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<p>Sex differences are a defining feature of neurodevelopmental disorders (NDDs), with males diagnosed up to four times more frequently than females. Gestational maternal immune activation (MIA) is an environmental risk factor for NDDs that produces stronger behavioral alterations among male offspring. To identify the contributions of sex chromosomes (XX vs. XY) and gonadal development (ovaries vs. testes) in this sex bias, we used the Four Core Genotypes (FCG) mouse model. We assessed placental, fetal, and juvenile brain immune responses, along with juvenile behavioral outcomes, following early (E12.5) or late (E17.5) gestational exposure to Poly(I: C), eliciting a robust systemic maternal immune response. Placental immune profiling revealed distinct sex-specific strategies: XX gonadal females mounted coordinated pro- and anti-inflammatory responses, whereas XY offspring and gonadal males exhibited relative immune suppression, particularly in late gestation, coinciding with the testicular androgen surge. Conversely, fetal brain chemo-cytokine responses 24&#xa0;h post-MIA were similar across XX females and XY males. However, XY offspring juvenile neuroimmune alterations were associated with increased social avoidance. Early MIA eliminated the typical social advantage of gonadal females, shifting behavior toward male-typical patterns. Together, we identify the placenta as a key site of sex-specific immune responses to MIA and demonstrate that gestational timing, sex chromosome complement, and gonadal signals interact to shape long-term neuroimmune and behavioral outcomes relevant to sex-bias in NDDs. </p> Graphical Abstract <p></p>

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Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Stephanie Salia,
  • Nadine T. Burry,
  • Meagan E. Hinks,
  • Kerri M. Sparkes,
  • Alison M. Randell,
  • Alexandre S. Maekawa,
  • Nicole Reid,
  • Lucas F. Fowler,
  • Rachel Q. Kelly,
  • Jai-Lynn Francis,
  • Madison C. Youden,
  • Stephanie H.G. Pelley,
  • Susan G. Walling,
  • Ashlyn Swift-Gallant

摘要

Sex differences are a defining feature of neurodevelopmental disorders (NDDs), with males diagnosed up to four times more frequently than females. Gestational maternal immune activation (MIA) is an environmental risk factor for NDDs that produces stronger behavioral alterations among male offspring. To identify the contributions of sex chromosomes (XX vs. XY) and gonadal development (ovaries vs. testes) in this sex bias, we used the Four Core Genotypes (FCG) mouse model. We assessed placental, fetal, and juvenile brain immune responses, along with juvenile behavioral outcomes, following early (E12.5) or late (E17.5) gestational exposure to Poly(I: C), eliciting a robust systemic maternal immune response. Placental immune profiling revealed distinct sex-specific strategies: XX gonadal females mounted coordinated pro- and anti-inflammatory responses, whereas XY offspring and gonadal males exhibited relative immune suppression, particularly in late gestation, coinciding with the testicular androgen surge. Conversely, fetal brain chemo-cytokine responses 24 h post-MIA were similar across XX females and XY males. However, XY offspring juvenile neuroimmune alterations were associated with increased social avoidance. Early MIA eliminated the typical social advantage of gonadal females, shifting behavior toward male-typical patterns. Together, we identify the placenta as a key site of sex-specific immune responses to MIA and demonstrate that gestational timing, sex chromosome complement, and gonadal signals interact to shape long-term neuroimmune and behavioral outcomes relevant to sex-bias in NDDs.

Graphical Abstract