THU641 Single-cell Transcriptomic Analysis Reveal Dysregulated Immune Modulation In The Pituitaries Of Letrozole-induced Mouse Model Of PCOS

Abstract

Abstract Disclosure: G. De Robles: None. The most common endocrine disorder, affecting both the reproduction and metabolism of females, is polycystic ovary syndrome (PCOS). Characterizations of the heterogeneous disorder include anovulation, biochemical hyperandrogenemia, insulin resistance, and obesity, which can be recapitulated with a letrozole-induced PCOS mouse model. Immune abnormalities have also been reported in PCOS human patients, including pro-inflammatory factor secretion imbalance and endothelial cell dysfunction. The extent to which the letrozole-induced mouse model for PCOS can represent these immune dysregulations remain unclear, specifically its relevance to disrupting hormone-regulating centers, such as the pituitary gland. Using a PCOS mouse model developed via letrozole induction, we performed single-cell mRNA sequencing on the pituitaries to study impairment in hormone activity and immune regulation. We also carried out a multiplexed immunoassay on stimulated splenocytes to profile cytokines under different immune cell activations. We identified B cells, neutrophils, microglia, T memory cells, and interestingly, sub-populations of macrophages in the pituitary. Differential expression analysis revealed affected genes in the total macrophages of PCOS mice, such as the up-regulation of Pf4, Il1a, and Ccl7. Differentially expressed genes, such as Lyz2, Ctss, Apoe, and H2-Aa, were also down-regulated in the T memory cells of PCOS mice. Pituitary cell types also exhibited dysregulated expressions, including lactotropes, corticotropes, gonadotropes, and somatotropes. Differences in cytokine expression from the multiplex immunoassays also allowed the mice to be distinct from those treated with letrozole or not via principal component analysis. Altogether, the letrozole-treated mice presented disrupted immune responses and hormonal imbalances in their transcription and cytokine profiles that further strengthens their ability to model PCOS. Presentation: Thursday, June 15, 2023