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Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Neuropsychopharmacology (2023)Cite this article

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A Correction to this article was published on 05 April 2024

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Abstract

Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11β-hydroxylase (11βHSD) inhibitor used to treat hypercortisolism in pregnant, lactating, and neonatal populations. Maternal, placental, and fetal brain levels of corticosterone and placental 11βHSD enzymes type 1 and 2 were measured 3-hrs post treatment. Offspring social behaviors were evaluated across critical phases of development. MIA was associated with increased maternal, placental, and fetal brain corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11βHSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure attenuated MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Metyrapone-exposure reversed MIA-induced transcriptional changes in monoamine-, glutamate-, and GABA-related genes in adult male ventral hippocampus, but not in females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinically available drug, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.

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Fig. 1
Fig. 2: Effect of metyrapone (MET) on maternal immune activation (MIA)-induced sickness behaviors and 3-hr post LPS physiological response measures in dams, placenta, and fetal brain.
Fig. 3: Effect of maternal immune activation (MIA) and metyrapone (MET) on offspring behavioral measures in infancy, adolescence, and adulthood.
Fig. 4: Transcriptomic analyses of ventral hippocampus tissue samples collected from adult male offspring.
Fig. 5: Transcriptomic analyses of ventral hippocampus tissue samples collected from adult female offspring.
Fig. 6: Summary of findings and proposed mechanisms.

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Data availability

RNA-seq data has been deposited to GEO (GSE240604). All other data is available on request.

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There is no code associated with this work.

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Funding

This project was funded by NIMH under Award Numbers R15MH114035 (to ACK), and R01MH120066 (to MLS), and the Massachusetts College of Pharmacy and Health Sciences (MCPHS) Center for Research and Discovery (to LG). The authors wish to thank Holly DeRosa, Ada Cheng, and Arianna Smith for their technical assistance during earlier phases of this research. The authors would also like to thank the MCPHS Schools of Pharmacy and Arts & Sciences for their continual support, and Azenta Life Sciences where the RNA-seq was performed. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the financial supporters.

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Authors and Affiliations

  1. School of Arts & Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, 02115, USA

    Julia Martz, Laurel Geist & Amanda C. Kentner

  2. Department of Psychiatry, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA, 15219, USA

    Micah A. Shelton & Marianne L. Seney

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  1. Julia Martz
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Contributions

JM, LG, & MAS ran the experiments; JM, MAS, MLS, & ACK analyzed and interpreted the data; JM and ACK wrote the manuscript; ACK, designed and supervised the study.

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Correspondence to Amanda C. Kentner.

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The original online version of this article was revised: In response to a Comment/Letter to the Editor submitted by Karadag et al., (2024), Figures 2B and 2C have been revised to show a “ND” or non-detectable indicator for experimental groups, where the data values fell below the range of the assay, rather than the sensitivity. The associated Figure 2 caption, the results section of the manuscript, and Supplemental Results Table 2 have been revised accordingly. These revisions, based on Karadag’s recommendations, do not change the study findings or conclusions. The data validate that LPS induced an inflammatory response.

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Martz, J., Shelton, M.A., Geist, L. et al. Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01771-5

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