Researchers from the Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences and the Institute of Cancer Research in Shenzhen Bay Laboratory have identified the molecular and cellular programs that androgens alter in the context of sex differences at the single-cell level.

A high-dimensional single-cell transcriptomic atlas of over 2.3 million mouse cells was integrated with the UK Biobank dataset, and genes that could be involved in sex-biased disease antigen presentation and potential cellular targets were discovered.

This study not only provides solid evidence for the androgen pathway as a potential treatment strategy for gender-biased diseases in general but also lays the groundwork for understanding how androgens orchestrate sex differences.

The research article, “Sex differences orchestrated by androgens at single-cell resolution,” was published in Nature.

The anti-androgenous androgens

An interplay between endogenous factors and exogenous environmental exposures shapes phenotypic sex differences. Sex bias—genes expressed exclusively or significantly differentially between the sexes—is believed to have strong hormonal roots, particularly in the androgen and oestrogen hormones.

The clinical phenotype that women with androgen excess and men with androgen deficiency have some similar metabolic phenotypes, such as obesity, serves as an example of sex-specific responses to androgens.

There is now increasing recognition that the androgen pathway in various human diseases can drive the sex-biased magnitude of clinical benefits from drugs. Patients with prostate cancer have greatly benefited from drugs like enzalutamide and abiraterone, which target androgen receptors and androgen synthesis to inhibit the androgen pathway. Not only that, but new research shows that androgen receptor activity is connected to different responses in women to anti-PDL1 treatment in colon cancer and BRAF/MEK-targeted therapy in melanoma.

To enable precision medicine by targeting the androgen pathway, defining androgen-associated sex-biased differentially expressed genes in each cell type is necessary. This will help identify sex-biased genes that androgens can regulate.

Identification of putative causal genes for sex-biased diseases

This study investigated the regulation of sex differences by androgens from various angles and identified significant molecules and cell types that may account for human sex bias.

They did this by profiling the transcriptomes of single cells from tissues from four groups of mice: two males and two females. The male mice underwent either androgen deprivation through castration surgery (male castration) or underwent sham surgery. The female mice were subjected to either androgen supplementation through sustained release of dihydrotestosterone (DHT) or underwent sham surgery.

A comprehensive dataset comprising 1,294,831 eligible cells, exhibiting an average of 2,070 identified genes across 17 different tissues, was acquired and subsequently subjected to annotation. The top three cell types with the largest proportional differences between sexes tended to vary across tissues. For instance, male mice displayed significantly lower proportions of T and B cells in the liver than female mice. Similarly, male mice exhibited a higher proportion of lymphatic endothelial cells in the adipose tissue.

Using data for the incidence rates of 214 diseases between male and female individuals in the UK Biobank, the researchers found 119 diseases with a sex-biased prevalence (sex-biased diseases). Among these 119 sex-biased diseases, malignant neoplasms of the stomach, kidney, and lung were male-biased, whereas asthma was female-biased, consistent with their clinical prevalence.

Cross-species analyses with the single cell RNA seq data led to the identification of five categories of sex-biased diseases into five major groups: Immune 1 (macrophages, dendritic cells, and B cells), Immune 2 (T cells and NK cells), Immune 3 (neutrophils and monocytes), Strom-adipo (mesenchymal cells, endothelial cells, and adipocytes) and neural (neural cells). Cardiovascular diseases were found to be associated with Strom-adipo in fibroblasts and endothelial cells, and gastritis and duodenitis with Immune 3 in neutrophils and monocytes, reflecting their respective clinical manifestations.

These findings emphasize the importance of conducting more research into the androgen pathway as a potential therapeutic target for sex-biased diseases and the mechanisms by which androgens regulate sex differences. 

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