"Females are not just 'protected' males:" Sex-specific vulnerabilities in placenta and brain after prenatal immune disruption.
Introduction: Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased towards 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. Method: Pregnant C57Bl/6 mice were treated with low dose lipopolysaccharide (LPS) 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. Results: 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. Conclusions: 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 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.SIGNIFICANCE STATEMENT Given the common practice of excluding female animals from studies of maternal immune activation during pregnancy, it appears to be widely assumed that female outcomes are simply attenuated versions of more severe male outcomes. However, when females fetuses and offspring are closely examined in a model of lipopolysaccharide-induced maternal inflammation during pregnancy, we find that sex confers selective vulnerabilities and outcomes that impact the placenta, fetal brain, adult brain, and behavior in ways that are categorically distinct and in some cases opposite between females and males. Therefore, the effect of maternal immune activation on female offspring cannot be inferred from male outcomes and must be studied independently to fully understand the mechanisms that underlie prenatal vulnerability to maternal insults.
View details for DOI 10.1523/ENEURO.0358-19.2019
View details for PubMedID 31611335