioning of the immune system. Prenatal alcohol exposure results in a reduction in the number of thymocytes (cells in the thymus that play an important role in the bodys defense against infection) and a marked reduction in T-lymphocyte responses to mitogens (substances that ordinarily stimulate the immune system) in fetal and neonatal mice (Ewald 1989; Ewald and Frost 1987). A decreased thymic as well as splenic T-cell proliferative response to the mitogen concanavalin A has been observed in 21-day-old rats exposed prenatally to alcohol (Redei et al. 1989). Moreover, deficits in immune function have been demonstrated in adult alcohol-exposed offspring (Gottesfeld, Christie et al. 1990; Norman et al. 1989, 1991; Weinberg and Jerrells 1991). There is probably no single mechanism that accounts for such a complex biological phenomenon as immune regulation and function. In fact, it is now recognized that the immune system is responsive to and communicates with both the nervous and endocrine systems (Felten et al. 1987; Grossman 1985). Hence, alcohol may disrupt the developing immune system either directly, by influencing immune tissue, or indirectly, by perturbing neuroendocrine systems or components of the autonomic nervous system that are intimately involved in immune regulation. Recent evidence supports the theory that prenatal alcohol exposure may adversely affect the immune system through its effects on the HPA axis (Redei et al. 1989), the HPG axis (Kelce et al. 1990; McGivern et al. 1988), or both. Because the sympathetic nervous system plays an important role in the regulation of immune responses (Felten et al. 1987), a series of studies have been conducted to examine the possibility that prenatal alcohol exposure may interfere with normal immune function by altering autonomic nervous innervation of lymphoid organs, a major source of cells of the immune system. Mice exposed to alcohol in utero displayed persistent suppression of cell-mediated immunity and selective neurochemical changes in lymphoid organs, including enhanced norepinephrine turnover, lower tissue levels of norepinephrine, and reduced numbers of B-adrenoceptor binding sites (Gottesfeld, Christie et al. 1990; Gottesfeld, Morgan, and Perez-Polo 1990). The fact that these changes were observed in spleen and thymus tissue but not in heart tissue suggests that the neurochemical effects were organ-specific and were not related to a generalized effect on the sympathetic nervous system. In addition, mice exposed prenatally to alcohol displayed a marked enhancement of nerve growth factor (NGF) binding activity, particularly in the thymus (Gottesfeld, Morgan, and Perez-Polo 1990). Because sympathetic neurons require NGF for their development and maintenance and because NGF may play a role in modulating immune responses, these data suggest that alcohol may disrupt the effects of NGF on modulation of immune function. These deficits in immune function and neurochemical alterations in lymphoid tissue were also observed in mice exposed to alcohol through their mother's milk (Gottesfeld and LeGrue 1990). This finding is particularly significant because blood alcohol levels in suckling pups following lactational exposure to alcohol are typically lower than blood alcohol levels found in pups exposed to alcohol in utero. These results suggest that in mice the nascent immune and nervous systems may be especially sensitive to teratogenic actions of alcohol during the critical period of early postnatal development. Taken together, the results of these studies indicate that prenatal alcohol exposure results in long-lasting immune deficiency. This detrimental effect on the developing fetus may be the result of a direct influence of alcohol on immunederived elements (thymocytes), an indirect effect of alcohol on neural activity and NGF, or humoral (HPA and HPG hormonal activity) factors. Clearly, additional research will be required to further elucidate the mechanisms by which alcohol interacts with this developing neuro-immuneendocrine network. Furthermore, it has been postulated that measures of immune responsiveness may serve as potentially useful markers for identifying individuals exposed to alcohol in utero (Norman et al. 1989, 1991). Studies on Mechanisms of The study of mechanisms underlying alcohol standing the underlying mechanisms of FAS is essential for developing such treatment strategies. Randall et al. (1990) and Schenker, Becker et al. (1990) have reviewed recent studies on mechanisms of alcohol-induced fetal damage that have focused primarily on four general areas: (1) acetaldehyde (ACH) embryotoxicity; (2) placental dysfunction and nutritional deficiency; (3) fetal hypoxia (impaired delivery of oxygen to the fetus); and (4) the role of prostaglandins. The study of mechanisms underlying alcohol teratogenesis holds some promise for devising effective prevention and intervention measures for alcohol-related fetal injury, including FAS and FAE. Alcohol Versus Acetaldehyde At present, the role of ACH (the primary metabolite of alcohol) in alcohol teratogenicity is unresolved. Although it is clear that alcohol has direct fetotoxic effects in experimental systems where alcohol is not metabolized to ACH and that therefore ACH does not play a role (e.g., Brown et al. 1979), the potential of ACH as a contributing teratogen exists (e.g., Blakely and Scott 1984; Campbell and Fantel 1983; Dreosti et al. 1981; Priscott 1985). Recent studies suggest that ACH may play some role in alcohol teratogenesis (Hurley et al. 1990; Simm and Murdoch 1990), particularly because ACH has been demonstrated to reach the fetus in rodents (Zorzano and Herrera 1989), sheep (Clarke et al. 1989), and humans (Karl et al. 1988), albeit in concentrations lower than those observed in maternal circulation. Placental Dysfunction and There are at least two ways in which fetal undernutrition may result from maternal alcohol abuse. First, the mother herself may be undernourished and have suboptimal levels of essential nutrients to transfer to the fetus. Second, even if the mother is adequately nourished, placental capacity to transport nutrients to the fetus may be compromised by maternal alcohol consumption. In human studies, maternal alcohol use has been associated with reduced placental weight and placental dysmorphology (Baldwin et al. 1982; Halmesmaki et al. 1987). Similarly, animal studies have revealed histopathological and growth anomalies in rodent placental tissue following maternal alcohol ingestion (Eguchi et al. 1989; Gordon et al. 1985; Jollie 1990). Such structural changes may result in alterations in the functioning of this vital organ system. maternal alcohol ingestion impairs the uptake and transport of several nutrients, vitamins, and minerals essential for fetal growth and development. Indeed, maternal alcohol ingestion impairs the uptake and transport of several nutrients, vitamins, and minerals essential for fetal growth and development. For example, chronic maternal alcohol intake in rodents and primates adversely affects fetal uptake and placental transport of various amino acids, which are the building blocks of protein (Fisher et al. 1982, 1983; Henderson et al. 1982; Lin 1981; Snyder et al. 1989). In one study, fetal rat tissue levels of histidine and tryptophan were significantly reduced (Lin et al. 1990). This impairment may have important implications for CNS function, because these amino acids are the precursors for the neurotransmitters histamine and serotonin. In contrast, acute alcohol exposure has not been found to influence placental transport of amino acids in primates (Fisher and Karl 1990; Schenker et al. 1989; Schenker, Becker et al. 1990). Placental transport of glucose, which is the primary fuel for fetal metabolism, is impaired following maternal alcohol treatment in rats (Singh et al. 1989; Snyder et al. 1986). This effect, however, was not obtained in perfused human placentas given acute exposure to alcohol (Schenker et al. 1989). Less is known about placental transport of essential vitamins and minerals. Some evidence suggests that the transport of folate (essential for DNA synthesis and general growth) may be impaired in rats (Fisher et al. 1985), whereas thiamine transport in the perfused human placenta is apparently not affected by acute alcohol exposure (Schenker, Johnson et al. 1990). Although experimental zinc deficiency potentiates the teratogenic effects of alcohol (Keppen et al. 1990), the effects of alcohol on placental transport of this trace metal remain controversial (Fisher et al. 1988; Ghishan et al. 1982; Greeley et al. 1990; Harris 1990). Thus, impaired placental transport of nutrients has been demonstrated in rodent models, although evidence for a similar effect on human placental function is sparse. In addition, the role of dysfunctional placental transport and maternal nutritional deficiency in alcohol-related total injury remains unsettled; protein supplementation ameliorated the adverse effects of alcohol in some cases (Weinberg et al. 1990) but failed to improve pregnancy outcome in others (Weinberg 1985). Fetal Hypoxia Fetal hypoxia (lack of oxygen) has been implicated in the etiology of alcohol-induced growth retardation (Abel 1985). Support for this hypothesis comes from studies demonstrating reduced placental and umbilical blood flow in alcoholtreated pregnant rats (Jones et al. 1981), sheep (Falconer 1990), and monkeys (Mukherjee and Hodgen 1982). Maternal intravenous alcohol infusion (1 gram per minute for 1 to 7 hours) decreased placental blood flow in pregnant ewes, an effect that persisted for at least 2 hours after cessation of alcohol infusion (Falconer 1990). Human umbilical artery strips undergo spasm following in vitro alcohol administration (Altura et al. 1983; Savoy-Moore et al. 1989; Yang et al. 1986). Furthermore, in a clinical study, maternal alcohol abuse was associated with elevated fetal erythropoietin levels, which are an indirect sign of fetal hypoxia (Halmesmaki et al. 1990). In contrast, a recent study in humans employed the noninvasive Doppler technique and found no effect of alcohol on uterine blood flow (Erskine and Richie 1986). However, in the latter study, maternal blood alcohol levels were very low (below 40 mg/dL). The issue of alcohol-induced disruption of fetoplacental blood flow and resultant hypoxia as a potential mechanism involved in the teratogenic actions of alcohol warrants further investigation and resolution. Role of Prostaglandins Prostaglandins (PGs) are members of a family of 20-carbon-chain fatty acid structures, called eicosanoids, that are derived from arachidonic acid metabolism. PGs and other arachidonic acidderived eicosanoids, such as thromboxane and prostacyclin, are involved in a wide range of biological activities, including reproductive function as well as fetal growth and development (Gold berg and Ramwell 1975; Persaud 1978). Because alcohol influences PG activity in several body tissues (Anggard 1983), an interaction between alcohol and PGs may represent an important etiologic factor in alcohol teratogenesis (Randall et al. 1987a, 1989). Support for this possibility comes from studies demonstrating the ability of PG synthesis inhibitors, such as aspirin (Randall and Anton 1984; Randall et al. 1989), indomethacin (Randall et al. 1987b), and ibuprofen (Randall, Becker, and Anton 1991), to reduce the incidence of alcohol-induced birth defects and growth retardation in mice. Indomethacin also ameliorates alcohol-induced fetal hypoplasia in a chick model (Pennington 1988; Pennington et al. 1985) and alcohol-induced suppression of breathing movements in near-term fetal sheep (Smith, Brien, Homan et al. 1989). This protective effect afforded by drugs that block PG synthesis may not, however, apply to all adverse effects of alcohol on the developing fetus (Bonthius and West 1989). Nevertheless, these results provide indirect support for the hypothesis that PGs may mediate some of the teratogenic actions of alcohol. The hypothesis is further supported by recent data on human pregnancies suggesting that maternal alcohol exposure increases fetal prostanoid release (Ylikorkala et al. 1988). More direct evidence in support of a role for PGs in alcohol teratogenesis is derived from recent work indicating that in vivo maternal alcohol exposure increases prostaglandin E1 (PGE) and thromboxane production in gestation day 10 mouse uterine and embryo tissue (Anton et al. 1990). Moreover, aspirin reduced the incidence of alcohol-induced fetal malformations, and this effect was positively correlated with the dosedependent ability of aspirin to inhibit PGE production in gestation day 10 mouse uterine and embryo tissue (Randall, Anton et al. 1991). Thromboxane and prostacyclin possess predominantly vasoconstrictive and vasodilatory action, respectively. Because the normal neural control of blood flow is lacking in placental tissue, making humoral influences especially significant, a balance between these two vasoactive prostanoids is important in the regulation of umbilical (Makila et al. 1983) and placental (Makila et al. 1986) blood flow. Thus, maternal alcohol consumption may impair normal placental transport of oxygen and nutrients by perturbing the balance between the vasoconstrictive and vasodilatory actions of thromboxane and prostacyclin, respectively. Summary The deleterious consequences of alcohol consumption during pregnancy continue to represent a substantial public health problem as well as an economic burden on society. FAS is the leading known environmental cause of mental retardation in the Western World. The deleterious consequences of alcohol consumption during pregnancy continue to represent a substantial public health problem as well as an economic burden on society. The diagnostic criteria for FAS comprise prenatal and postnatal growth retardation, a characteristic constellation of craniofacial anomalies, and CNS dysfunction. If only some of these features are present in cases in which there is a history of prenatal alcohol exposure, the children may be categorized as having FAE or alcoholrelated birth defects. The harmful effects of prenatal exposure to alcohol exist on a continuum, ranging from gross morphological defects to more subtle cognitive and behavioral deficits. FAS has been identified only in children born to mothers who drank heavily while pregnant. Although such drinking increases the risk for FAS, not all women who drink excessively during pregnancy give birth to children with FAS or even FAE. Genetic and maternal variables may explain why some infants are spared. Research efforts have been directed toward identifying biological, genetic, and environmental factors that might place some children at greater risk for alcohol-related injury. Similarly, researchers are working to identify more effectively those women whose drinking places them at high risk. The development of reliable screening instruments is critical to this effort. A number of prospective longitudinal studies have been examining the relationship between the full range of drinking patterns during pregnancy and childhood development. Despite differences among these studies in sociodemographics and design, the results have shown, in general, a positive relationship between degree of prenatal alcohol exposure and physical birth defects, growth deficiencies, and numerous cognitive and behavioral deficits. Questions of threshold doses and critical periods of exposure are of great concern for accurate assessment of risk and for reliable public health education. Animal models have been developed to address these critical questions. Indeed, animal research has played a major role in advancing our knowledge of the myriad immediate and long-term adverse consequences that follow prenatal alcohol exposure, as well as in elucidating possible mechanisms underlying the teratogenic actions of alcohol. The use of animal models has allowed researchers to exert rigorous control over such variables as dose, pattern, timing, and duration of alcohol exposure, as well as a number of potentially confounding factors that are commonly associated with chronic alcohol use, such as malnutrition, postnatal rearing conditions, disease, smoking, and other drug use. Animal studies, conducted primarily with rodents, have provided a wealth of invaluable information on the effects of prenatal alcohol exposure on sensorimotor, neuroanatomical, neurochemical, neurohormonal, and immunological systems. Moreover, structure-function relationships between alcoholinduced perturbation of these systems and abnormal behavioral manifestations of prenatal alcohol exposure are beginning to be elucidated. Animal studies, conducted primarily with rodents, have provided a wealth of invaluable information on the effects of prenatal alcohol exposure on sensorimotor, neuroanatomical, neurochemical, neurohormonal, and immunological systems. Many recent experiments have focused on identifying the underlying mechanisms of alcohol-related fetal injury. To date, the results from basic research have explored several possibilities, including ACH toxicity, impaired placental transfer of essential nutrients, fetal hypoxia, and perturbation of PGs. It is probable that more than one mechanism is involved in FAS and other types of alcohol-related fetal injury, and that different features of FAS and FAE may be manifestations of different pathophysiologies. The ultimate goal of this research is to provide a better understanding of how alcohol exposure results in damage to the developing fetus. It is hoped that such information will lead to the development of effective treatment and prevention strategies that may be employed in the clinical setting. References Abel, E.L. In utero alcohol exposure and developmental delay of response inhibition. Alcohol Clin Exp Res 6:369-376, 1982. Abel, E.L. Fetal Alcohol Syndrome and Fetal Alcobol Effects. New York: Plenum Press, 1984. Abel, E.L. Prenatal effects of alcohol on growth: A brief overview. Fed Proc 44(7):2318–2322, 1985. Abel, E.L., and Dintcheff, B.A. Factors affecting the outcome of maternal alcohol exposure: II. Maternal age. Neurobehav Toxicol Teratol 7(3):263266, 1985. Abel, E.L., and Dintcheff, B.A. Increased marihuanainduced fetotoxicity by a low dose of concomitant alcohol administration. J Stud Alcohol 47(5):440-443, 1986. Abel, E.L., and Greizerstein, H.B. 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