Autism spectrum disorders (ASD) are characterized by signs that may be detectable by 6 months of age (Brooks & Meltzoff, 2007, 2008; Meltzoff & Brooks, 2007; Roos, McDuffie, Weismer, & Gernsbacher, 2008) that include (a) qualitative and quantitative impairments of social interaction, (b) deficits in the use and production of communicative means, (c) cyclic central nervous system (CNS) activity producing repetitive behaviors, and (d) a preference for environmental sameness coupled to an aversion for extremes in sensory novelty (Belva, Matson, Hattier, Kozlowski, & Bamburg, 2012; Lundström et al., 2012). The number of children diagnosed with disorders on the autism spectrum has increased since 2001 (Bertrand et al., 2001; Chakrabarti & Fombonne, 2001) to an approximated 3.5 million children nationwide, or an estimated 1 out of every 91 individuals in the United States (Kogan, Blumberg, Schieve, Boyle, & van Dyck, 2009) at a national cost of approximately US$26 billion annually (Baird et al., 2006) with males outnumbering females 4 to 1 (Fombonne, 2005). This degree of prevalence impels the search for discernible etiology, biological assay, evidence-based treatment, and practical routes to prevention.

Following Kanner (1943, 1949) and Bettelheim (1967), social outcry pushed many psychologists into a corner. While behaviorism was proclaiming mental disorder principally due to environment, parents argued any consideration of high-stress environments as attacking mothers, and many psychologists withdrew. Today, some still point to video data from Baranek (1999) suggesting that some parents may increase efforts to engage children on average by month 13.86 (SD = 7.43) though diagnosed with autism on average by month 32.55 (SD = 8.62). This study is sometimes taken to “prove” parental efficacy, although current studies (Brooks & Meltzoff, 2007, 2008; Meltzoff & Brooks, 2007; Roos et al., 2008) indicate that awareness of developmental abnormality likely began earlier than the stated time for parents’ first detection, standard deviation included (Baranek, 1999). This does not necessarily suggest attempts at deception. Neurotypical caregivers discern changes and respond in typical fashion, but these videos do not and cannot describe the early environment, in a broad sense, in relation to genetic variability prior to detection.

Neuropsychologists, neurophysiologists, psychiatrists, endocrinologists, immunologists, and behavioral geneticists continued to study the environmental influence on neurodevelopment, including that of infant maltreatment. For example, in the largest and most recent twin study of autism (Hallmayer et al., 2011), following current diagnostic standards, monozygotic and dizygotic pairs with at least one twin clinically diagnosed with an ASD or strict autism, environment was the critical factor overall. Heritability was estimated at .38, 95% confidence interval (CI) [.14, .67] for those with an ASD, whereas the shared environment was .58, 95% CI [.30, .80] (Hallmayer et al., 2011) regardless of gender. For those diagnosed with strict autism, males and females were again the same, where heritability was estimated at .37, 95% CI [.08, .84], whereas the shared environmental aspect was .55, 95% CI [.09, .81] (Hallmayer et al., 2011). This article does not suggest that all ASD is the result of widespread child abuse. Maternal nutrition and stress-induced epigenetic DNA regulation and methylation, neonatal nutrition, the general stress surrounding the home (e.g., urban areas of high violent crime, regions of the globe shattered by war, infectious disease), and environmental toxins are also part of the environment, and the common impacts on biology are key.

The purpose of this work is to synthesize from the available information a framework on which to build; to report that model as a unified whole, at one time; and through the best medium available, to avoid sequestration within disparate specialty journals. The result is the systems theory approach to autistogenesis (Malone, 2011a, 2011b, 2011c, 2011d), unifying current findings from diverse fields, capable of explaining why the previous study (Hallmayer et al., 2011) also detected a range of heritability (41% to 56% in males, 13% to 16% in females), yet shared twin environment (57% to 41% in males, 78% to 72% in females; Hallmayer et al., 2011).

This work begins with an examination of environmental stressors on infant neuronal development. Second, a source of dysfunction not well described is the potential hazards resulting from the metabolism of inadequate docosahexaenoic acid (DHA; n-3) to arachidonic acid (AA; n-6) ratios in breast milk and infant formula. Third, the influence of cytochrome P450-dependent and enzyme-independent reactions, which may convert DHA and AA into neuroprotective agents or toxic proinflammatory metabolites, are examined. Finally, this work identifies the predisposing gene that explains vulnerability to environmental triggers, reveals nearly a dozen links of male overrepresentation, and why both disintegration disorder and posttraumatic stress disorder (PTSD) are causally linked to the same pathophysiological processes.

Library holdings, MEDLINE, PsycINFO, ERIC, Academic Search Complete, JSTORE, ProQuest Central, SAGE Online Journals , Google Scholar, and the eBAY and PsycBOOKS e-book collections were explored to obtain articles for the present study. Studies containing permutations of the words autism, developmental disorder, infant, genetic linkage, mirror neuron, docosahexaenoic acid / DHA, fetal, arachidonic acid / AA, inflammation, sensitive period, environment, androgen, testosterone, estrogen, estradiol, fish oil, milk formula, stress, breast milk , and gender were considered. Reference lists of all acquired articles and book chapters were reviewed for potential sources, with allowances made for older works where previous findings illuminate current research in dissimilar fields of study.

Evidence-based medicine often relies on metanarrative review , and this method is used to illuminate how biology and environment intermingle in the systems theory of autistogenesis ( Malone, 2011a , 2011b , 2011c , 2011d ). Given that several journals are dedicated to autism research, and that many journals continually publish additional studies bearing on this multifaceted developmental disorder, inclusion criteria were necessarily liberal. Particular areas reviewed included clinical nutrition, pediatric neurology, lipid metabolism, cognitive neuroscience, molecular and cellular biology, clinical psychology, pharmacology, neurophysiology, developmental psychology, endocrinology, archeology and biological anthropology, brain morphology, immunology, genetics, and toxicology. Journal articles, conference papers and presentations, books and book chapters, and dissertations were considered eligible for inclusion. The nature of this study required direct telephone contact with pharmaceutical companies to ascertain chemical constituents. Resources not addressing associated genetic or metabolic processes, pervasive developmental disorders, autistic behaviors, or the evolutionary significance of such processes were typically excluded.

In 2009 , Bartel described a type of noncoding RNA sequences, miRNA, as biologically active regulators of transcription that function by binding to mRNA transcripts and impair translation. Pseudogene and competitive endogenous RNA (ceRNA) transcription may also result in the competitive inhibition of mRNA resulting in tissue pathogenesis ( Poliseno et al., 2010 ). The significance of these findings cannot be overemphasized as some of these lesser known candidates contributing to autistogenesis may not demonstrate a correlative signal on current linkage analysis ( Liu et al., 2008 ), and all may impinge on CYP19A1 at 15q21.2.

Another genetic source of dysfunction is pseudogene expression and micro-RNA (miRNA)–linked regulation. Pseudogenes are defective genomic loci accumulated through phylogenic development once interpreted as nonsense DNA because they acquire silent mutations that impede successful protein translation ( Lee, 2003 ). Pseudogenes are well conserved and, through duplication and retrotransposition, have come to represent perhaps as much as half of the transcribed genome ( Harrison, Zheng, Zhang, Carriero, & Gerstein, 2005 ). Because cells only employ those aspects of the genome necessary for functioning as part of their organizing tissue, transcription of these genetic elements is highly tissue specific, although only a very small sample has been functionally characterized ( Poliseno et al., 2010 ).

Estradiol also modulates oxytocin receptor (OXTR) sites ( Nissenson, Flouret, & Hechter, 1978 ), which are known deficient in autism ( Gregory et al., 2009 ) and are linked to social cognition ( Gill, 2010 ). This understanding provides a well-founded theoretical explanation for why OXTR is greatly diminished in autism and yet RNA expression for OXTR remains normal ( Tansey et al., 2010 ). Because estradiol also regulates conversion of ALN to DHA, the aromatase gene appears a strong candidate for consideration as the genetic basis for both gender disparity and environmental triggers in autistogenesis.

To a limited extent, estradiol is synthesized de novo differentially across varying regions of the cortex, and the neonatal hippocampus generates up to 50%, yet cytochrome P450arom activity only begins postnatally ( MacLusky, Walters, Clark, & Toran-Allerand, 1994 ). McCarthy (2008) suggested that differing aspects of the developing brain are immune to the rapid and powerful influence of estradiol at different stages to prevent permanent aberrant neuronal hardwiring due to its powerful antiapoptotic neuroprotection. This is well in line with Kritzer (2006) who demonstrated that cortical development is regulated postnatally by estradiol via the alpha and beta estrogen receptor subtypes at different times, in differing patterns, and on different cortical cells.

McCarthy (2008) found that a dose of estradiol administered to an immature brain requires several hours to alter dendritic formation, yet creates lasting and substantial neurological changes, where minutes suffice in adults but yield only temporary results. Similar to its influence on PCs, estradiol promotes the growth and development of axons within the ventromedial nucleus (VMN) of the hypothalamus of males and is mediated at least at the cellular level ( McCarthy, 2008 ). It is helpful to remember how powerful the effects of female sex hormones are on circuits traversing the MNS, the orbital frontal cortex, the limbic system, the fusiform gyrus, and the superior temporal sulcus.

The issue of autism genotypes and subphenotypes is a principal concern. Many signal linkages are found on Chromosomes 2, 3, 7, 8, 11, 15, 16, 17, and 19, depending on the test of psychological impairment used to diagnose the disorder ( Liu, Paterson, & Szatman, & The Autistic Genome Project Consortium, 2008 ), excluding disorders of clear chromosomal etiology such as Rett syndrome and fragile X syndrome. Analysis of site-specific changes to the long arm of Chromosome 15 links it to the disorganized subtype of schizophrenia ( Freedman et al., 1997 ), language delays, IQ = 70, P50 sensory gating disorder, and the α7-nicotinic cholinergic receptor (CHRNA7) that modulates activation of localized neuronal circuits in the human cerebral cortex ( Albuquerque, Pereira, Eisenberg, Maelicke, & Alkodon, 2000 ).

The Genetics of Lipid Metabolism and Sex Hormones in the Brain

In a follow-up study, female conversion of ALN into EPA, n-3 DPA, and DHA was significantly greater than men from all previous studies ( Burdge et al., 2002 ) and found greatest conversion of ALN to DHA among those participants concurrently using an estradiol-based birth control pill. The difference in ALN to DHA conversion between males and females is due to estrogen up-regulation (Figure 1:1; Figure 4:1), which explains the 25% variation in DHA detected during pregnancy ( Burdge & Wootton, 2002 ). A more recent study ( Giltay, Gooren, Toorians, Katan, & Zock, 2004 ) found ALN to DHA conversion 15% higher in women than men, and that among women, those taking oral 17β-estradiol contraceptives had 10% higher DHA concentrations than those not on oral contraceptives. Administrations of both testosterone and the aromatase (Figure 4:1; Figure 6:6) inhibitor anastrozole, which blocks the conversion of testosterone to estradiol, decreased DHA conversion ( Giltay et al., 2004 ).

DPA is often overlooked in the literature regarding the link between lipid metabolism and autism, and this needs correction. DPA accumulates in the brain when DHA levels are low, and this occurs especially during fetal and infant development, maintaining the synthesis of phosphotidylcholine ( Galli, Trzeciak, & Paoletti, 1971 ; Kim, Bigelow, & Kevala, 2004 ). DPA is limited in its ability to translocate Akt , and so does not well support neuronal survival following insult or injury ( Garcia, Ward, Ma, Salem, & Kim, 1998 ; Hamilton, Greiner, Salem, & Kim, 2000 ). However, with three pathways for potential generation, DPA represents the primary route to growth and plasticity in response to DHA deficiency as both LNA and ALA pathways can produce DPA (Figure 2:9, 10, 11).

Makrides et al. (2009) demonstrated that high-dose DHA (1% total fatty acids) administered through preterm infant milk formula did improve Bayley Mental Development (MDI) scores at 18 months corrected age in female infants only . This raises an important point and leads to understanding another aspect of autism’s overwhelming gender bias. Burdge, Jones, and Wootton (2002) provided controlled diets to males of 27 to 40 years and median body mass index (BMI) containing C 13 -labeled ALN at dosage 16 times higher than previous studies ( Vermunt, Mensink, Simonis, & Hornstra, 1999 ) to assess conversion to DHA. Results indicate that approximately one third of ALN is used for energy during the first 24 hr following ingestion, and although capable of converting ALN to EPA and DPA to a limited extent, DHA synthesis in males was not sufficient to detect above background ( Burdge et al., 2002 ). As estradiol also enhances learning and provides neuroprotection against damage due to ischemia ( Zhang et al., 2004 ), the link between estradiol, DHA, and gender disparity is clear.

Breast milk deficiency is undoubtedly due to diet as current American EPA and DHA intake is estimated at approximately 10% of optimal ( Nestel, 1987 ; Neuringer, Anderson, & Connor, 1988 ). Abbott’s PediaSure and Mead Johnson’s Enfagrow Premium (vanilla and chocolate) contain DHA without AA (Similac Consumer Relations and Enfamil Product Information, personal communication, May 20, 2010). The Hain Celestial Group, Inc., makers of Earth’s Best infant formulas, as well as Gerber, Nature’s One, O for Baby, Nutramigen, and Vermont Organics, also use a DHA to AA ratio of 0.5 (Hain Celestial Group, Inc. Consumer Relations, personal communication, March 23, 2011).

Rapoport, Rao, and Igarashi (2007) provided an analysis of several studies directly assessing gray matter phospholipids and indicate the DHA/AA ratio of healthy brain tissues of approximately 1.35. Dietary ratios of DHA/AA below 0.56 (an AA/DHA ratio of 1.80) contribute to increased lipid peroxide levels, partly because the increased AA reduces the presence of DHA by decreasing its synthesis, and through physical replacement within membranes ( Hashimoto et al., 2002 ). Abbott, the makers of Similac, as well as Mead Johnson, the makers of Enfamil, offer commercially prepared infant formula with DHA to AA since 2002 with ratios of approximately 0.37 and 0.5, respectively (Similac Consumer Relations, personal communication, May 20, 2010; Enfamil Product Information, personal communication, May 20, 2010). Abbott representatives state that Similac established their DHA to AA ratio to replicate American women’s breast milk, which most closely resembles a study ( Jensen, Maude, Anderson, & Heird, 2000 ), indicating a DHA/AA ratio lower than that characteristic of typical neurons ( Kan et al., 2007 ), and 0.74 lower than the lowest of the top 10 countries (Figure 3) for DHA/AA in breast milk worldwide ( Brenna et al., 2007 ).

Diets containing various DHA to AA ratios were made available to rats. At ratios between 0.56 and 1.77, blood pressure is diminished through suppressed platelet aggregation without diminished platelet count ( Yamada et al., 1997 ) in vitro. In two more recent studies, human DHA/AA ratios within the cerebral cortex were measured at no less than 1.25 ± 0.06 and not more than 1.90 ± 0.07, and within the hippocampus of not less than 1.20 ± 0.05 and not more than 1.67 ± 0.09 ( Hashimoto et al., 2002 ; Hashimoto et al., 2005 ). Ratios of this type were associated with diminished neurological damage due to oxidative stress, diminishment of memory errors, improved spatial cognition, and reduced forebrain ischemia-induced cognitive deficiencies ( Hashimoto et al., 2002 ; Hashimoto et al., 2005 ).

Due to problematic designs and contradictory results, the final conclusion from two critical reviews ( Jain, Concato, & Leventhal, 2002 ; Koo, 2003 ) indicate no evidence regarding the comparative effects of breastfeeding on intelligence and vocabulary linked to mothers’ orally supplemented breast milk or supplemented infant milk formula. Confounds for studies reviewed include cultural food preferences and availability, formally tested intelligence and traditional schooling of the parents, age and experience of the mother, sex and birth order of the infant, power and duration of the test, lack of rigorous dietary control of the mother, socioeconomic status, and purchasing power required for supplemented milk formula.

Similar negative findings came from two studies of attention-deficit hyperactivity disorder (ADHD) children ( Hirayama, Hamazaki, & Terasawa, 2004 ; Voigt et al., 2001 ) where treatment with DHA alone was associated with results significantly lower on most measures than placebo. In addition to the possible generation of lipid peroxides, this article asserts that excessive DHA supplementation of infant formula, in combination with antioxidants during sensitive developmental stages, may result in premature neuronal hardwiring due to its powerful antiapoptotic neuroprotection. Such circumstances may contribute to autistogenesis in genetically or environmentally predisposed infants. This represents a case where neuroprotection may inhibit apoptosis in some regions necessary for appropriate developmental changes.

Excessive supplementation of DHA may also disrupt neuron membrane permeability and enzyme function and, without adequate antioxidants, may create an accumulation of lipid peroxides (Figure 1:8; Horrocks & Yeo, 1999 ) that can induce a runaway inflammatory insult to neuronal tissues. Neuroprostanes are generated within the brain through enzyme-independent reactions due to oxidative stress leading to apoptosis ( Mukherjee et al., 2004 ). Tests of visual acuity, measured by the Teller Acuity Card procedure, and both transient visual evoked potential latency and amplitude were lower in children receiving DHA-supplemented breast milk at 8 months of age compared with control ( Jensen et al., 2005 ). At 12 months of age, neurodevelopment outcomes of those children receiving DHA supplemented only breast milk were assessed using the development quotient from the Clinical Adaptive Test (CAT DQ) and the development quotient from the Clinical Linguistic and Auditory Milestone Scale (CLAMS DQ). Although significant differences were not detected in either test, that in both instances, children receiving the DHA supplemented only breast milk scored lower than control is interesting ( Jensen et al., 2005 ).

That dietary intake (Figure 6:7) influences microsomal reactions in LC-PUFA biosynthesis is clear ( Voss, Reinhart, Sankarappa, & Sprecher, 1991 ), and loss of DHA from adult healthy brain tissues is known to induce an inability to concentrate, loss of memory, and dementia ( Pawlosky & Salem, 1995 ). This assertion is supported by a study of polymorphisms of delta-6 desaturase (Figure 1: 7, 10), necessary for conversion of precursors into AA, n-6 docosapentaenoic acid (DPA), the estradiol-dependent precursor to DHA, with an advantage of 6.4 IQ points ( t = 6.35, p < .001) in children breastfed over those fed milk formula without LC-PUFA supplementation ( Caspi et al., 2007 ). Unfortunately, the Western diet in general has shifted from a historic omega-3 to omega-6 ratio of approximately 1:1 to ratios upward of 1:25, largely in part due to a paradoxical recommendation to consume unsaturated fatty acids to diminish the risk of heart disease ( Simopoulos, 2000 ). The change in n-3/n-6 ratios has correlated to an increased risk of inflammatory and cardiovascular diseases ( Ghosh, Novak, & Innis, 2007 ).

Dietary LC-PUFA Supplementation Through Breast Milk and Infant Formula

Cellular disruption also induces brain mast cell degranulation (Figure 2:14), which results in a release of histamine, serotonin, and heparin (Figure 2:15; Dvorak et al., 1992 ; Johnson & Krenger, 1992 ; Marshall, 2004 ; Penner & Neher, 1989 ). Some AA metabolites are capable of anti-inflammatory actions (Figure 6:6; Node et al., 1999 ), although the effect of AA on the overall self-limiting reaction may not diminish the inflammatory response at the tissue level for more than a week in humans. Therefore, a careful balance must be struck between AA and DHA as both share the same desaturation and elongation pathway (Figure 1:7) when converted from LA and ALN, respectfully.

AA is made throughout the body and stored within cell membranes of every tissue as a reservoir for the inflammatory response. Inflammation begins when cell disruption (Figure 2:7) induces the enzymatic conversion of free AA (arachidonate) into lipoxygenase-derived leukotrienes and cyclooxygenase-derived prostaglandins, and thromboxanes, each of which may result in additional toxic oxygen metabolites (TOM; Figure 2:8; Becker, Reece, & Poenie, 1996 ; Berg, Tymoczko, Stryer, 2010 ). Eicosanoids produced from this series of events not only alter vascular permeability (Figure 2:9) resulting in tissue swelling, but also lead to the production of more TOM while the apoptosis chain-reaction causes the release of more than 50 lysosomal enzymes (Figure 2:10) that injure or destroy neighboring cells, and ( Becker et al., 1996 ; Berg et al., 2010 ) lysosomal enzymes also cause cytokines (Figure 2:11) to activate complement (Figure 2:12), leading to further changes in vascular permeability, and initiating leukocytosis (Figure 2:13; Rhoades & Planzer, 1996 ).

Chronic neuroinflammation may lead to nonenzymatic oxidation of DHA producing reactive neuroketals and generates further toxic metabolites (Figure 6:5; for a list of proinflammatory AA and DHA biomarkers, see Farooqui et al., 2007 ). These processes also occur when eicosapentaenoic acid (EPA) is added without sufficient DHA ( Carlson, Werkman, & Tolley, 1996 ), and the potential negative effects of adding either without antioxidants ( Halliwell & Chirico, 1993 ). Diep, Touyz, and Schiffrin (2000) indicate that nonenzymatic oxidation of DHA may induce apoptosis through a translocation of 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.

DHA is also transformed by an enzyme similar to 15-LOX (Figure 1:4) into neuroprotectin D1 (NPD1), which is promoted during return of blood to tissues following ischemia, suppresses Aβ-42-induced toxicity in Alzheimer disease, inhibits apoptosis, blocks leukocyte infiltration, and modulates proinflammatory gene expression ( Horrocks & Farooqui, 2004 ; Morris et al, 2003 ). The inflammation cascade from AA metabolism is inhibited by DHA that enhances cell membrane fluidity, modulates protein kinase activity, inhibits membrane surface antigens and adhesion molecules induced by cytokine expression, and suppresses macrophage nitric oxide synthase ( Takahashi et al., 1997 ).

Studies indicate that long-chain polyunsaturated fatty acids (LC-PUFAs) are critical to neurodevelopment and function, including their connection to neuropsychological disorders ( Boure, 2004 ; Haag, 2003 ; Jefferey, Waisinger, Nauringer, & Mitchell, 2001 ; Mitchell, Niu, & Litman, 2003 ). The following sections describe the interplay between DHA, AA, and other LC-PUFAs, and the metabolic responses to stressors capable of inducing and mitigating neuroinflammatory responses. This work then introduces the genetic mechanism responsible for several routes to male overrepresentation and illustrates how environmental triggers potentiate biological processes linked to LC-PUFA metabolism in autistogenesis.

DHA is critical for the production and efficient function of neurons. Although not typically considered an essential fatty acid because synthesis occurs in humans, DHA requires several steps (Figure 1:2; Figure 6:3) toward elongation and desaturation from α-linolenic acid (ALN; 18:3 n-3). Considered ubiquitous in neuronal tissues, the cerebrovascular endothelium and astrocytes provide active transport, and only the liver and some astrocytes are capable of significant DHA synthesis ( Moore, 2001 ). There is clear in vivo evidence that DHA is vitally important to learning and memory at the component level as deficiency studies reveal smaller neuronal cell bodies in the hippocampus, hypothalamus, and the parietal cortex ( Ahmad, Moriguchi, & Salem, 2002 ). Uptake is highest during the final trimester, which also represents the greatest phase of neurogenesis, neurite formation, and arborization ( Green & Yavin, 1998 ).

DHA as an Essential Fatty Acid

Chronic neuroinflammation of similar etiology during infancy will produce strikingly similar effects if circumstances occur during the same developmental periods ( Rutter et al., 1999 ). The mirror neuron system (MNS), well rooted in the ventral premotor cortex, and the anterior, inferior fronto- and tempero-parietal regions, permeates the cerebral cortex ( Mukamel et al., 2010 ), including the primary somatosensory cortex. The MNS is intensely interconnected with limbic system, orbital frontal lobes, and insula, and each region experiences myelination at different rates during different periods of time ( Huttenlocher, 1990 ; Yakovlev & Lecours, 1967 ).

In patients with autism, cerebellar folia Purkinje cells (PC) approach 15 standard deviations below the mean compared with controls due to neuroinflammatory processes ( Kern & Jones, 2006 ). Immature PCs receive presynaptic inputs from olivocerebellar cells and experience axonal elongation through search mechanisms to deep nuclear neurons and other postsynaptic output targets ( Dusart, Airaksinen, & Sotelo, 1997 ). The output from the cerebellar cortex are PCs, which inhibit several regions of the cerebral cortex and dendritic development connecting to olivary cells, and require high cerebellar estradiol (Figure 1:4; Figure 4; Figure 6:1; Keller, Panteri, & Biamonte, 2010 ). Increased microglial and astroglial activation associated with the neuroinflammatory response (Figure 2:1) is found in areas of reduced PCs, astroglial response in the granular cell layer of the cerebellar white matter, and the middle frontal gyrus (MFG) and anterior cingulate gyrus (ACG) of autistic patients ( Vargas, Nascimbene, Krisnan, Zimmerman, & Pardo, 2004 ). The reduction in PC development is male biased and linked to a gender-based mechanism described in this study.

Stressors and the Sensitive Period

For every step in the genetic, metabolic, and environmental pathway to autistogenesis, there is an opportunity for early detection, treatment, and intervention. Neuronal maturation occurs throughout the brain in predictable fashion and these events provide a roadmap with mileposts to guide intervention. The younger the child is without competent aromatase expression, or with inappropriate dietary DHA/AA ratios, confronted by any neuroinflammatory event, the greater the chance for damage to sensitive domains. Likewise, the sooner that socially engaging and neurologically appropriate intervention is targeted to those specific brain regions, the greater chance for improvement. Therapy must include activity that provides neurodevelopmentally appropriate stimulation targeting areas likely damaged, such as the Floortime® model, so that remaining plasticity may remodel faulty interconnections. Neurologists employing modern scanning and imaging techniques might determine cortical areas with aberrant electrical activity, or inadequate BOLD response, and provide neuropsychologists with a plan for therapists to develop brain region–specific intervention and suitable dietary LC-PUFA supplementation.

Studies are also needed to determine the exact means by which estradiol governs LC-PUFA metabolism in response to a variety of environmental stressors. As estradiol is powerfully neuroprotective, studies are needed to determine if this is due to a fundamental property of estradiol alone, or due to the close link with LC-PUFA metabolism. It remains a question whether estradiol shuttles 24:6n-3 through the peroxisome membrane, but it may be that estradiol insensitivity can occur as a result of the testosterone surge, something akin to the etiology of diabetes mellitus type 2. This is an interesting hypothesis as adrenoleukodystrophy (ALD), a peroxisomal disorder leading to profound neurodegeneration and sometimes death, is a male-only disease and some cases may result not from inadequate conversion of LC-PUFAs but rather a deficit due to estradiol insensitivity.

Current attempts at linkage analysis demonstrate a key misunderstanding because environmental stimulus can induce pervasive developmental disorders. Correctly functioning testosterone aromatization remains a potential causative factor if environmentally predisposed, especially with incorrect DHA/AA supplementation, and this explains why CYP19A1 may not produce a linkage signal with logarithm of odds scores as high as 3.6; a well-functioning gene can still predispose the disorder (Figure 5). Testosterone overexpressors are not genetically well characterized, and research must determine if there is a significant presence of developmental disorders in families possessing such a trait. As the male does not produce significant levels of DHA, and precisely because both males and females do produce AA, excessive AA supplementation can shift into metabolic pathways toxic for neuronal growth and development, producing a runaway effect. The inflammatory cascade can also result in nonenzymatic oxidation of DHA when present in excess, which generates yet more highly reactive toxic metabolites. Researchers must determine the effects of repeatedly acute and chronic stress on neonatal development concurrent with varying DHA/AA ratios and concentrations to understand the ramifications of infant milk formula based on deficient models.

The three overlapping spheres of primary influence in autistogenesis are clear: the genetics supporting aromatization of testosterone into estradiol, LC-PUFA metabolism as modulated by estradiol, and the thousand natural shocks that flesh is heir to. Gender disparity is important to understanding the etiology of autism and subphenotypes, including many learning disabilities overrepresented in the male population. New studies must examine the effects of dysregulation of an already complex CYP19A1 . This gene controls or influences placental DHA absorption and mammary gland DHA production, and the developing infant’s levels of testosterone and estradiol. CYP19A1 also regulates oxytocin, MET response, antioxidant metabolism, and modulates several aspects of the inflammatory response. Efforts must also seek to determine the effects of at least 13 known CYP19A1 alleles ( Online Mendelian Inheritance in Man, 2011 ) and the gene’s multiple inherent potentials for failure. Such studies will necessarily include consideration of epigenetic methylation, pseudogenes, miRNA, ceRNA, and any form of posttranslational modification because most if not all of these may go undetected in traditional linkage assays. Furthermore, as each of the above represents a possible gear in the autistogenesis mechanism, it becomes clear that a bioassay for early detection will include polymerase chain reaction (PCR) screening for CYP19A1 alleles, pseudogenes, and transcription-level regulators.

Infant milk formula supplemented with a DHA/AA ratio determined previously as potentially detrimental could have potentiated circumstances in some children now on the autism spectrum that may never have been. A new line of study must examine whether EPA, DPA, or DHA, alone or together, in combination with antioxidants, would not prove an effective intervention. Whereas both DPA and DHA enhance neuronal elongation and neurite outgrowth, only DHA supports growth under dietary disturbance or environmental stress. Although the neuroprotective properties of DHA are impressive, apoptosis makes way for new connections, and myelination may hinder plasticity. It therefore seems that DPA, which promotes growth while maintaining plasticity, could prove a better choice for other treatment needs.

Implications and New Directions for Study

Infant males moving into the testosterone surge incapable of aromatase conversion will not possess neuroprotective capacity to protect against testosterone toxicity (Figure 7) or environmental stress as DHA concentrations within the brain fall after parturition. Only healthy breast milk or correctly formulated infant milk replacement may provide an adequate DHA/AA ratio. Infants with faulty P450arom genetics may grow normally, but overwhelming stress during sensitive stages of development may induce regression as neuroinflammation results in physiological debridement. Circumstances such as these explain how seemingly similar male children exposed to similar stressors may suddenly depart along very different developmental trajectories.

Where most young children can tolerate a degree of stress for a certain period of time, others with deficient P450arom expression or function may not develop healthy connections during sensitive periods. An infant with competent aromatase function may develop aberrant connections if exposed to reasonably normal levels of stress if concurrently oversupplemented with AA that promotes the feed-forward neuroinflammatory response. Infants receiving excessive nutritional supplementation of DHA alone may not experience appropriate cell death, and so lose some remodeling in domains where new connections must form, while other areas wither under DHA’s potential for proinflammatory influence.

Environmental influences have powerful sway over sensitive aspects of the developing infant brain and can induce hard-wired changes in the maturing primate brain attempting to adapt to an inhospitable environment. Any strongly acute or chronic environmental stress will initiate the neuroinflammatory cascade, as in the cytotoxic effects of cortisol or testosterone, but social and emotional stress can also cause the initiation of DHA and AA cascades through neurotransmission through PLA21 coupled receptors ( Rapoport, Rao, & Igarashi, 2007 ). Toxic metal exposure, overwhelming allergic reactions, the effects of bacterial and viral infection, metabolic dysfunction and dietary inadequacies, and direct injury can lead to unsuitable maturation through myelination of aberrant connections following synaptic pruning under the weight of neuroinflammatory processes. Neuroinflammation results in an expanding sphere of physiologic debridement, whereas the remaining cells experience aberrant myelination leading to developmental disorder.

Therefore, this article asserts that a spectrum of developmental disorders results from damage or impairment to one or more components within a system of overlapping spheres of influence: (a) the genetic mechanisms and metabolic processes of testosterone conversion to estradiol, (b) estradiol’s regulation of oxytocin and n-3 fatty acid metabolism, (c) the central role of fatty acid metabolism in neuroinflammation, and (d) the inflammatory response initiated by environmental stressors (Figure 5). The CYP19A1 gene represents the center of a web of events responsible for gender disparity. Estradiol, EPA, DPA, DHA, and NPD1 mediate neuronal development and specialization while safeguarding against cascading neurodegenerative events when interconnectivity is most susceptible. Dyslexia, attention-deficit disorder (ADD)/ADHD, certain types of language impairment, and varying degrees of antisocial behaviors are grossly overrepresented in males ( Auyeung et al., 2009 ). These developmental challenges are responsive to DHA supplementation ( Richardson, 2006 ), and the systems theory of autistogenesis provides a powerful framework for explaining primary aspects of their respective etiologies, including nearly a dozen mechanisms responsible for gender bias.

The correct ratio of estradiol to testosterone in preterm mothers, neonates, and developing infants is critical for neurogenesis, neuronal differentiation, neurite outgrowth, and enhances long-term potentiation. Furthermore, estradiol inhibits the neurodegenerative inflammatory response and suppresses apoptosis. Testosterone is converted into estradiol by cytochrome P450arom, and failure in this sequence of events leads to significantly lower estradiol and increased testosterone. Diminished conversion of testosterone into estradiol inhibits neurogenesis, reduced neurite outgrowth, and greater vulnerability to cytotoxic metabolites from neuronal inflammation. Without functioning aromatase enzymes, normal levels of testosterone become excessive, generating free radicals that transform DHA and AA into cytotoxic inflammation metabolites through increased lipid peroxidation.

Incorrect ratios or inadequate levels of these LC-PUFAs result in reduced neurogenesis, diminished neurite outgrowth, and increased susceptibility to a runaway neuroinflammatory cascade, which includes additional cell death and the damaging effects of neuronal inflammation such as brain swelling constrained within the skull. The correct n-3/n-6 LC-PUFA ratio will mitigate or ameliorate insult and injury due to environmental toxins, ischemia, oxidative stress, excess sex hormones, and the many pathways through the neuroinflammatory cascade. Incorrect dietary n-3/n-6 ratios can enhance or even induce neurodegenerative processes in some instances.

Injury or insult to sensitive brain regions results in cortical dysgenesis and retention of unsuitable interconnections. Any cellular disruption may induce neuroinflammation leading to reduction in perceptual, intellectual, language, and learning capacities, and diminished self-regulation, and distortion of emotional and social operations result. Important dietary antioxidants are metabolized with female gender bias and are consumed at trace levels only in the modern Western diet ( Sen, Khanna, & Roy, 2006 ). Furthermore, only females demonstrate significant ability to synthesize DHA, to meet the demands of developing infants. Preterm and term infants can produce AA after 33 weeks gestation ( Uauy, Mena, Wegher, Nieto, & Salem, 2000 ), which calls into question AA supplementation. There exists competition for enzymes (Figure 7) between n-3 and n-6 fatty acids ( Brenner, 1974 ) so the relative proportions of each carry biological consequences. Adequate supplies of these LC-PUFAs, in the correct ratio, inhibit the neurodegenerative aspects of inflammation and suppress apoptosis while concurrently enhancing long-term potentiation.

Autism is a pervasive developmental disorder that includes both a qualitative and quantitative impairment of social interaction, cyclic CNS activity producing repetitive physical and cognitive behaviors, deficits in communication skills of all types, and an aversion for extremes in sensory novelty linked to a preference for environmental sameness. Sensitive periods exist as a consequence of plasticity during infant brain development due to overwhelming synaptic remodeling of gray matter connections in different regions, at different rates, and at different times whereas other regions experience advancing myelination. The result is specific adaptation of pathways contributing to aspects of anthropoid cognition such as perception, attention, learning, memory, symbolic representation, and the scaffolding on which is built imitation and theory of mind.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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