Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

Abstract

Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulinassociated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment.

Proteomic Analysis of Baboon Cerebral Artery Reveals Potential Pathways of Damage by Prenatal Alcohol Exposure*

“…On a final note, two large protein groups (metabolism and structure) identified in cerebral arteries as targets of PAE, are strikingly like data from a global chemo-biology approach used to analyze murine neuronal tissue following PAE (74). This similarity raises the question as to whether PAE exerts universal effect on various tissues/organs.…”

Hippocampal neuron populations are reduced in vervet monkeys with fetal alcohol exposure

“…Effects on fetal micronutrient levels in the brains of FAE offspring are both more plausible and less amenable to control (Shankar, Ronis, & Badger, 2007; Weinberg, 1984). It is known (review: Feltes, de Faria Poloni, Nunes, & Bonatto, 2014) that ethanol impairs intestinal absorption and metabolism of particular vitamins and other micronutrients and that normally sufficient levels of zinc and iron (Keen et al, 2010; Rufer et al, 2012) may be inadequate for neural development under conditions of maternal ethanol consumption. Of the principal vitamins, folic acid, a micronutrient critical to fetal brain development (Christensen & Rosenblatt, 1995), and nicotinamide (Ieraci & Herrera, 2006) are selectively depleted by chronic ethanol exposure, while conversion of vitamin A to retinoic acid (Keir, 1991; Zachman & Grummer, 1998) is competitively antagonized by ethanol.…”

“…Supplementation with each of these micronutrients, as well as vitamins C and E, produced modest improvement in either the neural and/or behavioral effects of fetal ethanol exposure (e.g., Hewitt et al, 2011;Ieraci & Herrera, 2006;Marino Aksenov, & Kelly, 2004;Naseer et al, 2011;Wang et al, 2009), but the mechanisms of damage and amelioration have not been persuasively identified. Using a systems approach and transcriptome data, Feltes et al (2014) have shown that genes related to retinoic acid, the niacin component of nicotinamide, and folate metabo-lism were underexpressed in mice exposed to ethanol at 14-16 days of gestation. Another relevant focus of contemporary study is the epigenome: among other effects, ethanol enhances global DNA hypermethylation in frontal cortex and hippocampus (Muralidharan, Sarmah, Zhou, & Marrs, 2013;Zhou et al, 2011).…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…The important role of CYP2E1 in producing carcinogenic etheno-DNA lesions was consistently reported in the experimental model and alcoholic individuals ). In addition, abnormal retinoic acid metabolism is considered important in fetal alcohol syndrome or effects due to its importance in early development and differentiation (Feltes, de Faria Poloni, Nunes, & Bonatto, 2014;Kane, Folias, Wang, & Napoli, 2010;Keyte & Hutson, 2012).…”