Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | ENEURO.0358-19.2019 |
| Journal | eNeuro |
| Volume | 6 |
| Issue number | 6 |
| DOIs | |
| State | Published - Nov 1 2019 |
Funding
Received September 5, 2019; accepted September 27, 2019; First published October 14, 2019. The authors declare no competing financial interests. Author contributions: A.E.B., P.A.C., B.A.B., H.M.M., and T.D.P. designed research; A.E.B., P.A.C., B.A.B., A.R.N., M.L.K., H.M.M., A.S., J.S., V.S., and U.H. performed research; A.E.B., P.A.C., and U.H. analyzed data; A.E.B. wrote the paper. This work was supported by the March of Dimes (Grant 12-FY06-240), Autism Speaks (Grant 3713), the Simons Foundation (Grants 206574 and 323220), and the National Institutes of Health (NIH; Grants MH-091865, MH-108659, and MH-108660; to T.D.P.); the Regina Casper Stanford Graduate Fellowship (to A.B.); the California Institute for Regenerative Medicine (Grant TB1-01181; to A.S.); and the NIH (Grant F32-NS-60427) and the Lucile Pack-ard Foundation (to P.C.). Correspondence should be addressed to Amy E. Braun at Amybraun@ stanford.edu. https://doi.org/10.1523/ENEURO.0358-19.2019 Copyright © 2019 Braun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. All animal studies were performed in accordance with National Institutes of Health (NIH) guidelines for the humane use of animals, and all procedures were reviewed and approved by the Stanford Institutional Animal Care and Use Committee. C57BL/6J mice purchased from The Jackson Laboratory were used for all studies.
Keywords
- Corticogenesis
- Developmental origins of health and disease
- Female resilience
- Maternal immune activation
- Pregnancy complications
- Sex differences
ASJC Scopus subject areas
- General Neuroscience