Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social relationships and repetitive or restricted behavioral patterns. This paper explores whether trauma-induced epigenetic changes in parents may contribute to the development of ASD in their offspring. In addition, it evaluates the effectiveness and limitations of current treatment approaches. Emerging evidence suggests that parental Adverse Childhood Experiences (ACEs) and prenatal maternal stress are associated with increased ASD susceptibility. These associations are further supported by findings from animal models, which help clarify the underlying biological mechanisms. Additionally, ASD has been shown to be more prevalent in males than in females. Studies have shown that epigenetic mechanisms such as DNA methylation, histone modifications, and miRNA dysregulation may disrupt neurodevelopment and contribute to ASD risk. However, a new frontier study suggests that histone modifications can be the underlying solution to reversing the risk of ASD, but research is still ongoing. Advancements in technology and epigenetic research offer a deeper understanding of ASD and how trauma can contribute to its development. This growing understanding paves the way for future research to develop epigenetically-informed therapeutic strategies.

Introduction

Trauma can leave behind more than just emotional scars, reshaping our genes across generations. As people age, the largest influence on the epigenome is the environment. Influences such as diet can affect one’s epigenome, as demonstrated by the Dutch famine studies (Al Aboud et al., 2023). Autism is between 60-90% heritable, but this does not rule out environmental links through epigenetics (Khogeer et al., 2022). Environmental exposure links to epigenetic mechanisms, and trauma may similarly influence gene expression, increasing the risk of Autism Spectrum Disorder (ASD) (Eshragi, 2018).

Autism, often considered a severe and life-changing form of neurodevelopmental disorder, has seen a sharp rise in diagnosis rates. Data from the New Jersey Autism Study at Rutgers New Jersey Medical School, spanning more than 16 years, revealed that autism rates doubled to 4.6 cases per 1,000 eight-year-olds (Smith et al., 2023). 

ASD is a complex developmental condition involving persistent challenges with social communication, restricted interests and repetitive behavior. It is a lifelong condition that requires support services tailored to the individual’s challenges. A child with autism will likely need more time, structured environments, and basic instructional scaffolding in educational programs.

Conrad Waddington introduced the term “epigenetics” in the 1940s, defining it as the study of interactions between genes and their products that result in observable traits. Today, epigenetics is the study of changes in gene function that do not involve alterations to the DNA sequence (NIH, 2020).

Trauma is defined as a disturbing experience that causes intense and lasting negative effects on a person’s attitudes, behavior, and functioning. Examples include war, sexual assault, or severe accidents.

Background

ASD is a critical topic that needs continued research, especially regarding how epigenetic changes may elevate its risk. Diagnosed individuals face serious challenges that can impact their social, educational, and professional lives (Hodges et al., 2017). Approximately 8 in 10 individuals with autism experience mental health challenges such as anxiety, depression, or psychosis, and are statistically more likely to die by suicide compared to the general population (Newell et al., 2023).  This paper explores whether trauma-induced epigenetic changes may increase ASD risk in future generations and whether current treatment models are equipped to address this possibility.

Early signs of ASD may appear before age one, with a more definitive diagnosis usually by age two to three. Social communication challenges include difficulty with eye contact, limited use of gestures, and trouble forming friendships. Repetitive behaviors like hand flapping and sensory hypersensitivity are also common symptoms. Interventions such as Applied Behavior Analysis (ABA), social skills training, occupational therapy, and medications like risperidone or aripiprazole can help manage symptoms (Alsayouf et al., 2017).

TRANSGENERATIONAL EPIGENETICS, ASD, AND THE ENVIRONMENT

One well-documented example of epigenetic inheritance is the Agouti viable yellow (Avy) allele in mice, which is influenced by maternal diet (Dollinoy et al., 2008). Researchers are investigating whether children conceived via Assisted Reproductive Technologies (ART) are affected by similar mechanisms. Researchers are doing this due to evidence from animal studies that show that in vitro culture conditions can affect epigenetic marks, including DNA methylation. An increase in observed health outcomes can be seen throughout the years, with increasing statistics of health implications (Wang, 2021). Histone acetylation and DNA methylation are considered heritable epigenetic marks that regulate gene expression. Key mechanisms include DNA methylation, histone modifications, and non-coding RNA, all of which influence gene silencing (Al Aboud et al., 2023). 

DNA methyltransferase enzymes catalyze DNA methylation, adding methyl groups to cytosines in CG sequences. Environmental stressors and trauma can induce lasting epigenetic changes, influencing how genes are expressed long-term (Al About et al., 2023).

Treatments and ethical, therapeutic, and preventive implications

As growing awareness of the genetic predisposition and trauma-induced epigenetic modification of autism spectrum disorder (ASD) reopens questions about the adequacy and appropriateness of current treatment paradigms, traditional behavioral and developmental therapies tend more toward external functional outcomes, such as improved eye contact, social compliance, or reduction of repetitive behaviors, than internal processes such as sensory regulation, emotional well-being, or underlying neurological or gastrointestinal function. With ongoing discoveries in neurogenetics and molecular biology clarifying the molecular underpinnings of ASD, primarily in environmentally mediated epigenetic dysregulation, the need to critically assess both the therapeutic value and the moral rationale for existing treatments is imperative. Some of the most widespread interventions are described in this section, not only assessing their therapeutic impact but also how much they address or ignore the multifaceted biological and intergenerational nature of ASD. This raises serious questions about whether our current treatments are effective in light of growing knowledge about autism’s causes and whether new developments must shift toward more integrative, more individualized, and more ethically responsible models of care.

APPLIED BEHAVIOR ANALYSIS (ABA)

Applied Behavior Analysis (ABA) is a systematic intervention based on the science of behavior to teach core skills and reduce problem behavior in individuals with autism. Discrete trial training (breaking tasks into small, trainable steps), prompting and fading, functional behavior assessment, and reinforcement systems like token economies are primary strategies. Practitioners, most typically Board Certified Behavior Analysts (BCBAs), collect ongoing data to assess progress, adjust interventions, and guide instructional decisions (Fernandes & Amato, 2013).

There have been criticisms of conventional ABA for prioritizing neurotypical compliance over autistic autonomy, identity, and dignity. It highlights ethical risks from compliance-based procedures, such as escape extinction and withheld reinforcement, and calls for placing autistic voices at the center of all stages of treatment planning (Mathur et al., 2024).

TREATMENT AND EDUCATION OF AUTISTIC AND RELATED COMMUNICATION HANDICAPPED CHILDREN (TEACCH)

TEACCH is founded on the principle that people with autism are visual learners who function best in structured settings. It structures learning into four main components: physical structure (clearly defined work areas), visual schedules of routine activities, work systems that create tasks in fragmented pieces in a linear sequence, and task structure that specifies expectations at each point (Mesibov, 2009).

There have been treatment and ethical concerns with structured instructional approaches typically used with autism education, such as the TEACCH model. Structure can help with predictability and reduce anxiety, yet it is believed that excessive rigidity, such as inflexible visual schedules or structured work systems, can suppress students’ cognitive, emotional, and creative development. Therapeutically, this needs more responsive pedagogy: a pedagogy that is consistent yet flexible, acknowledges the experienced reality of autism, and values participation, curiosity, and self-expression (Howley, 2021).

EARLY START DENVER MODEL (ESDM)

The Early Start Denver Model (ESDM) is a manualized, naturalistic developmental-behavioral intervention for toddlers (typically ages 12–48 months). Play-based, child-led sessions based on real-life contexts integrate developmental and applied behavioral analytic approaches. ESDM covers cognitive, language, social, and motor skills through warm, relationally-oriented teaching (Dawson et al., 2016).

Critiques have been made based on significant therapeutic and ethical grounds, based on early interventions for autism, like the ESDM. Although ESDM is described as fun and child-led, there have been questions regarding whether this terminology sufficiently counterbalances the gravity of such a high-intensity intervention. Ethical implications include the risk of reinforcing social disparities, exclusion of families that cannot obtain or sustain participation, and prioritizing standardized results over individualized, culturally-sensitive care. The authors urge more holistic, family-based models that align treatment objectives with the real lives of diverse communities and press models like ESDM to adapt or face ethical failures in the face of clinical potential (Mottron, 2017).

PROGRAM FOR THE EDUCATION AND ENRICHMENT OF RELATIONAL SKILLS (PEERS)

The Program for the Education and Enrichment of Relational Skills (PEERS) is a social skills intervention manual for high‑functioning adolescents with autism. Delivered in weekly 90‑minute group sessions over approximately 14–16 weeks, the curriculum covers topics like conversation initiation and maintenance, choosing friends, dealing with teasing or rejection, humor, electronic etiquette, and dating rules. The program is based on cognitive-behavioral techniques and structured practice in peer group settings (P∤atos et al., 2022).

Therapeutic and ethical concerns must be remembered in the case of PEERS by recognizing that teaching social skills that lack ecological validity, i.e., skills inapplicable to real-life peer interactions, produces negative consequences. Preventatively, maladapted interventions can be more damaging, imposing rigid scripts that are likely to lead to social failure or exclusion (P∤atos et al., 2022).

MICROBIOTA TRANSFER THERAPY (MTT)

Microbiota Transfer Therapy (MTT) is a multistep treatment designed to durably alter the gut microbiota of children with Autism Spectrum Disorder (ASD), who often have both gastrointestinal (GI) symptoms and distinctive microbial imbalances. The treatment begins with a two-week course of the antibiotic vancomycin to reduce the existing, often dysbiotic, gut microbial community. A high initial dose of screened, purified fecal microbiota from a healthy donor is then delivered, either orally or rectally, followed by daily maintenance doses for seven to eight weeks. The entire protocol takes about ten weeks. MTT not only seeks to restore microbial diversity, but to bring about long-term colonization of beneficial bacterial strains (Kang et al., 2019).

Although MTT remains experimental for ASD with gastrointestinal symptoms (such as chronic constipation, diarrhea, abdominal pain, and indigestion), therapeutic and ethical caution is warranted. The open-label, no-placebo control design of the trial lowers interpretability and raises the specter of placebo responses that must be disclosed transparently at informed consent. While there was a promising long-term advantage in GI and ASD symptoms at two-year follow-up, the long-term consequences of introducing donor microbiota are unknown. More controlled and rigorous trials are necessary before MTT can be safely recommended for broader clinical use (Kang et al., 2019).

Epigenetic mechanisms relevant to ASD

HISTONE MODIFICATION LINKAGE WITH DEVELOPING ASD

Recent research, such as that by Takahashi et al. (2023), suggests that some histone modifications are heritable through the germline, escaping epigenetic reprogramming during gametogenesis and early embryogenesis, and thereby potentially contributing to transgenerational epigenetic inheritance of ASD risk. Environmental exposures, such as prenatal valproic acid (a known histone deacetylase inhibitor), can induce persistent histone hyperacetylation, leading to autistic-like phenotypes in offspring. Histone modifications are chemical changes, often the addition of molecules like acetyl or methyl groups, to the histone proteins. Acetylation is typically linked to increased gene expression because it loosens DNA packaging. Methylation, on the other hand, can be associated with either increased or decreased gene expression, depending on the specific site and context. (Choi & Javaid et al., 2017). Mutations in chromatin remodeling genes, including CHD8, ARID1B, and ADNP, all of which regulate nucleosome positioning and chromatin accessibility, are significantly enriched in individuals with ASD (Salari et al., 2023).

Furthermore, the study found that underdiagnosis, especially among older adults, remains a major issue, as much as 60–70% of individuals with autism may not yet have received a formal diagnosis. Multiple post‑mortem brain studies (prefrontal and temporal cortex) found consistent dysregulation of H3K27ac across ~68% of both syndromic and idiopathic ASD cases, suggesting a convergent epigenetic signature. So, in ASD, when brain studies show dysregulation of H3K27ac, it means that important genes related to brain development or synaptic function may be inappropriately activated or silenced, depending on whether acetylation is increased or decreased. Histone methylation and chromatin remodeling in ASD are another predominant root that can induce genes such as KMT5B, ASH1L, KDM5C, disrupting H3K4me2/3 and H3K9me3 regulation, altering gene activation or repression during neurodevelopment (Zurcher, Hooker, McDougle & Tseng et al., 2021). Disrupted chromatin structure can therefore interfere with the timely activation or repression of neurodevelopmental genes, leading to altered brain circuit formation, synaptic dysfunction, and the behavioral phenotypes seen in ASD (Millis & Mbadiwe et al., 2013).

Intriguingly, recent research suggests that histone modifications not only contribute to the onset of ASD during early brain development but may also be reversible, opening the door to potential epigenetic therapies (Tseng et al., 2022). For example, preclinical studies using histone deacetylase (HDAC) inhibitors, such as valproic acid derivatives or novel brain-penetrant compounds, have demonstrated the ability to normalize dysregulated H3K27ac patterns and partially restore gene expression profiles in neuronal models of ASD (Ganai, Ramadoss & Mahadevan et al., 2016). A part of this investigation was profoundly exhibited by transgenic mice (Kim et al., 2019).

HOW MICRO-RNAS INFLUENCE ASD

MicroRNAs (miRNAs) are small (~22 nucleotides), non-coding RNA molecules that regulate gene expression at the post-transcriptional level by binding to the 3’ untranslated regions (3′ UTR) of target mRNAs, leading to mRNA degradation or translational repression. In the context of ASD, numerous studies have shown that dysregulated miRNA expression can disrupt neural development, synaptic plasticity, and immune signaling – all processes implicated in ASD (O’Brien, Hayder, Zayed & Pend et al., 2018).

Specific miRNAs such as miR-132, miR-146a, miR-155, and miR-181b have been found to be abnormally expressed in the brains or blood of individuals with ASD. For example, miR-132, which regulates neuronal differentiation and synaptic growth, is often downregulated in ASD patients; this leads to deficits in synaptic formation and plasticity. miR-146a and miR-155, involved in neuroimmune signaling, are often upregulated, which may contribute to neuroinflammation, an emerging pathological hallmark in ASD. Meanwhile, miR-181b has been linked to the regulation of GABAergic signaling, which plays a role in the excitation/inhibition (E/I) balance disrupted in ASD (Hicks & Middleton et al., 2016).

Importantly, miRNAs can also modulate the expression of chromatin remodeling factors and histone-modifying enzymes, creating a feedback loop between miRNA regulation and epigenetic architecture. This makes miRNAs a key bridge between environmental exposures (e.g., toxins, maternal stress) and long-term gene expression changes involved in ASD. As miRNAs circulate in bodily fluids (like blood and cerebrospinal fluid), they hold promise not only as biomarkers for early ASD diagnosis, but also as potential therapeutic targets, representing a powerful intersection of genetics, epigenetics, and neuroscience. 

DNA METHYLATION (DNA-M)

Among all the different mechanisms of epigenetics, DNA methylation continues to be the most studied. The process of DNA methylation involves the addition of a methyl group, typically to cytosine residues at CpG sites, a process which is catalyzed by DNA methyltransferases (DNMTs) (Jiang et al., 2019). Most of the time, DNA methylation acts as a means to repress gene expression, which is done by blocking transcription factors (Jiang et al., 2019; MDPI, 2023). However, in some cases, it can also be used to increase gene expression (Jiang et al., 2019). DNA methylation plays a prominent role in the silencing of genes, genomic imprinting, and X-chromosome inactivation, proving to be fundamental. Hydroxymethylcytosine (5-hmC) is heavily involved in learning, memory, and stress responses, and is mostly found in the brain (Jiang et al., 2019). Dysregulation of DNA methylation is often associated with various diseases, such as Rett syndrome, Prader-Willi Syndrome, and Angelman Syndrome, which are known to have overlapping symptoms with ASD.

In the context of ASD, DNA methylation has been recognized for its potential role in increasing risk. Environmental factors have been shown to influence modifications. Specifically, regions on chromosomes 15q and 7q are being studied as “epigenetic hotspots” that seem to be correlated with ASD. This can be attributed to the fact that duplications of the maternal copy of genes on 15q11-13 have been heavily linked to autism. Recent research has also shown widespread abnormalities of DNA methylation within the dorsal raphe nucleus, a region in the brain crucial for signaling serotonin, in brain samples from individuals with ASD (Technology Networks, 2025). These findings also include hypermethylation of the genes OR2C3 and HTR2C, which are known to be involved in neural circuits underlying sensory processing, and hypomethylation of RABGGTB (Technology Networks, 2025). These alterations are known to directly contribute to the disruption of normal serotonin signaling pathways in the brain (Technology Networks, 2025). Furthermore, paternal stress has also been linked with changes in epigenetic markers in sperm. Specifically, the reprogramming of DNA methylation suggests the potential for intergenerational transmission of environmental information (Biological Psychiatry, 2017).

Influence of trauma in ASD

Intergenerational effects of parental adversity on ASD susceptibility

Stressful or traumatic events experienced in childhood or adolescence can result from a broad range of life events, including physical injury, natural disaster, bullying, and childhood maltreatment. Genetic, epigenetic, and environmental factors, and their interactions, contribute to the differential health outcomes induced by childhood trauma (Jiang et al., 2019). A growing body of research examines how these factors may influence the transmission of ASD risk via epigenetic mechanisms.

A recent study suggests that traumatized parents may be functionally unavailable to their infant, which results in enhanced symptomatology in their child that can be passed on to the next generation (Zhang, 2021). However, the mechanism behind this remains unclear. 

According to a neural diathesis-stress model, both genetic predisposition and environmental factors contribute to the development of mental disorders (Jiang et al., 2019). A more recent adaptation of this model integrates insights from psychoanalytic theory, proposing that adverse experience in early childhood can exert lifetime effects on physical and psychological functioning (McCutcheon et al., 2006). During neurodevelopment, genetic factors may predispose individuals to certain vulnerabilities (McCutcheon et al., 2006), while environmental factors, such as stress or trauma, can influence gene expression through epigenetic mechanisms (Stankiewicz et al., 2013). Their interaction produces a stable, individual phenotype that governs perception and responsiveness to salient features of the environment (Ladd et al., 2000). Prolonged and intense stimuli can induce lasting alterations in stress response mechanisms, as well as in the structure and function of the brain itself. These changes could contribute to cognitive deficits and behavioral alterations that can translate to neurodegenerative or mental illnesses (Stankiewicz et al., 2013). This framework enhances our understanding of how parental early life stress may alter offspring neurodevelopment, contributing to ASD-related outcomes.

BEHAVIORAL AND BIOLOGICAL PATHWAYS

Women exposed to childhood abuse are more likely to smoke, use drugs, experience stress or violence, and be overweight during pregnancy, all of which may increase fetal ASD susceptibility. The experience and effects of childhood abuse can alter the maternal hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamic-pituitary-gonadal (HPG) axis, and provoke immune dysfunction, which, along with inflammation, including neuroinflammation, affects the developing brain and has been hypothesized as a potential contributing factor in the onset of autism. Researchers identified an intergenerational association between childhood exposure to abuse and risk for autism in the subsequent generation. Notably, women exposed to the highest level of abuse had a 60% higher risk of having a child with autism compared with women not exposed to abuse. The prevalence of autism was higher in this group, 1.8% vs. 0.7% in women not abused (P = 0.005), and the risk ratio after adjusting for demographic factors was 3.7 (95% confidence interval=2.3, 5.8). Even after adjusting for adverse perinatal variables, the association of maternal abuse with autism was still significant, with an attenuated risk ratio of  3.0 (95% confidence interval=1.9, 4.9). It was also found that an array of perinatal factors was associated with both child abuse history and autism risk (Roberts et al., 2013). These findings highlight the need to explore underlying molecular pathways.

Both maternal and paternal lines exhibit epigenetic signatures of stress, and understanding their influence on offspring brain development can offer insight into the origins of mental health disorders. This process includes several mechanisms such as DNAm, histone post-translational modifications (PTMs), and non-coding RNAs. Stress experienced during critical developmental windows can lead to epigenetic alterations in sperm and oocytes, resulting in transmission of altered marks to the zygote. These alterations can subtly shift developmental processes, leading to changes in cell proliferation, migration, or differentiation, key steps in the molecular cascade from the sperm epigenome to offspring brain function (Rodgers et al., 2015), which ultimately affect offspring behavior and physiology and may contribute to disease vulnerability or altered stress regulation. Following conception, stress exposure during pregnancy can also directly alter epigenetic programming of the fetus by disrupting the function of extra-embryonic tissues, including the placenta, to promote alterations in key developmental signals throughout gestation. The observation that stress exposures across the male lifespan can lead to the programming of offspring phenotypes has brought mounting attention to the examination of epigenetic marks in sperm, which have been implicated in transmitting environmental information to the next generation (Chan et al., 2017).

PATERNAL GERMLINE EPIGENETICS

Feinberg et al. (2015) identified relatively large inter-individual differences in paternal sperm DNAm that associate with later 12-month ASD-related phenotype in their offspring, with many regions mirroring cerebellar methylation patterns in ASD, supporting a parental epigenetic contribution to autism risk in offspring. However, how stress induces such site-specific sperm methylation changes and how these changes influence the programming of adult offspring tissues to produce behavioral phenotypes are unknown (Chan et al., 2017). This is partly because epigenetic marks undergo near-complete erasure and reprogramming following fertilization, and only a few may survive. Nevertheless, exactly which DNA methylation patterns escape erasure or are reprogrammed remains to be elucidated (Duffy et al., 2021). There is also limited insight into the molecular processes by which epigenetic changes in germ cells affect specific neuronal populations in the brain and how those adaptations alter neural circuitry to create the abnormal behaviors (Cunningham et al., 2019).

Animal studies have helped bridge this gap: artificial reproductive techniques, including in vitro fertilization and zygote microinjection, allow researchers to manipulate sperm epigenetic marks and assess their transmission through the male germline. These approaches provide experimental evidence demonstrating the role of sperm epigenetic marks in transgenerational reprogramming (Rodgers et al., 2015).

Collectively, this data indicates that preconception parental adversity imprints epigenetic marks in gametes that may shape ASD risk in the next generation.

Prenatal markers linking maternal adversity to ASD susceptibility

Prenatal stress, which is more common among mothers with Adverse Childhood Experiences (ACEs) (Kurbatfinski et al., 2024), can disrupt a unique period of rapid neurogenesis (Abdelrazek et al., 2021) and has been linked to neurodevelopmental disorders in children, including an increased risk of attention deficit hyperactivity disorder (ADHD), ASD, cognitive delay, and schizophrenia (Abrishamcal et al., 2024).

GENE × ENVIRONMENT INTERACTIONS AND EPIDEMIOLOGICAL EVIDENCE

Family discord (Ward, 1990), stressful life events (Beversdorf et al., 2005), and hurricanes and tropical storms (Kinney et al., 2008), during pregnancy have all been shown to be associated with elevated risk for autism in the resulting offspring (Ronald et al., 2011).

To explain why prenatal stressors might contribute to autism, a gene × environment interaction (G × E) model offers valuable insight. These models suggest that the impact of stress exposure is heightened in certain genetically susceptible individuals. One gene of particular interest is the serotonin transporter (SERT) gene, which plays a key role in stress reactivity. This gene encodes the SERT protein, which transports extracellular serotonin back into the neuron. Genetic variations in this gene can affect its function. The most widely studied variation is an insertion or deletion of a 44-base-pair segment of DNA in the promoter region of the SERT gene, SLC6A4, resulting in a long (L) or short (S) allele. The clinical significance of this model has been explored more recently, finding that the relationship between prenatal stress exposure and ASD may be influenced by maternal genetic susceptibility to stress, particularly in mothers carrying the S-allele. Additionally, linkage studies have associated rigid-compulsive behaviors in autism patients with the genomic region containing SERT (Beversdorf et al., 2018). This suggests that the elevated risk linked to prenatal stressors may depend on genetic sensitivity to stress, rather than stress exposure alone.

EXPERIMENTAL APPROACHES

Abdelrazek et al. (2021) tested whether reported correlations between maternal prenatal stress and offspring ASD traits were due to maternally inherited factors or consistent with a potentially causal prenatal exposure effect. The study used an in-vitro fertilization cross-fostering design, comparing pregnant mothers biologically related to their child (n = 365) with those who were not (n = 111). Subjective late pregnancy stress was associated with increased offspring ASD traits in the whole sample (β = 0.089, p = 0.073) and more strongly in the subgroup of unrelated mothers and children (β = 0.233, p = 0.029), compared to the related group (β = 0.045, p = 0.424). This demonstrated that the mechanisms underlying the association between maternal stress and ASD and birth outcomes are likely to be similar and environmentally driven. These findings set the stage for understanding the underlying molecular mechanisms.

MOLECULAR MECHANISMS

The maternal immune activation (MIA)-induced inflammatory perturbations in utero are considered important risk factors for abnormalities in fetal neurodevelopment. Cytokines are the most frequently measured indicators of the inflammatory response. The placenta and umbilical cord, key structures for the exchange of nutrients and various metabolites at the mother-fetus interface, play pivotal roles in the association between MIA and fetal neurodevelopment. MIA-induced inflammatory cytokines can either trigger a direct placental inflammatory response or enter the fetus through the umbilical cord, disrupting the balance between inflammatory cytokines in the maternal–fetal circulation and eliciting a long-lasting effect on fetal neurodevelopmental processes (Geng et al., 2025).

Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) is a crucial enzyme in the placenta that protects the fetus from excessive exposure by converting cortisol/corticosterone into inactive metabolites, thereby acting as a buffer against their potentially harmful effects. However, previous studies indicate that adverse prenatal experiences can lead to a down-regulation of this enzyme, thus limiting its capacity to protect the developing fetus. Findings provide novel evidence for the epigenetic regulation of HSD11B2 as a potential mechanism linking maternal stress during gestation, dysregulation of placental gene expression, and neurodevelopmental outcomes in offspring (Peña et al., 2012).

Beyond inflammatory pathways, epigenetic modifications in stress-regulatory genes further highlight the complex interplay between maternal experiences and offspring neurodevelopment. Several candidate gene studies have investigated differential DNAm in genes such as 11β-HSD2, FKBP5, and NR3C1 as potential mediating factors of prenatal stress effects on neurodevelopment. For example, differential DNAm in 11β-HSD2 and NR3C1 and their respective interaction with prenatal depression have been associated with neurodevelopmental difficulties (Abrishamcal et al., 2024).

Despite growing evidence for prenatal epigenetic and inflammatory markers in ASD, the literature on this subject is incomplete and requires further research. Future work should integrate these markers into predictive models for early ASD identification.

Animal Models

Potential causes and treatments for ASD have been studied in humans as well as animal models. There are multiple studies conducted on animal models examining the impact that both physical factors (e.g., exposure to pesticides) and emotional factors (e.g., chronic stress) have on ASD-like phenotypes in future generations.

PHYSICAL FACTORS

The example study concerning physical factors discussed in this article examined how intrauterine exposure to valproic acid (VPA), a drug that is used to treat epilepsy and bipolar disorder in humans and known to impact neurodevelopment, might influence the development of ASD like phenotypes later in life and even the following generations. For this purpose, they injected 300mg of VPA/kg into pregnant mice on day 10 of their pregnancies. In the offspring of those pregnancies (F1 generation), there was no significant difference in the number of offspring and weight when compared to a control group. What did differ, however, was social behavior. Reduced sociability, hyperactivity, and increased sensitivity to electroshock stimulation were noticeable in the F1 generation. To test for intergenerational inheritance, VPA-exposed males were bred with VPA-naive females to ensure that the ASD like phenotypes in the following generations (F2, F3) would not be caused by abnormal maternal care that female VPA-exposed mice might have provided. But still, some of the same ASD characteristics observed in F1 mice were noticeable in generations F2 and F3. Some of those characteristics are most likely to be caused by epigenetic changes. VPA is known to have histone deacetylase inhibitory properties. This affects transcription factors in the brain, thus inhibiting regular brain development, resulting in ASD-like phenotypes (Choi et al. 2016).

EMOTIONAL FACTORS

A model exploring emotional trauma in rodents and its impact on ASD was created to assess the impact chronic stress could have on ASD in future generations (Pisu et al., 2019). Rats aged 21 days were either placed in cages with four other rats or placed in a cage alone, effectively isolating those rats from the rest, subjecting them to chronic stress for which social isolation is a common source (Xia & Li, 2018). This specific time frame was chosen because the mice had just entered adolescence at 21 days old, which is a critical developmental stage. After one month, the isolated male rats were paired with isolated female rats, and group-housed males were paired with group-housed females for breeding. The resulting offspring of the Isolated Offspring (ISO-O) rats exhibited increased seizure sensitivity compared to the Group Housed Offspring (GH-O) after both were injected with isoniazid, as well as impaired social learning and non-social behavior, which are all phenotypes linked to ASD in humans (Frye et al., 2016; O’Haire et al., 2013; Vivanti & Rogers, 2014). The results published by Pisu et al. were derived from male ISO-O only, as females did not show any of the behavioral alterations that had been observed in males. While in humans it is not the case that ASD doesn’t occur in females at all, the findings of this study do go along with findings in human studies, that generally females seem to be diagnosed with ASD less often, which will be looked at in more detail in this review later. 

In both studies, parental exposure to environmental factors, either during pregnancy or preconception, increased the expression of ASD like phenotypes in offspring rodents. This strongly indicates that ASD is not just heritable, but can also be influenced by other factors, such as epigenetics.

Sex differences 

Sex differences are believed to significantly contribute to the etiology of ASD. Early on, studies discovered that ASD occurred more frequently in males rather than females, with numbers fluctuating depending on the study (Wing, 1981; Tsei & Beisler, 1983). Recent research suggest a 3:1 male to female ratio (Loomes et al., 2017; Stroh et al., 2022), though these numbers can be influenced by the age range of the test group or even geographical location (Nordahl, 2023).

Another factor that makes determining the correct ratio difficult is that there is evidence suggesting that in many cases, women with ASD were either misdiagnosed or not diagnosed at all, particularly if they show no intellectual disabilities or psychiatric symptoms (Nordahl, 2023). But precise ratio aside, a common factor in many studies is that males are more affected by ASD.

Sex may also influence the specific traits and severity of ASD symptoms (Stroh et al., 2022) There is, for example, empirical evidence that girls and women with ASD show greater social motivation and capacity for friendships than males with ASD, and are less likely to show overt patterns of restricted and limited interests than males (Napolitano et al., 2022; Stroh et al., 2022).

FEMALE PROTECTIVE EFFECT

One theory to explain the sex differences in ASD is called the Female Protective Effect (FPE). It suggests that females need either a greater number or larger magnitude of risk factors to manifest ASD (Dougherty et al., 2022). A study conducted in 2025 by Mouat et al. had findings that supported the FPE theory while focusing on DNA methylation. Mouat et al. assayed the DNA methylation in the blood of newborns that were later diagnosed with ASD and a control cohort of whole genome bisulfite sequencing of newborn dried blood spots. They found that females with ASD showed stronger and more consistent DNA methylation patterns related to ASD. These findings open up many new research possibilities, especially seeing how there are not many studies exploring sex differences in epigenetic marks in ASD (Mouat et al., 2025).

EXTREME MALE BRAIN HYPOTHESIS

Another theory is known as the extreme male brain hypothesis. It suggests that autism is associated with an exaggerated typical male brain (Ejik & Zietsch; 2022) – a brain that shows more systemizing rather than empathizing according to the empathizing-systemizing theory of psychological sex differences. The explanation that Cohen proposed was a heightened fetal exposure to testosterone (Cohen, 2005). There are studies supporting this theory (Greenberg et al., 2018; Crepsi et al., 2019), however, there has been criticism towards it from a philosophical standpoint as well as conflicting evidence (Ridley, 2019; Ejik & Zietsch, 2022).

Conclusion

ASD is a neurodevelopmental condition in which the number of cases rises globally, influenced by both environmental factors and genetic predispositions. Psychological trauma was identified as one of these significant environmental factors. By examining epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, which regulate gene expression without altering the underlying DNA sequence, we gain insight into how environmental factors can impact biological processes. The evidence suggests a link between trauma-induced changes and an increased risk of ASD across generations. The animal models exemplify this concept, demonstrating that parental exposure to stress often leads to heritable epigenetic modifications and ASD-like traits in offspring. While human studies are more challenging, there are indications that maternal and paternal stress exposures can imprint epigenetic marks in germline cells as well as influence fetal neurodevelopment, in turn increasing offspring susceptibility to ASD. Specific epigenetic dysregulations, including altered histone modifications, microRNA expression, and DNAm patterns in brain regions and germ cells, are associated with ASD pathogenesis. 

Regarding the efficacy of current treatments, while established interventions such as Applied Behavior Analysis (ABA), TEACCH, Early Start Denver Model (ESDM), PEERS, and Microbiota Transfer Therapy (MTT) are vital for managing symptoms and improving adaptive skills, they primarily address the behavioral and functional aspects of ASD. With the emerging understanding of ASD, we can see that these solutions fail to target the underlying molecular contributions to the disorder. With more research on epigenetics than ever, the potential for novel epigenetic therapies that directly modulate gene expression becomes a possibility, offering a more direct approach. 

In conclusion, the connection between trauma, epigenetics, and intergenerational ASD is becoming increasingly relevant. This understanding highlights the great impact of environmental experiences across generations and emphasizes that while current treatments are beneficial, a newer approach may involve targeting epigenetic mechanisms. Future research may be crucial toward integrating these findings that can transform the way we treat ASD, moving toward personalized medicine to address the biological roots of ASD.

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