PMID- 37495868
OWN - NLM
STAT- MEDLINE
DCOM- 20231204
LR  - 20240320
IS  - 1573-6822 (Electronic)
IS  - 0742-2091 (Linking)
VI  - 39
IP  - 6
DP  - 2023 Dec
TI  - Hyperhomocysteinemia lowers serum testosterone concentration via impairing 
      testosterone production in Leydig cells.
PG  - 3077-3100
LID - 10.1007/s10565-023-09819-4 [doi]
AB  - 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.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature B.V.
FAU - Su, Zhiyuan
AU  - Su Z
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Liu, Zhuoliang
AU  - Liu Z
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Lei, Wenjing
AU  - Lei W
AD  - Department of Nephrology, The First Affiliated Hospital of USTC, Division of Life 
      Sciences and Medicine, University of Science and Technology of China, Hefei, 
      230001, Anhui, China.
FAU - Xia, Kai
AU  - Xia K
AD  - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem 
      Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, 
      Guangzhou, 510080, Guangdong, China.
AD  - National-Local Joint Engineering Research Center for Stem Cells and Regenerative 
      Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 
      510080, Guangdong, China.
FAU - Xiao, An
AU  - Xiao A
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Hu, Zheng
AU  - Hu Z
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Zhou, Miaomiao
AU  - Zhou M
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Zhu, Fengxin
AU  - Zhu F
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Tian, Jianwei
AU  - Tian J
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Yang, Manqiu
AU  - Yang M
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Wang, Dong
AU  - Wang D
AD  - Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China.
FAU - Xiang, Andy Peng
AU  - Xiang AP
AD  - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem 
      Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, 
      Guangzhou, 510080, Guangdong, China.
AD  - National-Local Joint Engineering Research Center for Stem Cells and Regenerative 
      Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 
      510080, Guangdong, China.
FAU - Nie, Jing
AU  - Nie J
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, China. niejing@smu.edu.cn.
LA  - eng
GR  - 81900609/Nature and Science Foundation of China/
GR  - 81730019/Nature and Science Foundation of China/
GR  - 2019B1515120075/Nature and Science Foundation of Guangdong province/
GR  - 2018GZR110102004/Outstanding Scholar Program of Guangzhou Regenerative Medicine 
      and Health Guangdong Laboratory/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230727
PL  - Switzerland
TA  - Cell Biol Toxicol
JT  - Cell biology and toxicology
JID - 8506639
RN  - 3XMK78S47O (Testosterone)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Mice
MH  - Male
MH  - Animals
MH  - *Leydig Cells/metabolism
MH  - Testosterone
MH  - *Hyperhomocysteinemia/metabolism
MH  - Macrophages/metabolism
MH  - Transcription Factors/genetics
OTO - NOTNLM
OT  - Hyperhomocysteinemia
OT  - Leydig cell
OT  - Single-cell RNA sequencing
OT  - Testosterone
EDAT- 2023/07/27 01:09
MHDA- 2023/12/04 12:42
CRDT- 2023/07/26 23:33
PHST- 2022/12/29 00:00 [received]
PHST- 2023/07/12 00:00 [accepted]
PHST- 2023/12/04 12:42 [medline]
PHST- 2023/07/27 01:09 [pubmed]
PHST- 2023/07/26 23:33 [entrez]
AID - 10.1007/s10565-023-09819-4 [pii]
AID - 10.1007/s10565-023-09819-4 [doi]
PST - ppublish
SO  - Cell Biol Toxicol. 2023 Dec;39(6):3077-3100. doi: 10.1007/s10565-023-09819-4. 
      Epub 2023 Jul 27.