Exposure of Hyperandrogen During Pregnancy Causes Depression- and Anxiety-Like Behaviors, and Reduced Hippocampal Neurogenesis in Rat Offspring

The hippocampus is a region in which neurogenesis persists and retains substantial plasticity throughout lifespan. Accumulating evidences indicate an important role of androgens and androgenic signaling in the regulation of offspring hippocampal neurogenesis and the survival of mature or immature neurons and gliocyte. Hyperandrogenic disorders have been associated with depression and anxiety. Previous studies have found that pregnant hyperandrogenism may increase the susceptibility of the offspring to depression or anxiety and lead to abnormal hippocampal neurogenesis in rats. In this study, pregnant rats were given subcutaneous injection of aromatase inhibitor letrozole in order to establish a maternal hyperandrogenic environment for the fetal rats. The lithium chloride (LICl) was used as an intervention agent since a previous study has shown that lithium chloride could promote neurogenesis in the hippocampus. The results revealed that pregnant administration of letrozole resulted in depressive- and anxious-like behaviors in the adolescent period. A remarkable decrease in immature nerve cells marked by doublecortin and mature neurons co-expressed by Brdu and NeuN in adult years were detected in the hippocampal dentate gyrus of adolescent rats. Lithium chloride alleviated the effects on neurobehavioral and promoted the differentiation and proliferation of neural progenitor cells, while a hyperandrogenic intrauterine environment had no effects on astrocytes marked by GFAP in the dentate gyrus. Furthermore, the Wnt/β-catenin signaling pathway related to normal development of hippocampus was examined but there was no significant changes in Wnt signaling pathway members. Our study provides evidence that exposure of androgen during pregnancy leads to alterations in depressive, anxious and stereotypical behaviors and these phenotypes are possibly associated with changes in neurogenesis in the dentate gyrus.