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Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

Significance Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility characterized by excessive androgen secretion. PCOS women are at an increased risk of developing depression and anxiety disorders. Although the etiology of PCOS is unclear, it is proposed to originate during fetal development because of maternal androgen excess. We describe here, in rodent models reflecting the anxiety phenotype of PCOS, evidence for disordered androgen receptor function in the amygdala, together with changes in estrogen receptor-α, serotonergic and GABAergic genes in the amygdala, and hippocampus. These findings define a previously unknown mechanism that may be critical in understanding how maternal androgen excess has the potential to increase the risk of developing anxiety disorders in daughters and sons of PCOS mothers. During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.