**2. Alcohol's impact on evolution, epigenetics, neurodevelopmental (functional) birth defects, and the etiology of ASD**

The origins of the earliest fertile crescent agricultural settlements have been associated with the production of beer for feasting and celebrations as early as the pre-pottery neolithic age (PPNA) [18] approximately 11,500 to 11,000 years ago around the end of the last ice age. *Homo sapiens* is the only species to have fermented, distilled, and mass-produced alcohol for large scale population consumption and exposure to laboratory animals to study the effects. Alcohol is therefore the oldest and most pervasive recreationally used neurodevelopmental teratogen, affecting human neurodevelopment since the earliest known neolithic agricultural settlements. Hence, widespread use of our social drug of choice has influenced human evolution through preconceptional (epigenetic) and prenatal exposures since those ancient times. Alcohol metabolic variants have been found among Southeast Asian human populations [19], with their fermentation of rice and berry wines dating back to 6500 to 7000 BC [20]. Hence, alcohol's transgenerational effects for 10,000 years on our evolution as a species may account for metabolic and phenotypic variance in human populations.

Given the range of effects on developing limbic brain systems, some of our most severe mental illnesses can be traced to preconceptional and prenatal alcohol exposure. Many neuropsychiatric and neurodevelopmental conditions are reported to be familial and/or transmitted intergenerationally, most likely through epigenetic [21], multifactorial gene–environment interactions. Prenatal and preconceptional alcohol exposure result in genetic and epigenetic [22] variants, which also have been described in ASD [23], schizophrenia [24], as well as other neuropsychiatric conditions [25]. Further, genetic and epigenetic variants of serotonin, dopaminergic and norepinephrine metabolism may account for the clustering of mental health disorders such as schizophrenia and bipolar disorder in families with histories of alcohol abuse.

### **2.1 Epigenetics, teratogenicity, and neurodevelopmental (functional) birth defects**

Neurodevelopmental teratogens are chemicals that cause functional birth defects in the developing zygote or embryo. In contrast to physical birth defects, functional (or neurodevelopmental) birth defects are those associated with changes in brain, central nervous system, sensorium, motor nerves, and somatosensory function [26]. Alcohol has long since been known to be a potent, prevalent and preventable neurodevelopmental teratogen leading to atypical social communication, neurocognitive processes, sensory integration and motor problems, and mood regulation/autonomic arousal. These children, adolescents, and young adults often have difficulty with adaptive functions (conceptual, social, and practical skills) despite a relatively normal intellect.

Neuroteratologists define functional birth defects as abnormalities in neurological, immune and endocrine systems, in contrast to physical anomalies such as phocomelia, cleft lip or palate, hypospadias or other structural malformations. Whereas

#### *Perspective Chapter: Autism Spectrum Disorder Neurophenotype with Preconceptional… DOI: http://dx.doi.org/10.5772/intechopen.108820*

structural problems may be identified at birth, functional abnormalities can take months or years to identify. Alcohol can cause physical birth defects but is more potent as a neurodevelopmental teratogen. An increased understanding of epigenetic effects on neurodevelopment may expand the definition of neuroteratogens to include chemicals that cause methylation effects in the gametes, not simply effects in the embryo, zygote and fetus.

Alcohol has long been described as a neurodevelopmental teratogen, affecting sperm beginning as early as 3 months preconceptionally (epigenetic) and within 2 to 3 weeks postconceptionally in the embryo (teratogenic). An array of *de novo* DNA damage (microdeletions, microinsertions, translocations) can happen as a result of alcohol's effects on the gamete, conceptus, zygote, early embryo and fetus. Carefully designed animal studies and epidemiological human studies have provided clues to the neurodevelopmental teratogenicity of alcohol – leading to many different types of *de novo* microdeletions, insertions, translocations, and epigenetic mechanisms for atypical development.

An appreciation of the epigenetic influence on ND-PAE begins before conception and embryonic neurodevelopment. Spermatogenesis takes 3 months for sperm maturation, during which time the male gametes are susceptible to a father's use of alcohol. Epigenetic effects mediated by histone protein methylation during spermatogenesis make the zygote and early embryo more susceptible to neuroteratogenic effects of prenatal alcohol exposure (i.e., maternal alcohol use) [27]. This epigenetic susceptibility of the zygote interacts with maternal factors (e.g., timing, duration, blood alcohol concentration, nutrition, metabolism, stress hormone secretion, other drug exposure) to worsen the prognosis.

#### **2.2 ND-PAE as a preventable cause of ASD**

Developmental deficits, executive functioning issues, neuropsychiatric sequelae, and adaptive functioning issues make ND-PAE a challenging, under-appreciated, and costly neurodevelopmental condition for the individual, family and society [28]. Given the association between prenatal alcohol exposure, neuroteratogenicity, and *de novo* genetic changes, our social drug of choice, alcohol may be the leading known and preventable cause of ASD. Gamete and embryonic exposure leading to microdeletions and insertions associated with autism features. As a solvent, alcohol is lipophilic – penetrating every barrier in the human body, from the blood–brain barrier to the maternal-fetal circulation, to the gut-circulatory system. Clinical overlap between symptoms necessitates a careful preconceptional and prenatal history to accurately identify patients with ND-PAE with or without comorbid ASD.

Despite public health warnings by the Centers for Disease Control and Prevention (CDC) for women to abstain from alcohol if pregnant or planning to be, and to contracept if using alcohol, the Fetal Alcohol Spectrum Disorder incidence has been reported to be as high as 1 in 20 grade school children in the United States. The simple fact that neuroteratogenic effects of prenatal alcohol exposure begins as early as the late 3rd to early 4th week post conception means that an unplanned pregnancy in a "social drinking" couple may be associated with exposure prior to pregnancy recognition. Recent reports indicate the convergence of two "perfect storm" situations: nearly 50% of pregnancies are mistimed or unplanned and drinking rates among childbearing age women has been steadily on the rise, exceeding that of males for some age groups.

Like other DSM-5 conditions, the diagnosis of Autism Spectrum Disorder (ASD) as a DSM-5 disorder is made based on symptoms rather than etiology, with a wide array of genetic and environmentally-acquired issues giving rise to the phenotypic expression. A number of neurodevelopmental teratogens have been identified in our human ecosystem, from petroleum derivatives, solvents, recreational substances, and pharmaceuticals. However, the heterogeneity of symptoms and difficulty with cause-effect clinical research has left large gaps in understanding etiology of autism spectrum disorder, outside of the known associated rare genetic disorders [29]. The American Academy of Child and Adolescent Psychiatry recommends genetic testing (chromosomes and a microarray) of individuals with ASD to rule out genetic variants associated with syndromic conditions. Findings may not be associated with any known clinical disorder because of the range of possible mutations that may lead to a phenotypic change.
