The Journal of Birth Defects Research has published an open access special issue on #FASD

Fetal alcohol spectrum disorders: Mechanisms, diagnosis, treatment, and prevention

With respect to mechanisms, in this issue, Flentke et al. showed that in a chick model, alcohol’s calcium transient uncouples the Snai2/p53 regulatory loop that normally prevents apoptosis during epithelial‐mesenchymal transformation. This finding represents a novel pathway in alcohol’s potential for neurotoxicity.

The variability of the effects of alcohol during development has long been a topic of intense scrutiny. Using several lines of transgenic zebrafish, Buckley et al. demonstrated further evidence that the effects of ethanol are timing‐ and dose‐dependent, affecting embryonic lethality as well as various neuronal populations at different points of development. In addition, the authors discovered the developmental alcohol‐induced formation of hindbrain heterotopias in the fourth ventricle. This is a very novel finding, as heterotopias resulting from developmental alcohol exposure have been described in other regions of the brain; however, this is the first known report of hindbrain‐associated heterotopias.

To fully understand what alcohol does during development, it is necessary to elucidate its basic mechanisms of action. In a comprehensive review by Bhatia et al., the authors provide an overview of how reactive oxygen species (ROS) are formed, how excessive ROS impact cellular homeostasis and DNA damage repair, the cellular mechanisms that deal with excessive ROS, and the role of these ROS during embryonic/fetal development. The authors go on to describe how prenatal alcohol exposure may alter ROS levels and how this may impact cell proliferation and toxicity. Finally, the authors discuss how individual genetic variation in oxidative stress and DNA damage pathways determine risk for adverse effects of prenatal alcohol exposure, as well as potential ways to mitigate these risks.

In the ongoing pursuit of biomarkers of prenatal alcohol exposure, in this issue Holbrook et al. describe their examination of angiogenesis‐related proteins and cytokines in human placenta in subjects with or without confirmed prenatal alcohol exposure. Interestingly, they found that VEGFR2 and annexin‐A4 were significantly down‐regulated in alcohol‐exposed subjects and that two cytokines, TNF‐alpha and Il‐13, trended higher. With statistical modeling of the data, the authors demonstrated that using a combinatorial approach they were able to obtain very good diagnostic classification of prenatal alcohol exposure. In addition to providing some mechanistic clues about alcohol‐induced pathogenesis, this work greatly adds to our repertoire of potential biomarkers to identify prenatally‐exposed children.

In an intriguing paper by Breit et al., the potential long‐term behavioral effects of alcohol and cannabinoids, both alone and combined, during the third trimester equivalent in rats were examined. The authors demonstrated that co‐exposure to alcohol and a synthetic cannabinoid can aggravate the hyperactive phenotype caused by either drug alone. This is an important finding because we know these drugs interact, but we know relatively little regarding their effects during this critical period of brain development.

In a similar vein, Boa‐Amponsem et al. used a zebra fish model to examine the independent and combined effects of a cannabinoid agonist and alcohol on FASD phenotypes, dysmorphic features, and behavior. Acute or chronic exposure to high doses of the cannabinoid agonist produced FASD phenotypes. In addition, acute subthreshold doses of the cannabinoid antagonist and acute 1% ethanol produced similar phenotypes, and combined exposure induced risk‐taking behavior. These studies suggest that marijuana alone, as well as combined exposure to lower levels of alcohol and marijuana may be capable of inducing FASD‐like morphological and behavioral impairments.

In a paper by Coles et al., using a sample from Ukraine that is part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), the authors examined the independent and mediating effects of preterm delivery on infant cognitive and motor outcomes at 6 months of age. While heavy prenatal alcohol exposure increased the risk of both preterm delivery and reduced cognitive and motor development of the infants, some of the deficits in performance were mediated through preterm delivery. These data suggest that in the presence of prenatal alcohol, later gestational age at delivery may be associated with better developmental outcomes.

With respect to the consequences of prenatal alcohol exposure, O’Neill et al. explored the unique characteristics of alcohol‐associated attention deficit‐hyperactivity disorder (ADHD). ADHD is one of the most prevalent neurobehavioral conditions affecting children. There are numerous, likely interacting genetic and environmental factors involved in mediating ADHD and its severity. However, it has been recognized that ADHD in children with prenatal alcohol exposure may be quantitatively different than ADHD in children without that exposure. O’Neill et al. used proton magnetic resonance spectroscopic imaging and diffusion tensor imaging to examine the anterior corona radiata (ACR) in children with prenatal alcohol exposure, with or without ADHD; children with ADHD, but without prenatal alcohol exposure; and typically developing controls. The authors found that fractional anisotropy (a measure of fiber integrity) was reduced in children with prenatal exposure, regardless of ADHD diagnosis; however, they found that levels of choline compounds were reduced in the ACR only in children with both prenatal alcohol and ADHD. These findings provide a better understanding of the neurobiological underpinnings of prenatal alcohol‐related ADHD. It is also intriguing that imaging choline compounds in the ACR may prove to be an important biomarker of alcohol exposure in children with ADHD but with unknown alcohol status.

Doyle et al. explored the relationship between intellectual functioning and adaptive functioning including communication, socialization, and daily living skills in children with heavy prenatal alcohol exposure and controls as part of the CIFASD. The authors found that although intellectual performance and adaptive functioning are correlated in the unexposed, this relationship does not hold as strongly in children with heavy prenatal alcohol exposure who tend to have lower adaptive functioning (specifically, lower communication abilities) irrespective of their general intellectual ability. Further elucidation of factors contributing to adaptive function deficits of youth with prenatal alcohol exposure will help in understanding the etiology of these functional deficits and suggest targets for clinical intervention.

In a paper further exploring long‐term outcomes for children with prenatal alcohol exposure, O’Connor et al. presented concerning data on the risk of suicide in adolescents with FASD. The authors showed that more than twice as many adolescents with FASD in their sample reported suicidal ideation and/or made a serious suicide attempt in the last year compared to general U.S. adolescent statistics. This disparity was particularly glaring in young males with FASD among whom 29% reported a serious suicide attempt. This work suggests that health care providers should be aware of and address this specific vulnerability in adolescents with FASD, especially among males.

As FASD is theoretically a completely preventable disorder, prevention of risky drinking in pregnancy is of high importance. In a review paper by Manriquez et al., the authors describe the important prevention activities initiated by the American Congress of Obstetrics and Gynecology (ACOG) with support of the U.S. Centers for Disease Control and Prevention. In ACOG’s FASD Prevention Program, obstetric providers are helping to assess and improve the practice of Screening, Brief Intervention and Referral to Treatment (SBIRT) among women with alcohol use disorders in order to prevent FASD.

With respect to secondary prevention especially among vulnerable populations, Pei et al. assessed the impacts and cultural suitability of Parent and Child Assistance Programs (PCAP) in six first nation FASD networks. The authors showed that relational, trauma‐informed, and community‐centered FASD prevention programming was perceived to have positive impacts and to be well‐suited for use within Indigenous communities.

Although prenatal alcohol exposure is the proximal teratogen in FASD, this exposure rarely occurs in isolation. In a paper by Lebel et al., the authors addressed this complex issue and present a framework for evaluating prenatal alcohol exposure in the context of multiple pre‐ and postnatal adverse events and toxic exposures that are likely to co‐occur. In a sample of Canadian children, the authors demonstrated that 2/3 had multiple co‐occurring adverse events. In the spirit of accounting for cumulative risk, the authors presented a novel approach to addressing multiple domains of risk in order to provide a more comprehensive picture which can inform assessment and intervention approaches as well as policy.

FASD is one of the most complex developmental disabilities we face today. Together, this collection of manuscripts represents the broad range of topics such as biomarkers, mechanisms, interactions with other factors, and long term effects that require further investigation in order to prevent and ameliorate the effects of prenatal alcohol exposure, and to improve the lives of individuals with FASD.

We sincerely thank the many authors who contributed to this special issue and the many reviewers who contributed their time and effort to ensure the high quality of research represented here. We also thank Dr. Michel Vekemans and the staff of Birth Defects Research for their important contributions in making this issue possible.

Click here to access the free access special issue on FASD.

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