Hyperhomocysteinemia (HHcy) plays a salient role in male infertility. However, whether HHcy interferes with testosterone production remains inconclusive. Here, we reported a lower serum testosterone level in HHcy mice. Single-cell RNA sequencing revealed that genes related to testosterone biosynthesis, together with nuclear receptor subfamily 5 group A member 1 (Nr5a1), a key transcription factor for steroidogenic genes, were downregulated in the Leydig cells (LCs) of HHcy mice. Mechanistically, Hcy lowered trimethylation of histone H3 on lysine 4 (H3K4me3), which was bound on the promoter region of Nr5a1, resulting in downregulation of Nr5a1. Intriguingly, we identified an unknown cell cluster annotated as Macrophage-like Leydig cells (McLCs), expressing both LCs and macrophages markers. In HHcy mice, McLCs were shifted toward pro-inflammatory phenotype and thus promoted inflammatory response in LC. Betaine supplementation rescued the downregulation of NR5A1 and restored the serum testosterone level in HHcy mice. Overall, our study highlights an etiological role of HHcy in LCs dysfunction.
Keyphrases
- single cell
- induced apoptosis
- replacement therapy
- transcription factor
- inflammatory response
- high fat diet induced
- cell cycle arrest
- signaling pathway
- rna seq
- endoplasmic reticulum stress
- cell proliferation
- genome wide
- adipose tissue
- genome wide identification
- dna methylation
- type diabetes
- insulin resistance
- high throughput
- cell death
- high resolution
- cell therapy
- smoking cessation
- lps induced
- simultaneous determination
- cell wall