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Science AdvancesDevelopmental BiologyPeer-reviewed journal article

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

Irene Sanchez-MartiniD, Bharti KukrejaiD, Paige HendersoniD, Qianyu LiniD, Daniel DiMartino, Valerie Bagan, Justin ParkiD, Brian Thomas KalishiD, Lucas CheadleiD

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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 twenty-four 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 pro-inflammatory 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, IL-6, is required for MIA-evoked developmental abnormalities to emerge. Our data indicate that MIA drives a rapid shift from an immunosuppressive to a pro-inflammatory 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.

In-depth summary

Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (27 Aug 2026) · CC BY 4.0

A poly(I:C) dose at E12.5 causes placental junctional-zone breakdown, amniotic inflammation and developmental defects in a male-only subset of embryos within 24 hours, dependent on maternal IL-6.

Most MIA studies look at adult offspring behavior or at placentas days after injection, so the earliest events separating vulnerable from resilient embryos are unclear. This work profiles fetus, placenta and amniotic fluid within 24 hours and links male-restricted susceptibility to lost placental immunosuppression and IL-6.

Key results

  1. ShownWithin 24 hours of poly(I:C), a minority of embryos show at least one teratogenic abnormality (growth, craniofacial, vascular, sensory organ, spine or tail), while saline controls show none. The pattern replicated in a second mouse strain.

    About 30% of poly(I:C) embryos vs 0% of saline embryos had one or more abnormalities (unpaired t test, p < 0.0001; n = 34 litters per condition). Fetal weight: n = 63 saline and 103 poly(I:C) embryos from 10 and 19 litters. Also seen in BALB/c mice. · MIA elicits large-scale developmental…; Figure legends

  2. ShownThe abnormalities are restricted to males. No female embryo was affected, and a male's risk rose when neighboring embryos were also male. Embryo position relative to the injection site did not explain severity.

    Every embryo in the moderate and strong poly(I:C) groups was male (100%); roughly 60% of MIA males were affected vs 0% of females; about 30% of males per litter on average. Two-way ANOVA, sex ****p < 0.0001. Neighbor-sex effect **p < 0.01. Repeated in BALB/c. · MIA-induced deficits in embryonic development…; Figure legends

  3. ShownSingle-nucleus RNA-seq of male placentas shows expansion of the fetal spongiotrophoblast lineage and an inflammatory shift in maternal and fetal cells. Spongiotrophoblasts lose collagen, laminin and steroid hormone biosynthesis transcripts, and Col1a1 protein falls in affected males.

    197,237 nuclei, 20 cell types; the SpTMIA subcluster was twice as abundant; Hsd17b2 and Cyp11a1 fell by over 8-fold in SpTs (4.0 absolute fold change, FDR < 0.05). Col1a1 immunofluorescence reduced (unpaired t test, *p < 0.05; n = 3 placentas per condition). · Single-nucleus RNA sequencing reveals cell…; Genes encoding the extracellular matrix and…; A subpopulation of placental SpTs expressing…; Figure legends

  4. ShownAffected male placentas show lesions in the decidua and junctional zone, absent in normally developing males and in females. Male amniotic fluid gains immune cells, with T cells only in affected males, and 14 cytokines rise selectively in affected males, not females.

    Decidual degeneration scoring: n = 11 saline, 6 norm, 14 mod, 10 strong (one-way ANOVA with Tukey). Amniotic fluid flow cytometry: n = 5 saline and norm, 6 mod, 4 strong from 5 litters per condition. 14 of 37 cytokines rose in affected males, including IL-6, TNFα, IL-1β and IL-17. · MIA disrupts the structural integrity of the…; Innate and adaptive immune cells infiltrate the…; MIA induces a pro-inflammatory environment…; Figure legends

  5. ShownNeutralizing maternal IL-6 before poly(I:C) prevented the fetal and placental abnormalities, indicating that IL-6 is required for the early deficits.

    Anti-IL-6 antibody MP5-20F3 was given 1 hour before poly(I:C). Poly(I:C) alone yielded abnormalities in about 30% of embryos, whereas fetal and placental integrity was preserved with IL-6 neutralized. Fetal weight: n = 15 saline, 16 poly(I:C), 16 αIL-6 + poly(I:C); one-way ANOVA with Tukey. · IL-6 is required for MIA-driven deficits in male…; IL-6 blockade during MIA; Figure legends

Methods, data and reproducibility

Pregnant C57BL/6J dams received poly(I:C) (20 mg/kg) or saline at E12.5. Embryos, placentas and amniotic fluid were profiled at E13.5 by morphometry, bulk and single-nucleus RNA-seq, histology, flow cytometry, cytokine assays and maternal IL-6 antibody neutralization.

  • Embryos from poly(I:C) vs saline dams, morphometric and phenotype scoring at E13.5 (C57BL/6J; replicated in BALB/c) · Mouse · n = n = 63 saline and 103 poly(I:C) embryos (fetal weight)
  • Bulk RNA-seq of placentas from saline males vs poly(I:C)mod males · Mouse · n = n = 4 placentas per condition (Ceacam9 panel)
  • Single-nucleus RNA-seq of placentas from saline males vs poly(I:C)mod males · Mouse · n = 197,237 nuclei, 20 cell types · GSE315060
  • Reanalysis of placental single-cell RNA-seq from women with COVID-19 in pregnancy vs controls · Human · GSE171381
  • H&E placental pathology scoring in male placentas by phenotype (decidual degeneration) · Mouse · n = n = 11 saline, 6 norm, 14 mod, 10 strong
  • Amniotic fluid spectral flow cytometry of male embryos by phenotype · Mouse · n = n = 5 saline and norm, 6 mod, 4 strong; 5 litters per condition
  • Amniotic fluid multiplex cytokine measurements, both sexes and all phenotypes · Mouse · n = 37 cytokines reported in Results; assay described as 44-plex
  • Maternal IL-6 neutralization experiment: saline, poly(I:C), and αIL-6 + poly(I:C) groups · Mouse · n = n = 15 saline, 16 poly(I:C), 16 αIL-6 + poly(I:C) embryos (fetal weight)
Methods & tools
Cell Ranger v7.1.0, SoupX v1.6.2, Seurat v5.0.1, Harmony v0.1.1, MAST, DESeq2, STAR, HTSeq-count, clusterProfiler v4.0, prince (multiple correspondence analysis), decontX, GraphPad Prism 9.0
Reagents & environment
R v4.4.3; Cell Ranger v7.1.0; SoupX v1.6.2; Seurat v5.0.1; Harmony v0.1.1; clusterProfiler v4.0; Prism 9.0; mm10 reference (refdata-gex-mm10-2020-A).
Reproducibility gaps
Zenodo link is printed with an access token and may be restricted; GEO accession is given without a URL; no container or compute specification stated.
Limitations (5)
  • The mouse model limits direct extrapolation to human pregnancy, and placental architecture and immune regulation differ between the species. · stated by the authors
  • MIA outcomes vary with the commercial source of poly(I:C), so some effects may be absent or weaker with other sources; only inbred strains were used, and crosses between unrelated strains were not tested. · stated by the authors
  • The finding that neighboring male fetuses raise risk may not extend to adult behavior, and early outcomes precluded assessing how amniotic cytokines affect fetal brain development. · stated by the authors
  • Several validations rest on few replicates (Col1a1 immunofluorescence and TGC counts with n = 3 placentas per condition, bulk RNA-seq n = 4), and the snRNA-seq comparison covers only saline and poly(I:C)mod males. · noted in this summary
  • The proposed model of male-specific paternal antigens driving immune conflict was not directly tested; no male-specific antigen was identified, and IL-6 neutralization was systemic, so its site of action is unresolved. · noted in this summary

Read this if you study maternal immune activation, sex-biased neurodevelopmental risk or placental immunology and want 24-hour cellular and cytokine data from the poly(I:C) mouse model.

Citations
3
FWCI
12.50
Field percentile
top 1%

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