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| Status |
Public on Aug 15, 2023 |
| Title |
Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 the maternal, placental, and fetal compartments contribute 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, pregnant rat dams were treated with the clinically available 11β-hydroxylase inhibitor metyrapone, alongside administration of the bacterial mimetic lipopolysaccharide (LPS), on gestational day 15. Maternal, placental, and fetal CNS levels of corticosterone and placental 11ßHSD enzymes type 1 and 2 were measured 3-hrs post treatment. Subsequently, offspring social behaviors were measured across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11ßHSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure protected against MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Transcriptomic analyses revealed that metyrapone-exposure triggered opposing effects on gene expression to combat MIA-exposure in males, but not among females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinical drug already provided to pregnant people and neonates for the treatment of hypercortisolism, 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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| Overall design |
To investigate the effect of the maternal stress on the developmental trajectory of male and female rats, pregnant rat dams were treated with the clinically available 11β-hydroxylase inhibitor metyrapone, alongside administration of the bacterial mimetic lipopolysaccharide (LPS), on gestational day 15.
We then isolated RNA from ventral hippocampus of the offspring of treated animals and controls, and performed RNA-seq of total RNA from rats and compared gene expression between groups.
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| Contributor(s) |
Martz J, Shelton MA, Geist L, Seney ML, Kentner AC |
| Citation(s) |
38007547 |
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| Submission date |
Aug 10, 2023 |
| Last update date |
Nov 27, 2023 |
| Contact name |
Micah Aaron Shelton |
| E-mail(s) |
mas458@pitt.edu
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| Phone |
4439344618
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| Organization name |
University of Pittsburgh
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| Department |
Psychiatry
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| Lab |
Seney Lab
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| Street address |
2602 PITCAIRN RD
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| City |
Pittsburgh |
| State/province |
Pennsylvania |
| ZIP/Postal code |
15146 |
| Country |
USA |
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| Platforms (1) |
| GPL25947 |
Illumina NovaSeq 6000 (Rattus norvegicus) |
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| Samples (23)
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| GSM7703449 |
Ventral hippocampus, saline treated, male 1 |
| GSM7703450 |
Ventral hippocampus, saline treated, male 2 |
| GSM7703451 |
Ventral hippocampus, saline treated, male 3 |
| GSM7703452 |
Ventral hippocampus, LPS treated, male 1 |
| GSM7703453 |
Ventral hippocampus, LPS treated, male 2 |
| GSM7703454 |
Ventral hippocampus, LPS treated, male 3 |
| GSM7703455 |
Ventral hippocampus, MET treated, male 1 |
| GSM7703456 |
Ventral hippocampus, MET treated, male 2 |
| GSM7703457 |
Ventral hippocampus, MET treated, male 3 |
| GSM7703458 |
Ventral hippocampus, LPS-MET treated, male 1 |
| GSM7703459 |
Ventral hippocampus, LPS-MET treated, male 2 |
| GSM7703460 |
Ventral hippocampus, LPS-MET treated, male 3 |
| GSM7703461 |
Ventral hippocampus, saline treated, female 1 |
| GSM7703462 |
Ventral hippocampus, saline treated, female 2 |
| GSM7703463 |
Ventral hippocampus, saline treated, female 3 |
| GSM7703464 |
Ventral hippocampus, LPS treated, female 1 |
| GSM7703465 |
Ventral hippocampus, LPS treated, female 2 |
| GSM7703466 |
Ventral hippocampus, LPS treated, female 3 |
| GSM7703467 |
Ventral hippocampus, MET treated, female 2 |
| GSM7703468 |
Ventral hippocampus, MET treated, female 3 |
| GSM7703469 |
Ventral hippocampus, LPS-MET treated, female 1 |
| GSM7703470 |
Ventral hippocampus, LPS-MET treated, female 2 |
| GSM7703471 |
Ventral hippocampus, LPS-MET treated, female 3 |
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| Relations |
| BioProject |
PRJNA1004293 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE240604_RAW.tar |
36.6 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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