Blood alcohol concentration: A critical factor for producing fetal alcohol effects

doi:10.1016/0741-8329(86)90036-4

Alcohol

Volume 3, Issue 4, July–August 1986, Pages 269-272

https://doi.org/10.1016/0741-8329(86)90036-4 Get rights and content

Abstract

A dose of 6.6 g/kg of alcohol, delivered in 12 equally-spaced fractions each 24 hours via an artificial rearing procedure during postnatal days 4–10, produced mean blood alcohol concentrations (BACs) that were low (46.6 mg/dl), but stable with time. This relatively constant alcohol exposure did not limit brain growth in neonatal rats when measured on postnatal day 10. The same daily dose concentrated into 6 fractions over 12 hours (with 6 alcohol-free fractions the remaining 12 hours) resulted in cyclic BACs having high peaks (270.2 mg/dl). The cyclic regimen produced a significant reduction in brain growth. Thus, the peak blood alcohol concentration is a critical factor in determining the minimum dose for producing microencephaly and must be considered when estimating the relative teratogenic risks of alcohol intake during pregnancy.

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Cited by (132)

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Alcohol is one of the most widely misused substances in the world. Alcohol consumption by pregnant women often results in an array of fetal developmental abnormalities, but the damage to the fetus by alcohol remains poorly understood. The limited knowledge regarding the molecular targets of alcohol in the developing fetus constitutes one of the major obstacles in developing effective pharmacological interventions that could prevent fetal damage after alcohol consumption by pregnant women. The fetal cerebral artery is emerging as an important mediator of fetal cerebral damage by maternal alcohol drinking. In the present work, we conduct proteomics analysis of cerebral (basilar) artery lysates of near-term fetal baboons to search for protein targets of fetal alcohol exposure. Our study demonstrates that 3 episodes of binge alcohol exposure during the second trimester-equivalent of human pregnancy are sufficient to render profound changes in fetal cerebral artery proteome. These changes persisted, as they were detected in near-term fetuses. In particular, the relative abundance of 238 proteins differed significantly between control and alcohol-exposed fetuses. Enrichment analysis pointed at the group of metabolic activity proteins as a major class targeted by alcohol. Western blotting confirmed upregulation of the aldehyde dehydrogenase 6 family member A1 (ALDH6A1) in cerebral artery lysates from alcohol-exposed fetuses. This upregulation translated to greater ALDH activity of cerebral artery lysate of near-term fetuses following prenatal alcohol exposure when compared with controls.
Effects of prenatal binge-like ethanol exposure and maternal stress on postnatal morphological development of hippocampal neurons in rats
2017, International Journal of Developmental Neuroscience
Alcohol is one of the most commonly used drugs of abuse negatively affecting human health and it is known as a potent teratogen responsible for fetal alcohol syndrome (FAS), which is characterized by cognitive deficits especially pronounced in juveniles but ameliorating in adults. Searching for the potential morphological correlates of these effects, in this study, we compared the course of developmental changes in the morphology of principal hippocampal neurons in fetal-alcohol (A group), intubated control (IC group), and intact control male rats (C group) over a protracted period of the first two postnatal months.
Ethanol was administered to the pregnant Wistar dams intragastrically, throughout gestation days (GD) 7–20, at a total dose of 6 g/kg/day resulting in the mean blood alcohol concentration (BAC) of 246.6 ± 40.9 mg/dl. Ten morphometric parameters of Golgi-stained hippocampal neurons (pyramidal and granule) from CA1, CA3, and DG areas were examined at critical postnatal days (PD): at birth (PD1), at the end of the brain growth spurt period (PD10), in juveniles (PD30), and in young adults (PD60).
During postnatal development, the temporal pattern of morphometric changes was shown to be region-dependent with most significant alterations observed between PD1-30 in the CA region and between PD10-30 in the DG region. It was also parameter-dependent with the soma size (except for CA3 pyramids), number of primary dendrites, dendrite diameter, dendritic tortuosity and the branch angle demonstrating little changes, while the total dendritic field area, dendritic length, number of dendritic bifurcations, and spine density being highly increased in all hippocampal regions during the first postnatal month. Moderate ethanol intoxication and the maternal intubation stress during gestation, showed similar, transient effects on the neuron development manifested as a smaller soma size in granule cells, reduced dendritic parameters and lower spine density in pyramidal neurons at PD1. Full recovery from these effects took place within the first 10 postnatal days.
This study showed regional and temporal differences in the development of different morphometric features of principal hippocampal neurons in intact subjects over a protracted 2-months postnatal period. It also demonstrated an overlap in the effects of a moderate fetal ethanol intoxication and a mild maternal stress produced by the intragastric intubation, a commonly used method of ethanol administration to the pregnant dams. Fast recovery from the adverse effects on the soma size, dendritic arborization and spines density observed at birth indicates towards the fetal ethanol/stress induced developmental retardation.
Sex-specific effects of developmental alcohol exposure on cocaine-induced place preference in adulthood
2017, Behavioural Brain Research
Citation Excerpt :
The doses of alcohol used in this study (4.5 g/kg for dams and 3.0 g/kg for pups) were selected to give equivalent peak blood alcohol concentrations (BACs) of between 300 and 400 mg/dl in dams and pups, at three and two hours respectively [31,32]. These doses were selected for two reasons: 1) high doses are critical to produce reproducible reductions in brain growth [33], and 2) this model aims to represent the high BACs which would likely have been experienced by children with fetal alcohol syndrome, the most severe form of FASD [34]. Three hours after intubations on GD 20, 10 μl of blood was collected from ET and IC dams from the tail vein.
Fetal Alcohol Syndrome (FAS) is associated with high rates of drug addiction in adulthood. One possible basis for increased drug use in this population is altered sensitivity to drug-associated contexts. This experiment utilized a rat model of FASD to examine behavioral and neural changes in the processing of drug cues in adulthood. Alcohol was given by intragastric intubation to pregnant rats throughout gestation and to rat pups during the early postnatal period (ET group). Controls consisted of a non-treated group (NC) and a pair-fed group given the intubation procedure without alcohol (IC). On postnatal day (PD) 90, rats from all treatment groups were given saline, 0.3 mg/kg, 3.0 mg/kg, or 10.0 mg/kg cocaine pairings with a specific context in the conditioned place preference (CPP) paradigm. While control animals of both sexes showed cocaine CPP at the 3.0 and 10.0 mg/kg doses, ET females also showed cocaine CPP at 0.3 mg/kg. This was accompanied by a decrease in c-Fos/GAD₆₇ cells in the nucleus accumbens (NAc) shell and GAD₆₇-only cells in the NAc shell and PFC at this 0.3 mg/kg dose. ET males failed to show cocaine CPP at the 3.0 mg/kg dose. This was associated with an increase in c-Fos only-labeled cells in the NAc core and PFC at this 3.0 mg/kg dose. These results suggest that developmental alcohol exposure has a sexually-dimorphic effect on cocaine’s conditioning effects in adulthood and the NAc.
Safety assessment for ethanol-based topical antiseptic use by health care workers: Evaluation of developmental toxicity potential
2015, Regulatory Toxicology and Pharmacology
Citation Excerpt :
In monkeys, behavioral changes were reported at BACs in the 180–200 range; at BACs above 200, the incidence of major physical morphological differences and fetal mortality increased, including spontaneous abortions and pregnancy failures. Once maternal BAC levels are above 200 mg/dL in monkeys and 375 mg/dL in rats, there seems to be increased risk of fetal mortality (Bonthius and West, 1988; Bowden et al., 1983; Clarren et al., 1987; Pierce and West, 1986a; Vaglenova and Petkov, 1998). The small number of studies that have reported developmental effects at BACs below 150 mg/dL (Fig. 2) have been shown to have significant design flaws that reduce their utility in identifying the peak BAC associated with the onset of developmental effects.
Ethanol-based topical antiseptic hand rubs, commonly referred to as alcohol-based hand sanitizers (ABHS), are routinely used as the standard of care to reduce the presence of viable bacteria on the skin and are an important element of infection control procedures in the healthcare industry. There are no reported indications of safety concerns associated with the use of these products in the workplace. However, the prevalence of such alcohol-based products in healthcare facilities and safety questions raised by the U.S. FDA led us to assess the potential for developmental toxicity under relevant product-use scenarios. Estimates from a physiologically based pharmacokinetic modeling approach suggest that occupational use of alcohol-based topical antiseptics in the healthcare industry can generate low, detectable concentrations of ethanol in blood. This unintended systemic dose probably reflects contributions from both dermal absorption and inhalation of volatilized product. The resulting internal dose is low, even under hypothetical, worst case intensive use assumptions. A significant margin of exposure (MOE) exists compared to demonstrated effect levels for developmental toxicity under worst case use scenarios, and the MOE is even more significant for typical anticipated occupational use patterns. The estimated internal doses of ethanol from topical application of alcohol-based hand sanitizers are also in the range of those associated with consumption of non-alcoholic beverages (i.e., non-alcoholic beer, flavored water, and orange juice), which are considered safe for consumers. Additionally, the estimated internal doses associated with expected exposure scenarios are below or in the range of the expected internal doses associated with the current occupational exposure limit for ethanol set by the Occupational Safety and Health Administration. These results support the conclusion that there is no significant risk of developmental or reproductive toxicity from repeated occupational exposures and high frequency use of ABHSs or surgical scrubs. Overall, the data support the conclusion that alcohol-based hand sanitizer products are safe for their intended use in hand hygiene as a critical infection prevention strategy in healthcare settings.
Nutrition implications for fetal alcohol spectrum disorder
2014, Advances in Nutrition
Prenatal alcohol exposure produces a multitude of detrimental alcohol-induced defects in children collectively known as fetal alcohol spectrum disorder (FASD). Children with FASD often exhibit delayed or abnormal mental, neural, and physical growth. Socioeconomic status, race, genetics, parity, gravidity, age, smoking, and alcohol consumption patterns are all factors that may influence FASD. Optimal maternal nutritional status is of utmost importance for proper fetal development, yet is often altered with alcohol consumption. It is critical to determine a means to resolve and reduce the physical and neurological malformations that develop in the fetus as a result of prenatal alcohol exposure. Because there is a lack of information on the role of nutrients and prenatal nutrition interventions for FASD, the focus of this review is to provide an overview of nutrients (vitamin A, docosahexaenoic acid, folic acid, zinc, choline, vitamin E, and selenium) that may prevent or alleviate the development of FASD. Results from various nutrient supplementation studies in animal models and FASD-related research conducted in humans provide insight into the plausibility of prenatal nutrition interventions for FASD. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of multiple-nutrient supplementation.
Nuanced but significant: How ethanol perturbs avian cranial neural crest cell actin cytoskeleton, migration and proliferation
2013, Alcohol
Citation Excerpt :
It has been previously established that the effects on the fetus of prenatal ethanol exposure are dose dependent (Chernoff, 1977; Peiffer, Majewski, Fischbach, Bierich, & Volk, 1979; Samson & Grant, 1984). Moreover, as demonstrated in experimental animals, the occurrence of fetal abnormalities such as microcephaly and microencephaly are directly related not to the ethanol dose per se, but to high peak blood alcohol concentrations (BACs) achieved by the pattern and frequency of ethanol administration (Bonthius, Goodlett, & West, 1988; Maier, Strittmatter, Chen, & West, 1995; Pierce & West, 1986a,b; Schenker et al., 1990). The present authors aspired to accurately determine the ethanol concentration at which abnormalities will be observed in vitro.
Children with fetal alcohol syndrome (FAS) display striking craniofacial abnormalities. These features are proposed to result from perturbations in the morphology and function of cranial neural crest cells (cNCCs), which contribute significantly to the craniofacial complex. While certain pathways by which this may occur have been suggested, precise teratogenic mechanisms remain intensely investigated, as does the question of the teratogenic dose. The present study focused on examining how avian cNCC actin cytoskeleton, migratory distance, and proliferation are affected ex vivo by exposure to ethanol concentrations that simulate maternal intoxication. Chick cNCCs were cultured in 0.2% and 0.4% v/v ethanol. Distances migrated by both ethanol-treated and control cells at 24 and 48 h were recorded. Following phalloidin immunocytochemistry, treated and control cNCCs were compared morphologically and quantitatively. Apoptosis and proliferation in control versus treated cNCCs were also studied. Chick cNCCs cultured in ethanol lost their spindle-like shapes and their ordered cytoskeleton. There was a significant stage-dependent effect on cNCC migration at 24 h (p = 0.035), which was greatest at stage 10 (HH). Ethanol treatment for 48 h revealed a significant main effect for ethanol, chiefly at the 0.4% level. There was also an interaction effect between ethanol dose and stage of development (stage 9 HH). Actin microfilament disruption was quantitatively increased by ethanol at the doses studied while cNCC proliferation was increased but not significantly. Ethanol had no effect on cNCC apoptosis. At ethanol levels likely to induce human FAS, avian cNCCs exhibit various subtle, potentially significant changes in morphology, migration, and proliferation, with possible consequences for fated structures.

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ArticleBlood alcohol concentration: A critical factor for producing fetal alcohol effects

Abstract

Dev Brain Res

J Pediatr

Early Hum Dev

J Pediatr

Lancet

J Neurol Sci

Alcohol

Alcohol

Drug Alcohol Depend

Dev Brain Res

Alcohol

In utero ethanol exposure: Functional and structural brain damage

Neurobehav Toxicol Teratol

The fetal alcohol syndrome in mice: an animal model

Teratology

Impaired brain growth in neonatal rat pups exposed to ethanol

Science

The later development of the brain and its vulnerability

The quantitative growth and development of the human brain

Arch Dis Child

Drinking during pregnancy

J Stud Alcohol

Article
Blood alcohol concentration: A critical factor for producing fetal alcohol effects