Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders

Sanchez-Martin, Irene, Kukreja, Bharti, Henderson, Paige, Lin, Qianyu, DiMartino, Daniel, Bagan, Valerie, Park, Justin, Kalish, Brian T, Cheadle, Lucas (September 2026) Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders. Science Advances, 12 (38). eaeg0779. ISSN 2375-2548 (Public Dataset)

[thumbnail of 10.1126.sciadv.aeg0779.pdf]

PDF
10.1126.sciadv.aeg0779.pdf - Published Version
Available under License Creative Commons Attribution.
Download (1MB)

URL: https://www.ncbi.nlm.nih.gov/pubmed/42748249

DOI: 10.1126/sciadv.aeg0779

Abstract

Autism spectrum disorder (ASD) arises from genetic and environmental risk factors. One environmental factor, maternal immune activation (MIA)-in which pathogenic infection during pregnancy increases ASD risk in offspring-disproportionately 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-ranging from decreased fetal weight to altered sensory organ development-while 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-fetally 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-combined with MIA-induced loss of maternal immunosuppression-selectively derails male embryonic development.

Item Type:	Paper
Subjects:	organism description > animal organism description > animal > developmental stage organism description > animal > mammal organism description > animal > mammal > rodent > mouse organism description > animal > developmental stage > neurodevelopment organism description > animal > mammal > rodent
CSHL Authors:	Cheadle, Lucas Sanchez Martin, Irene Henderson, Paige Lin, Qianyu DiMartino, Daniel Bagan, Valerie Park, Justin
Communities:	CSHL labs > Cheadle lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Post Doctoral Fellows
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	18 September 2026
Date Deposited:	18 Sep 2026 15:16
Last Modified:	18 Sep 2026 15:16
PMCID:	PMC13580578
Related URLs:	Publisher
Dataset ID:	GEO: GSE315060
URI:	https://repository.cshl.edu/id/eprint/42315

Actions (login required)

Administrator's edit/view item