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Androgen Aggravates Chorioamnionitis-Induced White Matter Brain Injury and Neurobehavioral Impairments in Males
Seline Vancolen1,2, Mathilde Chevin2, Marie-Julie Allard2
1Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada.
Insights
Androgen blockade during pregnancy prevented neurobehavioral impairments and brain injury in male offspring exposed to chorioamnionitis (CA). This suggests androgens contribute to sex-specific developmental issues from perinatal inflammation.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Group B Streptococcus (GBS) colonization causes chorioamnionitis (CA), leading to fetal neurodevelopmental risks, particularly in males.
- Male fetuses show heightened placental inflammation during CA, correlating with more severe neurobehavioral impairments.
- Androgens are hypothesized to upregulate the placental immune response, contributing to autistic-like traits in male offspring.
Purpose of the Study:
- To investigate the effect of late-gestational androgen blockade on brain injury and neurobehavioral outcomes in offspring exposed to GBS-induced CA.
- To determine if androgen receptor antagonism mitigates CA-induced neurodevelopmental deficits in male offspring.
Main Methods:
- Lewis rat dams received vehicle or flutamide (androgen receptor antagonist) from gestational day 18-21.
- Dams were injected with saline or inactivated GBS from gestational day 19-21 to induce CA.
- Offspring underwent behavioral assessments (postnatal day 9-40) and brain histology (postnatal day 50).
Main Results:
- CA-exposed male rats exhibited impaired social interactions, which were prevented by flutamide treatment.
- Histology revealed enlarged lateral forebrain ventricles and reduced white matter thickness (corpus callosum, external capsule) in CA-exposed offspring.
- Flutamide treatment improved these brain structural outcomes and mitigated the reduction in oligodendrocyte density in the external capsule.
Conclusions:
- Androgens play a critical role in sex-specific developmental impairments following perinatal inflammation.
- Androgen blockade demonstrates potential for neuroprotection against CA-induced brain injury and behavioral deficits.
- Findings highlight the need for personalized, sex-specific neuroprotective strategies for developmental disorders.
Abstract:
Introduction: Group B Streptococcus (GBS) colonization leads to placental infection and inflammation, known as chorioamnionitis (CA). Fetal exposure to CA is linked to elevated risks of neurobehavioral impairments in offspring, including autism spectrum disorder, which is more prominent in males than females. In our preclinical model of GBS-induced CA, males exhibited heightened placental inflammation compared to females, correlating with more severe subsequent neurobehavioral impairments. We hypothesize that androgens upregulate the placental immune response in male fetuses, potentially contributing to GBS-induced autistic-like traits in male offspring. Our previous findings demonstrated that there were reduced pro-inflammatory cytokines and polymorphonuclear cell infiltration in flutamide (androgen receptor antagonist) plus GBS-infected compared to vehicle plus GBS-infected placenta. In this study, we investigated the effect of end gestational androgen blockade on brain injury patterns and neurobehavioral outcomes in offspring in utero exposed to GBS CA.
Methods:
Lewis dams received daily injections of vehicle or flutamide from gestational day (G) 18-21, followed by saline or inactivated GBS injections from G19 to 21. Behavioral assessments were conducted from postnatal day (P) 9-40 and brains were dissected on P50.
Results:
Behavioral assessments revealed impaired social interactions in CA-exposed versus unexposed male rats. These impairments were not observed in flutamide-treated rats. Histological analysis of forebrains at P50 showed lateral forebrain ventricle enlargement and reduced periventricular white matter thickness, namely the corpus callosum and external capsule in offspring exposed to CA contrasting with an improvement in these outcomes observed in flutamide treated rats. Exposure to CA reduced the density of CC-1+ oligodendrocytes in the external capsule whereas flutamide mitigated this reduction in offspring at P50.
Conclusion:
These findings suggest a significant role for androgens in the skewed sex ratio observed in developmental impairments resulting from perinatal inflammation, underscoring the need for personalized sex-specific neuroprotective therapies.
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