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eNeuro. 2019 Nov 7;6(6). pii: ENEURO.0358-19.2019. doi: 10.1523/ENEURO.0358-19.2019. Print 2019 Nov/Dec.

"Females Are Not Just 'Protected' Males": Sex-Specific Vulnerabilities in Placenta and Brain after Prenatal Immune Disruption.

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Institute for Stem Cell Biology and Regenerative Medicine and Department of Neurosurgery, Stanford University, Stanford, California 94305-5454
Institute for Stem Cell Biology and Regenerative Medicine and Department of Neurosurgery, Stanford University, Stanford, California 94305-5454.
Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
Unity Biotechnology, Brisbane, California 94005.
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon 97239.
Department of Biological Science, California State University, Fullerton, Fullerton, California 92831.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093.
Cortexyme, Inc, South San Francisco, California 94080.


Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased toward male outcomes. An argument is made that males are more vulnerable to gestational complications and neurodevelopmental disorders, the implication being that an understanding of disrupted development in males is sufficient to understand causal mechanisms that are assumed to be similar but attenuated in females. Here we examine this assumption in the context of immune-driven alterations in fetal brain development and related outcomes in female and male mice. Pregnant C57BL/6 mice were treated with low-dose lipopolysaccharide at embryonic day 12.5. Placental pathology, acute fetal brain inflammation and hypoxia, long-term changes in adult cortex cytoarchitecture, altered densities and ratio of excitatory (Satb2+) to inhibitory (parvalbumin+) neuronal subtypes, postnatal growth, and behavior outcomes were compared between male and female offspring. We find that while males experience more pronounced placental pathology, fetal brain hypoxia, depleted PV and Satb2+ densities, and social and learning-related behavioral abnormalities, females exhibit unique acute inflammatory signaling in fetal brain, postnatal growth delay, opposite alterations in cortical PV densities, changes in juvenile behavior, delayed postnatal body growth, and elevated anxiety-related behavior as adults. While males are more severely impacted by prenatal immune disruption by several measures, females exposed to the same insult exhibit a unique set of vulnerabilities and developmental consequences that is not present in males. Our results clearly outline disparate sex-specific features of prenatal vulnerability to inflammatory insults and warn against the casual extrapolation of male disease mechanisms to females.


corticogenesis; developmental origins of health and disease; female resilience; maternal immune activation; pregnancy complications; sex differences

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