The Autism Society Event and Education Recordings Archive

Statement of the problem: Evidence suggests a yet unidentified gene-gender-environment link to classical autism. Domains of the brain develop at different rates, during different developmental stages, resulting in differentially sensitive periods for each. High stress may induce damage to those regions, with negative feed-forward effects from cortisol toxicity, and interconnectivity is nullified as cytotoxic inflammatory metabolites degrade fledgling connections. This work presents four key learning objectives for advanced audiences that (a) explains the environment-gender-gene link, (b) describes the role of docosahexaenoic acid (DHA) and the function of estradiol in males, (c) introduces a previously unexamined gene most likely responsible for primary etiology, and (d) illustrates selective advantages arising from the mechanisms of autistogenesis.

Procedure: Meta-narrative review provides answers amenable to the biology and the psychology of this pervasive developmental disorder. Autistogenesis describes how genetic conformation orients the infant’s neurological response to negative aspects of the epigenetic matrix, including abuse and social isolation, inappropriate or inadequate nutrition, hormonal influence, and the inflammatory response resulting from illness, insult, injury, or immunoexcitotoxicity.

Results: Chronic illness or insult up-regulates neurotoxic inflammation mediators. These processes result in an autotoxic cycle leading to further neurodegeneration and autistic changes are not restricted to olivary-cerebellar pathways. MRI studies indicate individuals on the autism spectrum with significantly reduced, disordered, and dysfunction Von Economo neurons within the frontoinsular cortex and anterior cingulate and extending through layer 6.The neuroinflammatory cascade may lead to diminishment of connections to and from the amygdala, septal nuclei, cingulate gyrus, hippocampus, and the neocortex as neurite formation and synapses per axon is reduced. These events extend to the mirror neuron system (MNS), which permeates the cerebral cortex, and is well-rooted in the ventral premotor cortex, the anterior, inferior fronto- and tempero-parietal regions, and the primary somatosensory cortex.

The MNS is intensely interconnected with limbic system, orbital frontal lobes, insula and each region experiences myelination at different rates during different periods of time. Deficits within the MNS represent a key neurological correlate to essentially abrogated social behaviors diagnostic of classical autism. MNS activates while witnessing another’s actions, producing matching somatosensory experience, including proprioceptive feedback that is mapped onto the self. MNS is modulated by emotion and motivation, and provides the access to empathic experience of another’s emotion and pain, while creating the means by which facial expressions and other communicative gestures are interpreted.

Docosahexaenoic acid (DHA) inhibits apoptosis induced by sphingosine, improves neuronal differentiation, stimulates neurite growth factors, and enhances phospholipid production required for neurite elongation. Counter to these positive effects, extreme oxidative stress produces reactive oxygen species capable of generating DHA peroxidation products that induce neuronal damage. This paper asserts that DHA supplementation, without added arachidonic acid (AA) during sensitive developmental stages, may also result in permanent aberrant neuronal hardwiring due to antiapoptotic neuroprotection. Thus, neuroprotection may inhibit apoptosis where neurite pruning is necessary for appropriate development.

The greater proportion of women in American and Canadian society consumes less DHA than the suggested 300 mg/day. Though fetal demand is high, evidenced by the preference for DHA over other LC-PUFAs in the basal membrane of the placenta, there is not concurrent increase in mothers’ dietary selection for foods high in DHA concentration. Inadequate supply to the fetus may lead to irreversible neurological damage. Neurite outgrowth is suppressed by AA through the inhibition of ethanolamine glycerophospholipids, the induction of the inflammatory response cascade, and in concert with tumor necrosis factor.

Incorrect dietary ratios of DHA to AA may induce developmental abnormality characteristic of autism. Typical American diets result in reduced breast milk DHA compared with foreign equivalents, due to consumption of foods heavy in AA and its precursors, contributing to diminished DHA in the developing brain, hindering neurite outgrowth and reducing neuroprotection. Previous in vitro and in vivo studies suggest DHA/AA ratios in commercially prepared infant formulas are potentially toxic for normal brain development. At ratios of .56 or less, negative effects on health were detected in vivo, with critical levels for safety at a ratio of 1.8 in vitro. Since 2002, commercially prepared infant formula contains DHA to AA ratios of approximately .37 to .50, in attempt to  replicate American women’s breast milk, a DHA/AA ratio .74 lower than the top 10 countries for concentration of DHA/AA in breast milk worldwide.

Popular infant nutritional supplement drinks contain DHA without AA. Excess DHA without AA or adequate antioxidants induces apoptosis through a translocation of phosphatidylserine (PS), heightened bax and capase-3 activity subsequent to disruption of mitochondrial transmembrane potential, and activation of peroxisome proliferator-activated receptors (PPARs) via the p38 signaling pathway. Chronic neuroinflammation leads to non-enzymatic oxidation of DHA which produces highly reactive neuroketals and results in generation of further toxic metabolites.

Pseudogenes, competitive endogenous RNA, and microRNA represent genomic and transcription level sources of dysfunction not examined in existing literature. Abnormal cytochrome P450 genes contribute to neuroinflammatory damage leading to behaviors of the autism spectrum. Postnatal gonadotropin and sex steroids surge by 3 months of age resulting in hormonal expression above pubertal levels. In males, the hypothalamic-pituitary-testicular axis generates high serum androgens, though testosterone is a neurotoxin within the developing CNS. This author suggests P450arom on chromosome 15q21.2 aromatase represents a biomarker for autism as it converts testosterone to estradiol through similar mechanisms that convert excess DHA and AA by cytochromeP450 into feed-forward neurotoxic inflammatory metabolites.

Estradiol is a powerful neuroprotective agent, a modulator of oxytocin receptors known deficient in classical autism, and regulates conversion of precursors into neuroprotective DHA. A recent study indicates DHA administered to pre-term infants improves Bayley Mental Development (MDI) scores at 18 months corrected age in female infants only. The primary neuroprotective agent in males is estradiol as males do not produce DHA above dietary background.  Estradiol is converted from neurologically cytotoxic testosterone by the P450arom enzyme, and establishes a developmental defense against inflammation mediated damage, a paramount function as neuronal DHA concentrations fall during the gonadotropin surge. Therefore, converging evidence indicates a system linking environment, gender, and both translation and transcription level genetic regulation.

Evolutionary biology must inform evolutionary psychology. A maturing infant brain susceptible to change due to stress provides a powerful selective advantage. Environmental stressors cannot induce gene-based adaptation in the same generation, so infant physiology provides adaptive processes targeted to sexually dimorphic males. A so-called bully assumes a dominance position in naturalistic settings, without genetic alteration, due to increased risking taking, less empathic connection to competitors, and the inclination to not play well with others. Diets heavy with meat diminishes DHA to AA ratios, promoting offspring more likely to take risks, hunt quarry capable of returning the fight, and less likely to empathize with closely related hominid prey. Much of the earliest Homo sapiens ancestry lived along the Tsitsikamma coast of South Africa, enjoying diets rich in DHA, while ostensibly antisocial Neanderthal roamed central Europe on diets heavy with red meat.

Conclusions: Different regions of the developing brain progress at different rates, resulting in differentially sensitive periods for each, and high stress may induce damage to those regions. Interconnectivity is nullified as cortisol and inflammatory metabolites degrade fledgling connections as plasticity myelinates aberrant connections. DHA inhibits apoptosis, enhances neuronal differentiation, stimulates neurite growth factors, and up-regulates phospholipids necessary for neurite elongation. Excess DHA is transformed into toxic metabolites through peroxidation during extreme stress, and may inhibit apoptosis where neurite pruning is necessary for appropriate development.

American breast milk is typically lower in DHA compared with foreign equivalents, due to consumption of foods heavy in AA and its precursors, contributing to diminished DHA in the developing brain. Previous studies suggest DHA/AA ratios in commercially prepared infant formulas are potentially toxic for normal brain development. Chronic neuroinflammation may lead to non-enzymatic oxidation of excess DHA which produces highly reactive neuroketals and results in generation of further toxic metabolites.

Pseudogenes, competitive endogenous RNA, and microRNA represent genomic and transcription level sources of dysfunction. Abnormal cytochrome P450 genes contribute to neuroinflammatory damage leading to behaviors of the autism spectrum. This author suggests that the P450arom gene on chromosome 15q21.2 represents a biomarker for autism as its enzyme converts testosterone to estradiol. Estradiol is a powerful neuroprotective agent, a modulator of oxytocin receptors known deficient in classical autism, and regulates conversion of precursors into neuroprotective DHA.

The systems theory of autistogenesis adequately describes and predicts many mechanisms capable of inducing autism, yet the course may paradoxically grant selectively advantage in an inhospitable environment, as playing well with others is undesirable in a high stakes environment. Environmental stressors cannot induce gene-based adaptation in the same generation, so evolution provides infant physiology with adaptive processes targeted primarily to sexually dimorphic males, yet damage to any aspect of this powerful system leads to catastrophic consequences. Therefore, this systems theory explains the ontogeny and phylogeny of classical autism.