Early estradiol exposure masculinizes disease‐relevant behaviors in female mice

• Published in: The European journal of neuroscience 2021-04, Vol.53 (8), p.2483-2499
• Main Authors: Seiffe, Araceli, Ramirez, Mauro Federico, Barrios, Claudio Darío, Albarrán, María Milagros, Depino, Amaicha Mara
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Androgens; Anxiety; Anxiety disorders; Autism; behavioral despair; Brain architecture; Brain masculinization; Estrogens; Exploratory behavior; Females; Gender differences; juvenile play; Males; Mental depression; Mental disorders; Neonates; Neurodevelopmental disorders; Perinatal exposure; psychiatric disorders; Puberty; repetitive behavior; Sex; Sex differences; Sexual behavior; social behavior; Steroid hormones
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.15130

Most psychiatric disorders show a sex bias in incidence, symptomatology, and/or response to treatment. Males are more susceptible to neurodevelopmental disorders including autism spectrum disorder and attention‐deficit activity disorder, while women are more prone to major depressive disorder and anxiety disorders after puberty. A striking difference between males and females in humans and other mammals is that males undergo a process of brain masculinization due to the early exposure to gonadal hormones. In rodents, this developmental organization of the brain is essential for adult males to express the appropriate sexual behaviors in the presence of a receptive female. Our goal was to determine whether this process of brain masculinization influences behaviors relevant to psychiatric disorders. To this aim, we studied sex differences and the effect of neonatal 17β‐estradiol benzoate treatment of female mice on different disease‐relevant behaviors. Our analysis includes postnatal behavior, juvenile play, and adult tests for sociability, repetitive behaviors, anxiety, and depression. Our results show that the sex differences observed in exploration, repetitive behaviors, and depression‐related behaviors are largely reduced when females are neonatally treated with 17β‐estradiol benzoate. These results suggest a role of neonatal sex steroids in the development of disease‐relevant behaviors and provide evidence supporting a role for perinatal exposure to estrogens and androgens on the development and manifestation of psychiatric disorders. Sex differences are observed in repetitive behaviors, exploration, and depression‐related behaviors. Female mice neonatally exposed to 17β‐estradiol benzoate (E2) show reduced exploration in the Y maze and open field, and increased immobility in the forced swim test, when compared to control females. Our results suggest that neonatal E2 masculinizes these behaviors.