Androgen aggravates chorioamnionitis-induced white matter brain injury and neurobehavioral impairments in males.

Abstract

Introduction: Group B Streptococcus (GBS) colonization lead 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 to 21, followed by saline or inactivated GBS injections from G19 to 21. Behavioral assessments were conducted from postnatal day (P) 9 to 40 and brains were dissected on P50.

Results: Behavioral assessments revealed impaired social interactions in CA-exposed vs 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.  .