Placental infection: immune and nervous system effects modulated by androgens
Bibliographic record
Abstract
Group B Streptococcus (GBS) is a leading cause of placental infection, termed chorioamnionitis (CA), which is associated with an increased risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder. These impairments are more prominent in male offspring, but the mechanisms underlying this sex bias remain unclear. In a preclinical model of GBS-induced CA, male-associated placentas exhibited a heightened inflammatory response, correlating with more severe neurobehavioral impairments. We hypothesize that androgens upregulate the placental innate immune response, exacerbating inflammation and contributing to sex-specific neurodevelopmental outcomes. Lewis dams were injected daily from gestational day (G) 18 to 21 with either vehicle or the androgen receptor antagonist flutamide, followed by saline or GBS injections from G19 to G21. Our results demonstrated that while flutamide alone had no effect, GBS-infected placentas from flutamide-treated dams exhibited reduced pro-inflammatory cytokine levels and decreased polymorphonuclear cell infiltration compared to vehicle-treated controls. Furthermore, behavioral assessments revealed that CA-exposed males exhibited impaired social interactions, lateral forebrain ventricle enlargement, and reduced periventricular white matter thickness, including the corpus callosum and external capsule. Notably, flutamide treatment mitigated some of these deficits, preserving oligodendrocyte density in the external capsule. These findings suggest a key role for androgens in the sex-specific impact of perinatal inflammation on neurodevelopment.Extracellular vesicles (EVs) play a crucial role in placental-fetal communication, yet their involvement in GBS-induced chorioamnionitis remains unexplored. We isolated from control and GBS-infected placentas and characterized via nanoparticle tracking analysis, transmission electron microscopy, and mass spectrometry. Proteomic analysis revealed distinct EV cargo profiles, with enrichment in immune-related pathways, including alarmins (S100A8/9), complement activation, and cytokine signaling. Notably, IL-1α and IL-1β were identified as key upstream regulators, with a striking 44-fold increase in intracellular IL-1β in EVs from GBS-infected male placentas. These findings highlight a potential role for placental EVs as potential mediators of neuroinflammation.Our findings demonstrate that androgens exacerbate placental inflammation in response to GBS, contributing to male-biased neurodevelopmental impairments. Additionally, placental EVs may play a role in mediating fetal inflammation through IL-1β transport. These results highlight the need for sex-specific neuroprotective strategies in perinatal infection and inflammation
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".