Molly Dias

Background: Autism Spectrum Disorder (ASD) is a category of neurodevelopmental diseases characterized by verbal and social impairment often accompanied by repetitive behaviors.^{1, 2} Like most psychiatric disorders, the exact etiology is not well understood, but it is thought to be related to gene by environment (GxE) interactions. This approach has led to investigations of potential epigenetic etiology of ASD related to the interplay between genetic makeup of an individual and environmental effects on gene expression.^{1, 3} One concerning trend in the United States in recent years is the dramatic increase in prevalence from 1/68 children in 2018 to 1/44 children in 2022. ASD is typically diagnosed and treated in childhood and is markedly more common in males.^1,2,4 Current therapy standards rely on early identification using psychiatric tools such as the Autism Diagnostic Observation Schedule (ADOS) or Autism Diagnostic Interview – Revised (ADI-R), followed by symptomatic management with psychotherapy.^1,2

Objective: This narrative review and critical analysis explore oxytocin as a potential epigenetic therapy for pediatric male patients.

Search Methods: The database PubMed was used with the following keywords: “Autism Spectrum Disorder”, “epigenetics”, “epigenomics”, and “oxytocin.” Leads from resulting articles were followed as applicable.

Results: Three observations formed the basis for a strong suggestion that oxytocin is likely to be a suitable therapy for ASD. First, mouse models identified locus-specific methylation of Mecp2 as a transcriptional regulator responsible for phenotypes similar to those seen in ASD.5 Researchers used Mecp2 methylation to effectively turn “off” normal transcriptional regulation, using differential methylation as a therapeutic lever for further investigation. Second, a study demonstrating that Mecp2-null male mice displayed marked differences in oxytocinergic and vasopressinergic innervation in areas of the brain associated with social reasoning and aggression, evidence for a sexually dimorphic etiology to ASD that provides insights into possible treatment approaches.⁷ Perhaps most striking, a complete lack of oxytocinergic innervation to the lateral habenula of Mecp2-null male mice suggests that a deficiency in oxytocin in this tiny brain region could substantially contribute to ASD pathophysiology.⁷ Lastly, a surprisingly promising clinical trial in intranasal oxytocin administration suggests that chronic (rather than acute) administration was beneficial for pediatric ASD patients by way of epigenetic upregulation of the oxytocin receptor OXTR.^8,9 While previous attempts at administering oxytocin intranasally had been unsuccessful, this clinical trial suggests that previous failures may have been due to lack of adherence and longevity in treatment. Because oxytocin has a short half-life, it is believed that upregulation of this gene is likely responsible for symptom improvement.

Conclusion: While much more work is needed to elucidate exact mechanisms, the literature is becoming more and more suggestive of the contribution of epigenetic mechanism to the etiology of ASD. As a result, therapies targeting epigenetic modification are of great interest to the ASD community due at least in part to the promising results of chronic oxytocin administration in pediatric patients. In general, while not all therapeutic mechanisms are well understood, GxE approaches to treatment for autism are proving informative for the development of improved treatments for this serious developmentaldisorder.

Works Cited

1. Williams LA, LaSalle JM. Future Prospects for Epigenetics in Autism Spectrum Disorder. Mol Diagn Ther. 2022 Nov;26(6):569-579. doi: 10.1007/s40291-022-00608-z. Epub 2022 Aug 13. PMID: 35962910; PMCID: PMC9626414.
2. Waye MMY, Cheng Genetics and epigenetics of autism: A Review. Psychiatry Clin Neurosci. 2018 Apr;72(4):228-244. doi: 10.1111/pcn.12606. Epub 2017 Nov 13. PMID: 28941239.
3. LaSalle JM. Epigenomic signatures reveal mechanistic clues and predictive markers for autism spectrum disorder. Mol Psychiatry. 2023 May;28(5):1890-1901. doi: 10.1038/s41380-022-01917-9. Epub 2023 Jan 17. PMID: 36650278; PMCID:
4. Sikich L, Kolevzon A, King BH, McDougle CJ, Sanders KB, Kim SJ, Spanos M, Chandrasekhar T, Trelles MDP, Rockhill CM, Palumbo ML, Witters Cundiff A, Montgomery A, Siper P, Minjarez M, Nowinski LA, Marler S, Shuffrey LC, Alderman C, Weissman J, Zappone B, Mullett JE, Crosson H, Hong N, Siecinski SK, Giamberardino SN, Luo S, She L, Bhapkar M, Dean R, Scheer A, Johnson JL, Gregory SG, Veenstra-VanderWeele J. Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder. N Engl J Med. 2021 Oct 14;385(16):1462-1473. doi: 10.1056/NEJMoa2103583. PMID: 34644471; PMCID: PMC9701092.
5. Lu Z, Liu Z, Mao W, Wang X, Zheng X, Chen S, Cao B, Huang S, Zhang X, Zhou T, Zhang Y, Huang X, Sun Q, Li JD. Locus-specific DNA methylation of Mecp2 promoter leads to autism-like phenotypes in mice. Cell Death Dis. 2020 Feb 3;11(2):85. doi: 10.1038/s41419- 020-2290-x. PMID: 32015323; PMCID: PMC6997184.
6. Siecinski SK, Giamberardino SN, Spanos M, Hauser AC, Gibson JR, Chandrasekhar T, Trelles MDP, Rockhill CM, Palumbo ML, Cundiff AW, Montgomery A, Siper P, Minjarez M, Nowinski LA, Marler S, Kwee LC, Shuffrey LC, Alderman C, Weissman J, Zappone B, Mullett JE, Crosson H, Hong N, Luo S, She L, Bhapkar M, Dean R, Scheer A, Johnson JL, King BH, McDougle CJ, Sanders KB, Kim SJ, Kolevzon A, Veenstra-VanderWeele J, Hauser ER, Sikich L, Gregory SG. Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder. Autism Res. 2023 Mar;16(3):502- doi: 10.1002/aur.2884. Epub 2023 Jan 7. PMID: 36609850; PMCID: PMC10023458.
7. Martínez-Rodríguez E, Martín-Sánchez A, Kul E, Bose A, Martínez-Martínez FJ, Stork O, Martínez-García F, Lanuza E, Santos M, Agustín-Pavón C. Male-specific features are reduced in Mecp2-null mice: analyses of vasopressinergic innervation, pheromone production and social behaviour. Brain Struct Funct. 2020 Sep;225(7):2219-2238. doi: 10.1007/s00429-020-02122-6. Epub 2020 Aug 4. PMID: 32749543.
8. Siu MT, Goodman SJ, Yellan I, Butcher DT, Jangjoo M, Grafodatskaya D, Rajendram R, Lou Y, Zhang R, Zhao C, Nicolson R, Georgiades S, Szatmari P, Scherer SW, Roberts W, Anagnostou E, Weksberg R. DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders. J Autism Dev Disord. 2021 Oct;51(10):3610-3623. doi: 10.1007/s10803-020-04792-x. Epub 2021 Jan 4. PMID: 33394241.
9. Moerkerke M, Daniels N, Tibermont L, Tang T, Evenepoel M, Van der Donck S, Debbaut E, Prinsen J, Chubar V, Claes S, Vanaudenaerde B, Willems L, Steyaert J, Boets B, Alaerts K. Chronic oxytocin administration stimulates the oxytocinergic system in children with autism. Nat Commun. 2024 Jan 2;15(1):58. doi: 10.1038/s41467-023-44334-4. PMID: 38167302; PMCID: PMC10762037.