Researchers from the Shanghai Institute of Biochemistry and Cell Biology and the Shenzhen Bay Cancer Institute of the Chinese Academy of Sciences have identified the molecular and cellular programs that androgens alter at the single-cell level in relation to sex differences.
A high-dimensional single-cell transcriptome atlas of over 2.3 million mouse cells was integrated with the UK Biobank dataset to discover genes potentially involved in antigen presentation and potential cellular targets in sex-biased diseases. Ta.
This study not only provides solid evidence for the androgen pathway as a potential therapeutic strategy for gender-biased diseases in general, but also lays the foundation for understanding how androgens modulate sex differences. It is.
Research paper “Sex differences are modulated by androgens at single-cell resolution;” was published. Nature.
Androgens with anti-androgenic effects
Interactions between endogenous factors and exogenous environmental exposures shape phenotypic sex differences. Sex bias (genes that are expressed exclusively between the sexes or significantly differently between the sexes) is thought to have strong roots in hormones, especially androgen and estrogen hormones.
The clinical phenotype that androgen-hyperandrogen-deficient women and androgen-deficient men have similar metabolic phenotypes, such as obesity, serves as an example of a sex-specific response to androgens.
There is now increasing recognition that androgen pathways in a variety of human diseases may contribute to the sex-biased magnitude of clinical effects of drugs. Prostate cancer patients benefit greatly from drugs such as enzalutamide and abiraterone, which inhibit the androgen pathway by targeting the androgen receptor and androgen synthesis. Moreover, new studies show that androgen receptor activity is associated with different responses in women to anti-PDL1 therapy in colon cancer and BRAF/MEK-targeted therapy in melanoma.
To enable precision medicine targeting the androgen pathway, it is necessary to define sex-biased differentially expressed genes related to androgens in each cell type. This will help identify sex-biased genes that can be regulated by androgens.
Identification of genes presumed to cause gender-biased diseases
In this study, we investigated the regulation of sex differences by androgens from various angles and identified key molecules and cell types that may be responsible for sex bias in humans.
They did this by profiling the transcriptomes of single cells taken from tissue from four groups of mice: two males and two females. Male mice were either subjected to androgen removal by surgical castration (male castration) or sham surgery. Female mice received androgen supplementation with sustained-release dihydrotestosterone (DHT) or sham surgery.
A comprehensive dataset containing 1,294,831 eligible cells representing an average of 2,070 identified genes across 17 different tissues was obtained and subsequently annotated. The top three cell types with the largest proportion differences between sexes tended to vary by tissue. For example, male mice had significantly lower proportions of T and B cells in their livers than female mice. Similarly, male mice had a higher proportion of lymphatic endothelial cells in their adipose tissue.
Using prevalence data for 214 diseases among men and women in the UK Biobank, researchers found 119 diseases with gender-biased prevalence (sex-biased diseases). . Among these 119 gender-biased diseases, malignant neoplasms of the stomach, kidneys, and lungs had a male bias, while asthma had a female bias. This is consistent with clinical prevalence.
Cross-species analysis using single-cell RNA-seq data divided five categories of sex-biased diseases into five major groups: Immune 1 (macrophages, dendritic cells, B cells); Immune 2 (T cells) and NK cells), Immune 3 (neutrophils and monocytes), Strom-adipo (mesenchymal cells, endothelial cells, and adipocytes), and Neuro (nerve cells). It was found that cardiovascular diseases are associated with Strom-adipo in fibroblasts and endothelial cells, and gastritis and duodenitis are associated with Immune 3 of neutrophils and monocytes, reflecting their respective clinical symptoms.
These findings highlight the importance of further research into the androgen pathway as a potential therapeutic target for sex-biased diseases and the mechanisms by which androgens modulate sex differences.