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Adv."],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:p>Autism spectrum disorder (ASD) arises from genetic and environmental risk factors. One environmental factor, maternal immune activation (MIA)\u2014in which pathogenic infection during pregnancy increases ASD risk in offspring\u2014disproportionately affects males. However, the basis for this male-specific vulnerability and the mechanisms by which inflammatory signals cross the maternal-fetal interface to affect the male embryo remain largely unknown. Using the poly(I:C) mouse model of neurodevelopmental disorders, we characterize fetal, placental, and amniotic changes occurring within 24 hours of MIA. We find that 30% of embryos exhibit large-scale teratogenic abnormalities\u2014ranging from decreased fetal weight to altered sensory organ development\u2014while 70% develop normally. These abnormalities occur exclusively in a subset of males, never in females. Single-nucleus transcriptomics revealed robust induction of proinflammatory gene programs in the placentas of affected males across a broad range of cell types, and most prominently in spongiotrophoblasts\u2014fetally derived cells that partly form the maternal-fetal border. These cells simultaneously down-regulate extracellular matrix and hormone biosynthesis pathways, coinciding with a breakdown in placental structural integrity and the accumulation of immune cells and cytokines in the amniotic fluid. One such cytokine, interleukin-6, is required for MIA-evoked developmental abnormalities to emerge. Our data indicate that MIA drives a rapid shift from an immunosuppressive to a proinflammatory maternal-fetal interface in a vulnerable subset of male embryos, producing acute, sex-restricted developmental deficits. We propose that male embryos may express unique proteins capable of triggering this inflammatory response, which\u2014combined with MIA-induced loss of maternal immunosuppression\u2014selectively derails male embryonic development.<\/jats:p>","DOI":"10.1126\/sciadv.aeg0779","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:02:56Z","timestamp":1789581776000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9202-2618","authenticated-orcid":true,"given":"Irene","family":"Sanchez-Martin","sequence":"first","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7093-065X","authenticated-orcid":true,"given":"Bharti","family":"Kukreja","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Henderson","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA."},{"name":"Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0494-4186","authenticated-orcid":true,"given":"Qianyu","family":"Lin","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"DiMartino","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Bagan","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5794-4451","authenticated-orcid":true,"given":"Justin","family":"Park","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3184-018X","authenticated-orcid":true,"given":"Brian T.","family":"Kalish","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Boston, MA 02115, USA."},{"name":"F.M. 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