Male sex is a risk factor for placental vulnerability and cascading neurodevelopmental disruption in utero
- There is a widely recognized male bias in the incidence of neurodevelopmental disorders, and males in utero are also at higher risk for complications of pregnancy. This has led some to propose male sex as a risk factor for disrupted prenatal neurodevelopment. The central regulator of fetal development is the placenta, which is derived from the embryo and shares the chromosomal sex of the fetus. Clinical findings suggest that male and female placentas function differently in humans in response to maternal stress and inflammation. Using a mouse model of maternal immune activation during pregnancy, we tested the hypothesis that one factor underlying male-selective vulnerability to neurodevelopmental disruption is exacerbated placental dysfunction following a maternal inflammatory event. A mild challenge with lipopolysaccharide (LPS) on day 12.5 of the mouse pregnancy produces growth reduction and necrosis that is more severe in the male placenta. Male fetuses in LPS-challenged pregnancies also show elevated hypoxia and decreased proliferation in the developing cortex relative to females. This fetal sex-based divergence in neurodevelopmental trajectory persists into adulthood, producing lamina-specific reductions in Satb2+ and Parvalbumin+ cell densities in neocortex that are markedly more severe in males. Prenatal LPS exposure also produces significantly diminished social interaction, impaired spatial learning, and elevated behavioral stereotypies in males only. In contrast, females show an acute elevation in fetal brain cytokine abundance and a delay in postnatal body growth. Transcriptomic analyses of midgestation mouse and human placenta reveal sex-specific gene expression signatures that center on hubs of innate immune signaling, revealing an evolutionarily conserved divergence that can help explain differential vulnerability. Given these results, it may be useful to view male-selective neurodevelopmental impairment on a continuum of male vulnerability to in utero adversity. These findings also highlight the value of sex inclusion in animal research, since the customary exclusion of females would have led to spurious extrapolations from male to female biology. We also emphasize the existence of sex-dependent differences in many baseline measures. If improperly balanced in experimental design, these differences could lead to results that reflect the sex imbalance rather than treatment effects.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Braun, Amy Elizabeth
|Stanford University, Neurosciences Program.
|Stefanick, Marcia Lynn
|Stefanick, Marcia Lynn
|Statement of responsibility
|Amy Elizabeth Braun.
|Submitted to the Program in Neuroscience.
|Thesis (Ph.D.)--Stanford University, 2018.
- © 2018 by Amy Elizabeth Braun
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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