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Prenatal Alcohol Exposure as a Case of Involuntary Early Onset of Alcohol Use: Consequences and Proposed Mechanisms From Animal Studies.

ABSTRACT: Prenatal alcohol exposure has been found to be an important factor determining later consumption of this drug. In humans, despite the considerable diversity of variables that might influence alcohol consumption, longitudinal studies show that maternal alcohol intake during gestation is one of the best predictors of later alcohol use from adolescence to young adulthood. Experimental studies with animals also provide abundant evidence of the effects of prenatal alcohol exposure on later alcohol intake. In addition to increased consumption, other effects include enhanced palatability and attractiveness of alcohol flavor as well as sensitization to its sensory and reinforcing effects. Most of these outcomes have been obtained after exposing rats to binge-like administrations of moderate alcohol doses during the last gestational period when the fetus is already capable of detecting flavors in the amniotic fluid and learning associations with aversive or appetitive consequences. On this basis, it has been proposed that one of the mechanisms underlying the increased acceptance of alcohol after its prenatal exposure is the acquisition (by the fetus) of appetitive learning via an association between the sensory properties of alcohol and its reinforcing pharmacological effects. It also appears that this prenatal appetitive learning is mediated by the activation of the opioid system, with fetal brain acetaldehyde playing an important role, possibly as the main chemical responsible for its activation. Here, we review and analyze together the results of all animal studies testing these hypotheses through experimental manipulation of the behavioral and neurochemical elements of the assumed prenatal association. Understanding the mechanisms by which prenatal alcohol exposure favors the early initiation of alcohol consumption, along with its role in the causal pathway to alcohol disorders, may allow us to find strategies to mitigate the behavioral effects of this early experience with the drug. We propose that prenatal alcohol exposure is regarded as a case of involuntary early onset of alcohol use when designing prevention policies. This is particularly important, given the notion that the sooner alcohol intake begins, the greater the possibility of a continued history of alcohol consumption that may lead to the development of alcohol use disorders.

SUBMITTER: Gaztanaga M

PROVIDER: S-EPMC7066994 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Prenatal Alcohol Exposure as a Case of Involuntary Early Onset of Alcohol Use: Consequences and Proposed Mechanisms From Animal Studies.

Gaztañaga Mirari M Angulo-Alcalde Asier A Chotro M Gabriela MG

Frontiers in behavioral neuroscience 20200305

Prenatal alcohol exposure has been found to be an important factor determining later consumption of this drug. In humans, despite the considerable diversity of variables that might influence alcohol consumption, longitudinal studies show that maternal alcohol intake during gestation is one of the best predictors of later alcohol use from adolescence to young adulthood. Experimental studies with animals also provide abundant evidence of the effects of prenatal alcohol exposure on later alcohol in ...[more]

PMID: 32210773

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Project description:BackgroundAs large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR.ObjectivesWe aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected.MethodsUsing data from the Norwegian Mother, Father and Child Cohort Study (n = 2056) and Avon Longitudinal Study of Parents and Children (n = 6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified.ResultsThe MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied.ConclusionsOur results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumptions for their specific setting.

Project description:BackgroundIn animal models, it is possible to induce different alcohol-related dysmorphic abnormalities based on the timing of prenatal alcohol exposure (PAE). Our objective was to assess whether patterns of PAE differentially predict alcohol-related dysmorphic features in 415 infants.MethodsWe analyzed a prospective pregnancy cohort in western Ukraine enrolled between 2008 and 2014. Five distinct trajectories were previously identified to summarize PAE: (i) minimal/no PAE (n = 253), (ii) low/moderate PAE with reduction early in gestation (n = 78), (iii) low/moderate sustained PAE (n = 20), (iv) moderate/high PAE with reduction early in gestation (n = 45), and (v) high sustained PAE (n = 19). A dysmorphology examination of body size, 3 cardinal, and 15 noncardinal dysmorphic features was performed at approximately 6 to 12 months of age. A modified dysmorphology score was created based on previously published weights. Univariate comparisons were made between each dysmorphic feature and trajectory group. Features that differed by trajectory group were assessed in multivariable analyses. Models were adjusted for maternal age, prenatal vitamin use, socioeconomic status, smoking, and child's age at dysmorphology examination, with censoring weights for losses to follow-up.ResultsThe 3 highest trajectories predicted total dysmorphology score, with larger effects in sustained exposure groups. Cardinal features: The 3 highest trajectories were each associated with a 2- to 3-fold increased risk of having 2 + cardinal facial features. When assessed individually, there were no consistent associations between the individual trajectories and each cardinal feature. Noncardinal features: The 3 highest trajectories were associated with increased risk of hypotelorism. Only the highest trajectory was associated with heart murmur. The highest trajectory predicted <10th centile for sex and age on height, weight, and head circumference; and moderate/high with reduction trajectory also predicted height.ConclusionsWhile we did not observe differential results based on specific trajectories of exposure, findings support the wide range of dysmorphic features associated with PAE, particularly at high and sustained levels.

Project description:INTRODUCTION:Clinical research and studies using animal models have revealed a complex and relatively under-explored interaction between prenatal alcohol exposure (PAE) and alterations in sleep-wake behaviors. OBJECTIVES:To utilize a structured naturalistic observation-based methodology, consisting of descriptive elements, to provide insight into possible links between altered sleep and disruptive daytime presentations in children and adolescents with fetal alcohol spectrum disorder (FASD). To apply a similar structured behavioral observation protocol in a PAE animal model to compare outcomes from the experimental and clinical studies utilizing naturalistic observational methodology. METHODS:Forty pediatric patients with FASD (1.8-17.5 yrs, median age 9.4 yrs) and chronic sleep problems were assessed. In the PAE animal model, male offspring from PAE, Pair-Fed (PF), and ad libitum-fed Control (C) groups (n = 8/group) were assessed in the juvenile/preadolescent (23-25 days of age) and adolescent/pubertal (35-36 days of age) periods. RESULTS:In the clinical setting, we found that 95% of children with FASD showed disruptive or externalizing behaviors, 73% showed internalizing behaviors, 93% had circadian rhythm sleep disorders, all had chronic insomnia, and 85% had restless sleep, often with tossing/turning/kicking movements indicative of non-restorative sleep with hypermotor events. In the daytime, individuals showed excessive daytime sleepiness as well as hyperactive/hyperkinetic behaviors, an urge-to-move, and involuntary movements suggestive of hyperarousability. Alterations in sleep/wake behaviors in the PAE animal model paralleled the clinical data in many aspects, demonstrating greater sleep latencies, less total time asleep, more total time awake and longer awake bouts, more position changes, more time in transition, and longer transition bouts in PAE compared to PF and/or control animals. CONCLUSIONS:Thus, our findings provide support for the power and validity of naturalistic observational paradigms in revealing dysregulated sleep-wake behaviors and their association and/or exacerbating relationship with day and nighttime behavioral problems, such as disruptive behaviors, externalizing and internalizing disorders, and daytime sleepiness.

Project description:BackgroundThere are still inconsistent conclusions about the association of prenatal alcohol drinking with congenital heart defects (CHDs). We conducted this meta-analysis to investigate the association between prenatal alcohol exposure and the risk of overall CHDs and the CHDs subtypes.MethodsCase-control and cohort studies published before March 2015 were searched through PubMed and Embase. Two authors independently extracted data and scored the study quality according to the Newcastle-0ttawa Scale. The pooled ORs and 95%CI were estimated using the random-effects model and heterogeneity was assessed by the Q test and I2 statistic.ResultsA total of 20 studies were finally included. The results provided no evidence of the association between prenatal alcohol exposure and the risk of overall CHDs (OR = 1.06, 95%CI = 0.93-1.22), ventricular septal defects (VSDs) (OR = 1.04, 95%CI = 0.86-1.25), or atrial septal defects (ASDs) (OR = 1.40, 95%CI = 0.88-2.23). However, prenatal alcohol drinking was marginally significantly associated with conotruncal defects (CTDs) (OR = 1.24, 95%CI = 0.97-1.59) and statistically significantly associated with d-Transposition of the Great Arteries (dTGA) (OR = 1.64, 95%CI = 1.17-2.30). Moreover, both prenatal heavy drinking and binge drinking have a strong association with overall CHDs (heavy drinking: OR = 3.76, 95%CI = 1.00-14.10; binge drinking: OR = 2.49, 95%CI = 1.04-5.97), and prenatal moderate drinking has a modest association with CTDs (OR = 1.35, 95%CI = 1.05-1.75) and dTGA (OR = 1.86, 95%CI = 1.09-3.20).ConclusionsIn conclusion, the results suggested that prenatal alcohol exposure was not associated with overall CHDs or some subtypes, whereas marginally significant association was found for CTDs and statistically significant association was found for dTGA. Further prospective studies with large population and better designs are needed to explore the association of prenatal alcohol exposure with CHDs including the subtypes in specific groups.

Project description:Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels. Subsequently, ex vivo studies using green fluorescent protein (GFP)-LC3 mouse microvessel preparations revealed that ethanol treatment alters autophagy in endothelial cells. Primary cultures of mouse brain microvascular endothelial cells were used to characterize the underlying molecular mechanisms. LC3 and p62 protein levels were significantly increased in endothelial cells treated with 50?mM ethanol. The increase of autophagic vacuole number may be due to excessive autophagosome formation associated with the partial inhibition of the mammalian target of rapamycin pathway upon ethanol exposure. In addition, the progression from autophagosomes to autolysosomes, which was monitored using autophagic flux inhibitors and mRFP-EGFP vector, showed a decrease in the autolysosome number. Besides, a decrease in the Rab7 protein level was observed that may underlie the impairment of autophagosome-lysosome fusion. In addition, our results showed that ethanol-induced cell death is likely to be mediated by decreased mitochondrial integrity and release of apoptosis-inducing factor. Interestingly, incubation of cultured cells with rapamycin prevented ethanol effects on autophagic flux, ethanol-induced cell death and vascular plasticity. Taken together, these results are consistent with autophagy dysregulation in cortical microvessels upon ethanol exposure, which could contribute to the defects in angiogenesis observed in patients with FAS. Moreover, our results suggest that rapamycin represents a potential therapeutic strategy to reduce PAE-related brain developmental disorders.

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Prenatal Alcohol Exposure as a Case of Involuntary Early Onset of Alcohol Use: Consequences and Proposed Mechanisms From Animal Studies.

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Prenatal Alcohol Exposure as a Case of Involuntary Early Onset of Alcohol Use: Consequences and Proposed Mechanisms From Animal Studies.

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