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Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we separated the effects of pre-conception and gestational obesity. We found that maternal high fat diet (HFD) exposure prior to conception alone was sufficient to induce ASD-like behaviors in male offspring\u2014including altered vocalizations, reduced sociability, and increased repetitive grooming\u2014without anxiety-related changes. These phenotypes were absent in female offspring and those exposed only during gestation. Cortical transcriptome analysis revealed dysregulation and isoform shifts in genes implicated in ASD, including Homer1 and Zswim6. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternative Homer1 promoter, correlating with increased expression of the short isoform Homer1a, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behaviors. Our findings show that pre-conceptional maternal obesity can lead to lasting, isoform-specific transcriptomic and epigenetic changes in the offspring\u2019s brain. These results underscore the importance of maternal health before pregnancy as a critical and modifiable factor in ASD risk.<\/jats:p>","DOI":"10.3390\/cells14151201","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T10:50:21Z","timestamp":1754391021000},"page":"1201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pre-Conception Maternal Obesity Confers Autism Spectrum Disorder-like Behaviors in Mice Offspring Through Neuroepigenetic Dysregulation"],"prefix":"10.3390","volume":"14","author":[{"given":"Nina P.","family":"Allan","sequence":"first","affiliation":[{"name":"Yanagimachi Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7010-1294","authenticated-orcid":false,"given":"Amada","family":"Torres","sequence":"additional","affiliation":[{"name":"Yanagimachi Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Corley","sequence":"additional","affiliation":[{"name":"Yanagimachi Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96822, USA"},{"name":"Department of Medicine, Division of Geriatrics, Gerontology and Palliative Care, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0921-6046","authenticated-orcid":false,"given":"Brennan Y.","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Yanagimachi Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chantell","family":"Balaan","sequence":"additional","affiliation":[{"name":"Yanagimachi Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Yanagimachi Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Peres","sequence":"additional","affiliation":[{"name":"Yanagimachi Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0971-0175","authenticated-orcid":false,"given":"Yujia","family":"Qin","sequence":"additional","affiliation":[{"name":"Bioinformatics Core Facility, Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawai\u2019i at M\u0101noa, Honolulu, HI 96822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8652-2904","authenticated-orcid":false,"given":"Vedbar S.","family":"Khadka","sequence":"additional","affiliation":[{"name":"Bioinformatics Core Facility, Department of Quantitative Health Sciences, John A. 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