A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription: A possible link between twelve autism risk factors and the autism ‘epidemic’

Abstract

Human alpha-fetoprotein is a pregnancy-associated protein with an undetermined physiological role. As human alpha-fetoprotein binds retinoids and inhibits estrogen-dependent cancer cell proliferation, and because retinoic acid (a retinol metabolite) and estradiol (an estrogen) can both initiate cellular gene transcription, it is hypothesized here that alpha-fetoprotein functions during critical gestational periods to prevent retinoic acid and maternal estradiol from inappropriately stimulating gene expression in developing brain regions which are sensitive to these chemicals. Prenatal/maternal factors linked to increased autism risk include valproic acid, thalidomide, alcohol, rubella, cytomegalovirus, depression, schizophrenia, obsessive–compulsive disorder, autoimmune disease, stress, allergic reaction, and hypothyroidism. It will be shown how each of these risk factors may initiate expression of genes which are sensitive to retinoic acid and/or estradiol – whether by direct promotion or by reducing production of alpha-fetoprotein. It is thus hypothesized here that autism is not a genetic disorder, but is rather an epigenetic disruption in brain development caused by gestational exposure to chemicals and/or conditions which either inhibit alpha-fetoprotein production or directly promote retinoic acid-sensitive or estradiol-sensitive gene expression. This causation model leads to potential chemical explanations for autistic brain morphology, the distinct symptomatology of Asperger’s syndrome, and the differences between high-functioning and low-functioning autisms with regard to mental retardation, physical malformation, and sex ratio. It will be discussed how folic acid may cause autism under the retinoic acid/estradiol model, and the history of prenatal folic acid supplementation will be shown to coincide with the history of what is popularly known as the autism epidemic. It is thus hypothesized here that prenatal folic acid supplementation has contributed to the post-1980 increase in US autism diagnoses. In addition to explaining the epidemic within the wider retinoic acid/estradiol model of causation, this theory leads to potential explanations for certain genetic findings in autism, autistic regression, and changing trends in autism symptomatology with regard to mental retardation, wheat allergy, and gastrointestinal problems.

Introduction

Autism spectrum disorders (ASDs) are generally characterized by impairments in communication, social reciprocity, and imagination, accompanied by limited, repetitive interests and behaviors. ASDs appear in the fourth version of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) under the heading of pervasive developmental disorders (PDDs). PDDs include autistic disorder (autism), Asperger’s disorder, pervasive developmental disorder, not otherwise specified (PDD–NOS; also atypical autism), Rett’s disorder, and childhood disintegrative disorder (CDD). Some sources omit Rett’s disorder and/or CDD from discussion of ASDs, treating these two conditions as non-ASD PDDs. Symptoms of autism manifest prior to age three, but Asperger’s symptoms present later in childhood, when increasing social demands reveal the disability; PDD-NOS can present before or after age three [1]. The overall male to female ratio in ASDs is 4.5:1 [2].

In 1943, Kanner systematically described the symptoms of autistic children for the first time [3]. Before the 1980s, it was believed that autism affected only 1 in every 2000 children, but a recent study indicates that ASDs occur in about 1 in 110 US children [2]. Whether this apparent increase reflects a true change in prevalence or an effect of improved/broadened diagnostic criteria remains a topic of controversy. While it is suspected that both heredity and environment play a role in autism development, genetic research has yet to yield a consistent chromosomal liability in ASDs.

This paper will introduce a novel theory of autism causation which is built upon the ability of certain endogenous biochemicals to initiate cellular gene transcription. It will be shown how at least 12 autism risk factors may allow these special chemicals too much access to the developing fetal brain. This new causation model is particularly powerful because it leads to potential explanations for autistic brain morphology, the distinct symptomatology of Asperger’s syndrome, and the differences between high-functioning and low-functioning autisms with regard to mental retardation, physical malformation, and sex ratio. This model may also be able to explain the post-1980 increase in autism diagnoses popularly referred to as the autism epidemic, as will be discussed in the development of this paper’s secondary hypothesis. This new theory of epidemic causation leads to potential explanations for certain genetic findings in autism, autistic regression, and changing trends in autism symptomatology.