Exploring the Complexity of Intellectual Disability in Fetal Alcohol Spectrum Disorders

Abstract

Brain development in mammals is long lasting. It begins early during embryonic growth and is finalized in early adulthood. This progression represents a delicate choreography of molecular, cellular, and physiological processes initiated and directed by the fetal genotype in close interaction with environment. Not surprisingly, most aberrations in brain functioning including intellectual disability (ID) are attributed to either gene(s), or environment or the interaction of the two. The ensuing complexity has made the assessment of this choreography, ever challenging. A model to assess this complexity has used a mouse model (C57BL/6J or B6) that is subjected to prenatal alcohol exposure. The resulting pups show learning and memory deficits similar to patients with fetal alcohol spectrum disorder (FASD), which is associated with life-long changes in gene expression. Interestingly, this change in gene expression underlies epigenetic processes including DNA methylation and miRNAs. This paradigm is applicable to ethanol exposure at different developmental times (binge at trimesters 1, 2, and 3 as well as continuous preference drinking (70%) of 10% alcohol by B6 females during pregnancy). The exposure leads to life-long changes in neural epigenetic marks, gene expression, and a variety of defects in neurodevelopment and CNS function. We argue that this cascade may be reversed postnatally via drugs, chemicals, and environment including maternal care. Such conclusions are supported by two sets of results. First, antipsychotic drugs that are used to treat ID including psychosis function via changes in DNA methylation, a major epigenetic mark. Second, post-natal environment may improve (with enriched environments) or worsen (with negative and maternal separation stress) the cognitive ability of pups that were prenatally exposed to ethanol as well as their matched controls. In this review, we will discuss operational epigenetic mechanisms involved in the development of intellectual ability/disability in response to alcohol during prenatal or post-natal development. In doing so, we will explore the potential of epigenetic manipulation in the treatment of FASD and related disorders implicated in ID.

Acute Ethanol Increases IGF‐I‐Induced Phosphorylation of ERKs by Enhancing Recruitment of p52‐Shc to the Grb2/Shc Complex

“…In conclusion, our results indicate that acute (1–24 h) exposure to 50 mM ethanol leads to an enhanced IGF‐mediated increase in ERKs phosphorylation, which is most likely due to effects at the level of the interaction between the IGF‐IR and cellular membranes. This is significant because the IGF‐IR signaling pathway is critical in the development of the fetal brain and CNS, and thus, exposure to ethanol (and the perturbations to IGF‐IR signaling that result) during this critical period in development could contribute to the well‐known detrimental effects of in utero ethanol exposure on the cognitive function of individuals with FASD (Chokroborty‐Hoque et al, ).…”

“…Because this disorder has varying severity depending on many factors—genetics, timing, nutrition—its classification has been difficult; however, rates of the most common disorder that results from fetal alcohol exposure, fetal alcohol spectrum disorders (FASD), can reach as high as 5% of all lives births in the United States (Randall, ), although more recent estimates put this figure closer to 1% (Centers for Disease C, Prevention, ). Individuals affected by this disorder have pronounced difficulties in learning, speech, decision‐making, and behavior, which are often accompanied by malformations within the brain and CNS (Chokroborty‐Hoque et al, ). Further studies revealed that changes in CNS development and function are the result of multiple ethanol‐dependent changes at the cellular and molecular level (Torres and Zimmerberg, ; Breese et al, ).…”

Prevalence and factors associated with alcohol consumption during pregnancy

“…5,7 The US Centers for Disease Control and Prevention reports a prevalence of FAS between 0.2 and 1.5 per 1,000 live births, solidifying its position as one of the leading preventable causes of intellectual disability. 9 In the general infant population, the prevalence of FAS is estimated at 0.2 to 7 per 1,000, while FASD is much more common, with an estimated prevalence of 20 to 50 per 1,000. 8 A study conducted in the city of São Paulo estimated a prevalence of FAS and FASD at 1.52 per 1,000 and 38.69 per 1,000 newborns, respectively.…”

Making Sense of Epigenetics

“…FASD may include facial abnormalities, low birth weight, microcephaly, poor coordination, low intelligence, microophthalmia, and deficits in hearing and vision (Chokroborty-Hoque et al, 2014). Recent studies show that alcohol exposure specifically during early development induces major alterations in gene promoter methylation and histone modification and deregulates noncoding RNAs that are functionally consequential (Kleiber et al, 2014).…”